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Tioka L, Diez RC, Sönnerborg A, van de Klundert MAA. Latency Reversing Agents and the Road to an HIV Cure. Pathogens 2025; 14:232. [PMID: 40137717 PMCID: PMC11944434 DOI: 10.3390/pathogens14030232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Revised: 02/12/2025] [Accepted: 02/18/2025] [Indexed: 03/29/2025] Open
Abstract
HIV-1 infection cannot be cured due to the presence of HIV-1 latently infected cells. These cells do not produce the virus, but they can resume virus production at any time in the absence of antiretroviral therapy. Therefore, people living with HIV (PLWH) need to take lifelong therapy. Strategies have been coined to eradicate the viral reservoir by reactivating HIV-1 latently infected cells and subsequently killing them. Various latency reversing agents (LRAs) that can reactivate HIV-1 in vitro and ex vivo have been identified. The most potent LRAs also strongly activate T cells and therefore cannot be applied in vivo. Many LRAs that reactivate HIV in the absence of general T cell activation have been identified and have been tested in clinical trials. Although some LRAs could reduce the reservoir size in clinical trials, so far, they have failed to eradicate the reservoir. More recently, immune modulators have been applied in PLWH, and the first results seem to indicate that these may reduce the reservoir and possibly improve immunological control after therapy interruption. Potentially, combinations of LRAs and immune modulators could reduce the reservoir size, and in the future, immunological control may enable PLWH to live without developing HIV-related disease in the absence of therapy.
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Affiliation(s)
- Louis Tioka
- Faculty of Medicine, Erlangen-Nürnberg, Friedrich-Alexander-Universität, 91054 Erlangen, Germany;
- Division of Infectious Diseases, Department of Medicine Huddinge, Karolinska Institutet, 17177 Stockholm, Sweden; (R.C.D.); (A.S.)
| | - Rafael Ceña Diez
- Division of Infectious Diseases, Department of Medicine Huddinge, Karolinska Institutet, 17177 Stockholm, Sweden; (R.C.D.); (A.S.)
| | - Anders Sönnerborg
- Division of Infectious Diseases, Department of Medicine Huddinge, Karolinska Institutet, 17177 Stockholm, Sweden; (R.C.D.); (A.S.)
- Department of Infectious Diseases, Karolinska University Hospital, 17177 Stockholm, Sweden
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, 17177 Stockholm, Sweden
| | - Maarten A. A. van de Klundert
- Division of Infectious Diseases, Department of Medicine Huddinge, Karolinska Institutet, 17177 Stockholm, Sweden; (R.C.D.); (A.S.)
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Gentry ZO, McAteer OD, Hamad JL, Moran JA, Kim JT, Marsden MD, Zack JA, Wender PA. Synthesis and preclinical evaluation of tigilanol tiglate analogs as latency-reversing agents for the eradication of HIV. SCIENCE ADVANCES 2025; 11:eads1911. [PMID: 39854456 PMCID: PMC11778240 DOI: 10.1126/sciadv.ads1911] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Accepted: 12/20/2024] [Indexed: 01/26/2025]
Abstract
Tigilanol tiglate (EBC-46) is a selective modulator of protein kinase C (PKC) isoforms that is Food and Drug Administration (FDA) approved for the treatment of mast cell tumors in canines with up to an 88% cure rate. Recently, it has been FDA approved for the treatment of soft tissue sarcomas in humans. The role of EBC-46 and, especially, its analogs in efforts to eradicate HIV, treat neurological and cardiovascular disorders, or enhance antigen density in antigen-targeted chimeric antigen receptor-T cell and chimeric antigen receptor-natural killer cell immunotherapies has not been reported. Enabled by our previously reported scalable synthesis of EBC-46, we report herein the systematic design, synthesis, and evaluation of EBC-46 analogs, including those inaccessible from the natural source and their PKC affinities, ability to translocate PKC, nuclear factor κB activity, and efficacy in reversing HIV latency in Jurkat-Latency cells. Leading analogs show exceptional PKC affinities, isoform selectivities, and functional activities, serving as promising candidates for therapeutic applications.
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Affiliation(s)
- Zachary O. Gentry
- Department of Chemistry, Stanford University, Stanford, CA 94305, USA
| | - Owen D. McAteer
- Department of Chemistry, Stanford University, Stanford, CA 94305, USA
| | - Jennifer L. Hamad
- Department of Chemistry, Stanford University, Stanford, CA 94305, USA
- Department of Biology, Stanford University, Stanford, CA 94305, USA
| | - Jose A. Moran
- Department of Microbiology & Molecular Genetics, School of Medicine, University of California Irvine, Irvine, CA 92697, USA
| | - Jocelyn T. Kim
- Department of Medicine, Division of Infectious Diseases, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Matthew D. Marsden
- Department of Microbiology & Molecular Genetics, School of Medicine, University of California Irvine, Irvine, CA 92697, USA
- Department of Medicine (Division of Infectious Diseases), School of Medicine, University of California Irvine, Irvine, CA 92697, USA
| | - Jerome A. Zack
- Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, CA 90095, USA
- Department of Medicine, Division of Hematology and Oncology, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Paul A. Wender
- Department of Chemistry, Stanford University, Stanford, CA 94305, USA
- Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA
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Phan AT, Zhu Y. PTEN Mediates the Silencing of Unintegrated HIV-1 DNA. Viruses 2024; 16:291. [PMID: 38400066 PMCID: PMC10892664 DOI: 10.3390/v16020291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 01/31/2024] [Accepted: 02/12/2024] [Indexed: 02/25/2024] Open
Abstract
The integration of viral DNA into a host genome is an important step in HIV-1 replication. However, due to the high failure rate of integration, the majority of viral DNA exists in an unintegrated state during HIV-1 infection. In contrast to the robust expression from integrated viral DNA, unintegrated HIV-1 DNA is very poorly transcribed in infected cells, but the molecular machinery responsible for the silencing of unintegrated HIV-1 DNA remains poorly characterized. In this study, we sought to characterize new host factors for the inhibition of expression from unintegrated HIV-1 DNA. A genome-wide CRISPR-Cas9 knockout screening revealed the essential role of phosphatase and tensin homolog (PTEN) in the silencing of unintegrated HIV-1 DNA. PTEN's phosphatase activity negatively regulates the PI3K-Akt pathway to inhibit the transcription from unintegrated HIV-1 DNA. The knockout (KO) of PTEN or inhibition of PTEN's phosphatase activity by point mutagenesis activates Akt by phosphorylation and enhances the transcription from unintegrated HIV-1 DNA. Inhibition of the PI3K-Akt pathway by Akt inhibitor in PTEN-KO cells restores the silencing of unintegrated HIV-1 DNA. Transcriptional factors (NF-κB, Sp1, and AP-1) are important for the activation of unintegrated HIV-1 DNA in PTEN-KO cells. Finally, the knockout of PTEN increases the levels of active epigenetic marks (H3ac and H3K4me3) and the recruitment of PolII on unintegrated HIV-1 DNA chromatin. Our experiments reveal that PTEN targets transcription factors (NF-κB, Sp1, and AP-1) by negatively regulating the PI3K-Akt pathway to promote the silencing of unintegrated HIV-1 DNA.
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Affiliation(s)
| | - Yiping Zhu
- Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA;
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Duggan NN, Dragic T, Chanda SK, Pache L. Breaking the Silence: Regulation of HIV Transcription and Latency on the Road to a Cure. Viruses 2023; 15:2435. [PMID: 38140676 PMCID: PMC10747579 DOI: 10.3390/v15122435] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 12/12/2023] [Accepted: 12/13/2023] [Indexed: 12/24/2023] Open
Abstract
Antiretroviral therapy (ART) has brought the HIV/AIDS epidemic under control, but a curative strategy for viral eradication is still needed. The cessation of ART results in rapid viral rebound from latently infected CD4+ T cells, showing that control of viral replication alone does not fully restore immune function, nor does it eradicate viral reservoirs. With a better understanding of factors and mechanisms that promote viral latency, current approaches are primarily focused on the permanent silencing of latently infected cells ("block and lock") or reactivating HIV-1 gene expression in latently infected cells, in combination with immune restoration strategies to eliminate HIV infected cells from the host ("shock and kill"). In this review, we provide a summary of the current, most promising approaches for HIV-1 cure strategies, including an analysis of both latency-promoting agents (LPA) and latency-reversing agents (LRA) that have shown promise in vitro, ex vivo, and in human clinical trials to reduce the HIV-1 reservoir.
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Affiliation(s)
- Natasha N. Duggan
- Department of Immunology and Microbiology, Scripps Research, La Jolla, CA 92037, USA
| | - Tatjana Dragic
- Department of Immunology and Microbiology, Scripps Research, La Jolla, CA 92037, USA
| | - Sumit K. Chanda
- Department of Immunology and Microbiology, Scripps Research, La Jolla, CA 92037, USA
| | - Lars Pache
- NCI Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA
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Cossarini F, Aberg JA, Chen BK, Mehandru S. Viral Persistence in the Gut-Associated Lymphoid Tissue and Barriers to HIV Cure. AIDS Res Hum Retroviruses 2023; 40:54-65. [PMID: 37450338 PMCID: PMC10790554 DOI: 10.1089/aid.2022.0180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/18/2023] Open
Abstract
More than 40 years after the first reported cases of what then became known as acquired immunodeficiency syndrome (AIDS), tremendous progress has been achieved in transforming the disease from almost universally fatal to a chronic manageable condition. Nonetheless, the efforts to find a preventative vaccine or a cure for the underlying infection with Human Immunodeficiency Virus (HIV) remain largely unsuccessful. Many challenges intrinsic to the virus characteristics and host response need to be overcome for either goal to be achieved. This article will review the obstacles to an effective HIV cure, specifically the steps involved in the generation of HIV latency, focusing on the role of the gut-associated lymphoid tissue, which has received less attention compared with the peripheral blood, despite being the largest repository of lymphoid tissue in the human body, and a large site for HIV persistence.
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Affiliation(s)
- Francesca Cossarini
- Division of Infectious Diseases, Department of Medicine, Icahn School at Mount Sinai, New York, New York, USA
- Precision Immunology Institute, Icahn School at Mount Sinai, New York, New York, USA
| | - Judith A. Aberg
- Division of Infectious Diseases, Department of Medicine, Icahn School at Mount Sinai, New York, New York, USA
| | - Benjamin K. Chen
- Division of Infectious Diseases, Department of Medicine, Icahn School at Mount Sinai, New York, New York, USA
- Precision Immunology Institute, Icahn School at Mount Sinai, New York, New York, USA
| | - Saurabh Mehandru
- Precision Immunology Institute, Icahn School at Mount Sinai, New York, New York, USA
- Division of Gastroenterology, Department of Medicine, Icahn School at Mount Sinai, New York, New York, USA
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Zhou Z, Jiang Y, Zhong X, Yang J, Yang G. Characteristics and mechanisms of latency-reversing agents in the activation of the human immunodeficiency virus 1 reservoir. Arch Virol 2023; 168:301. [PMID: 38019293 DOI: 10.1007/s00705-023-05931-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Accepted: 10/23/2023] [Indexed: 11/30/2023]
Abstract
The "Shock and Kill" method is being considered as a potential treatment for eradicating HIV-1 and achieving a functional cure for acquired immunodeficiency syndrome (AIDS). This approach involves using latency-reversing agents (LRAs) to activate human immunodeficiency virus (HIV-1) transcription in latent cells, followed by treatment with antiviral drugs to kill these cells. Although LRAs have shown promise in HIV-1 patient research, their widespread clinical use is hindered by side effects and limitations. In this review, we categorize and explain the mechanisms of these agonists in activating HIV-1 in vivo and discuss their advantages and disadvantages. In the future, combining different HIV-1 LRAs may overcome their respective shortcomings and facilitate a functional cure for HIV-1.
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Affiliation(s)
- Zhujiao Zhou
- Department of Clinical Medicine, School of Medicine, Hangzhou City University, Hangzhou, China
- College of Pharmacy, Zhejiang University of Technology, Hangzhou, 310013, China
| | - Yashuang Jiang
- Department of Clinical Medicine, School of Medicine, Hangzhou City University, Hangzhou, China
| | - Xinyu Zhong
- Department of Clinical Medicine, School of Medicine, Hangzhou City University, Hangzhou, China
- College of Pharmacy, Zhejiang University of Technology, Hangzhou, 310013, China
| | - Jingyi Yang
- Department of Clinical Medicine, School of Medicine, Hangzhou City University, Hangzhou, China
| | - Geng Yang
- Department of Clinical Medicine, School of Medicine, Hangzhou City University, Hangzhou, China.
- Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, 310013, China.
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7
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Van Gulck E, Pardons M, Nijs E, Verheyen N, Dockx K, Van Den Eynde C, Battivelli E, Vega J, Florence E, Autran B, Archin NM, Margolis DM, Katlama C, Hamimi C, Van Den Wyngaert I, Eyassu F, Vandekerckhove L, Boden D. A truncated HIV Tat demonstrates potent and specific latency reversal activity. Antimicrob Agents Chemother 2023; 67:e0041723. [PMID: 37874295 PMCID: PMC10649039 DOI: 10.1128/aac.00417-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 08/09/2023] [Indexed: 10/25/2023] Open
Abstract
A major barrier to HIV-1 cure is caused by the pool of latently infected CD4 T-cells that persist under combination antiretroviral therapy (cART). This latent reservoir is capable of producing replication-competent infectious viruses once prolonged suppressive cART is withdrawn. Inducing the reactivation of HIV-1 gene expression in T-cells harboring a latent provirus in people living with HIV-1 under cART may result in depletion of this latent reservoir due to cytopathic effects or immune clearance. Studies have investigated molecules that reactivate HIV-1 gene expression, but to date, no latency reversal agent has been identified to eliminate latently infected cells harboring replication-competent HIV in cART-treated individuals. Stochastic fluctuations in HIV-1 tat gene expression have been described and hypothesized to allow the progression into proviral latency. We hypothesized that exposing latently infected CD4+ T-cells to Tat would result in effective latency reversal. Our results indicate the capacity of a truncated Tat protein and mRNA to reactivate HIV-1 in latently infected T-cells ex vivo to a similar degree as the protein kinase C agonist: phorbol 12-myristate 13-acetate, without T-cell activation or any significant transcriptome perturbation.
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Affiliation(s)
- Ellen Van Gulck
- Janssen Infectious Diseases, Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium
| | - Marion Pardons
- HIV Cure Research Center, Department of Internal Medicine and Pediatrics, Ghent University Hospital, Ghent University, Ghent, Belgium
| | - Erik Nijs
- Janssen Infectious Diseases, Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium
| | - Nick Verheyen
- Janssen Infectious Diseases, Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium
| | - Koen Dockx
- Janssen Infectious Diseases, Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium
| | - Christel Van Den Eynde
- Janssen Infectious Diseases, Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium
| | - Emilie Battivelli
- Janssen Infectious Diseases, A Division of Janssen Pharmaceutica NV, Brisbane, California, USA
| | - Jerel Vega
- Arcturus Therapeutics, Science Center Drive, San Diego, California, USA
| | | | - Brigitte Autran
- Faculty of Medicine Sorbonne-University, CIMI-Paris, UPMC/Inserm, Paris, France
| | - Nancie M. Archin
- University of North Carolina School of Medicine and UNC, HIV Cure Center, Chapel Hill, North Carolina, USA
| | - David M. Margolis
- University of North Carolina School of Medicine and UNC, HIV Cure Center, Chapel Hill, North Carolina, USA
| | - Christine Katlama
- Department Infectious Diseases, Hospital Pitié Salpetière, Sorbonne-University and IPLESP, Paris, France
| | - Chiraz Hamimi
- Faculty of Medicine Sorbonne-University, CIMI-Paris, UPMC/Inserm, Paris, France
| | - Ilse Van Den Wyngaert
- Discovery Sciences, Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium
| | - Filmon Eyassu
- Discovery Sciences, Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium
| | - Linos Vandekerckhove
- HIV Cure Research Center, Department of Internal Medicine and Pediatrics, Ghent University Hospital, Ghent University, Ghent, Belgium
| | - Daniel Boden
- Janssen Infectious Diseases, A Division of Janssen Pharmaceutica NV, Brisbane, California, USA
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Sachdeva M, Taneja S, Sachdeva N. Stem cell-like memory T cells: Role in viral infections and autoimmunity. World J Immunol 2023; 13:11-22. [DOI: 10.5411/wji.v13.i2.11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 07/06/2023] [Accepted: 07/27/2023] [Indexed: 08/14/2023] Open
Abstract
Stem cell-like memory T (TSCM) cells possess stem cell properties including multipotency and self-renewal and are being recognized as emerging players in various human diseases. Advanced technologies such as multiparametric flowcytometry and single cell sequencing have enabled their identification and molecular characterization. In case of chronic viral diseases such as human immunodeficiency virus-1, CD4+ TSCM cells, serve as major reservoirs of the latent virus. However, during immune activation and functional exhaustion of effector T cells, these cells also possess the potential to replenish the pool of functional effector cells to curtail the infection. More recently, these cells are speculated to play important role in protective immunity following acute viral infections such as coronavirus disease 2019 and might be amenable for therapeutics by ex vivo expansion. Similarly, studies are also investigating their pathological role in driving autoimmune responses. However, there are several gaps in the understanding of the role of TSCM cells in viral and autoimmune diseases to make them potential therapeutic targets. In this minireview, we have attempted an updated compilation of the dyadic role of these complex TSCM cells during such human diseases along with their biology and transcriptional programs.
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Affiliation(s)
- Meenakshi Sachdeva
- Department of Pediatrics, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh 160012, India
| | - Shivangi Taneja
- Department of Endocrinology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh 160012, India
| | - Naresh Sachdeva
- Department of Endocrinology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh 160012, India
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Zhang S, Zong Y, Chen L, Li Q, Li Z, Meng R. The immunomodulatory function and antitumor effect of disulfiram: paving the way for novel cancer therapeutics. Discov Oncol 2023; 14:103. [PMID: 37326784 DOI: 10.1007/s12672-023-00729-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 06/14/2023] [Indexed: 06/17/2023] Open
Abstract
More than 60 years ago, disulfiram (DSF) was employed for the management of alcohol addiction. This promising cancer therapeutic agent inhibits proliferation, migration, and invasion of malignant tumor cells. Furthermore, divalent copper ions can enhance the antitumor effects of DSF. Molecular structure, pharmacokinetics, signaling pathways, mechanisms of action and current clinical results of DSF are summarized here. Additionally, our attention is directed towards the immunomodulatory properties of DSF and we explore novel administration methods that may address the limitations associated with antitumor treatments based on DSF. Despite the promising potential of these various delivery methods for utilizing DSF as an effective anticancer agent, further investigation is essential in order to extensively evaluate the safety and efficacy of these delivery systems.
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Affiliation(s)
- Sijia Zhang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yan Zong
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Leichong Chen
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Qianwen Li
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Zhenyu Li
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Rui Meng
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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Disulfiram: Mechanisms, Applications, and Challenges. Antibiotics (Basel) 2023; 12:antibiotics12030524. [PMID: 36978391 PMCID: PMC10044060 DOI: 10.3390/antibiotics12030524] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 02/24/2023] [Accepted: 02/26/2023] [Indexed: 03/08/2023] Open
Abstract
Background: Since disulfiram’s discovery in the 1940s and its FDA approval for alcohol use disorder, other indications have been investigated. This review describes potential clinical applications, associated risks, and challenges. Methods: For this narrative review, a PubMed search was conducted for articles addressing in vivo studies of disulfiram with an emphasis on drug repurposing for the treatment of human diseases. The key search terms were “disulfiram” and “Antabuse”. Animal studies and in vitro studies highlighting important mechanisms and safety issues were also included. Results: In total, 196 sources addressing our research focus spanning 1948–2022 were selected for inclusion. In addition to alcohol use disorder, emerging data support a potential role for disulfiram in the treatment of other addictions (e.g., cocaine), infections (e.g., bacteria such as Staphylococcus aureus and Borrelia burgdorferi, viruses, parasites), inflammatory conditions, neurological diseases, and cancers. The side effects range from minor to life-threatening, with lower doses conveying less risk. Caution in human use is needed due to the considerable inter-subject variability in disulfiram pharmacokinetics. Conclusions: While disulfiram has promise as a “repurposed” agent in human disease, its risk profile is of concern. Animal studies and well-controlled clinical trials are needed to assess its safety and efficacy for non-alcohol-related indications.
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Rai M, Rawat K, Muhammadi MK, Gaur R. Edelfosine reactivates latent HIV-1 reservoirs in myeloid cells through activation of NF-κB and AP1 pathway. Virology 2022; 574:57-64. [DOI: 10.1016/j.virol.2022.07.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Accepted: 07/12/2022] [Indexed: 11/30/2022]
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12
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Solovieva M, Shatalin Y, Odinokova I, Krestinina O, Baburina Y, Mishukov A, Lomovskaya Y, Pavlik L, Mikheeva I, Holmuhamedov E, Akatov V. Disulfiram oxy-derivatives induce entosis or paraptosis-like death in breast cancer MCF-7 cells depending on the duration of treatment. Biochim Biophys Acta Gen Subj 2022; 1866:130184. [PMID: 35660414 DOI: 10.1016/j.bbagen.2022.130184] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 05/26/2022] [Accepted: 05/28/2022] [Indexed: 01/12/2023]
Abstract
BACKGROUND Dithiocarbamates and derivatives (including disulfiram, DSF) are currently investigated as antineoplastic agents. We have revealed earlier the ability of hydroxocobalamin (vitamin В12b) combined with diethyldithiocarbamate (DDC) to catalyze the formation of highly cytotoxic oxidized derivatives of DSF (DSFoxy, sulfones and sulfoxides). METHODS Electron and fluorescent confocal microscopy, molecular biology and conventional biochemical techniques were used to study the morphological and functional responses of MCF-7 human breast cancer cells to treatment with DDC and B12b alone or in combination. RESULTS DDC induces unfolded protein response in MCF-7 cells. The combined use of DDC and B12b causes MCF-7 cell death. Electron microscopy revealed the separation of ER and nuclear membranes, leading to the formation of both cytoplasmic and perinuclear vacuoles, with many fibers inside. The process of vacuolization coincided with the appearance of ER stress markers, a marked damage to mitochondria, a significant inhibition of 20S proteasome, and actin depolimerization at later stages. Specific inhibitors of apoptosis, necroptosis, autophagy, and ferroptosis did not prevent cell death. A short- time (6-h) exposure to DSFoxy caused a significant increase in the number of entotic cells. CONCLUSIONS These observations indicate that MCF-7 cells treated with a mixture of DDC and B12b die by the mechanism of paraptosis. A short- time exposure to DSFoxy caused, along with paraptosis, a significant activation of the entosis and its final stage, lysosomal cell death. GENERAL SIGNIFICANCE The results obtained open up opportunities for the development of new approaches to induce non-apoptotic death of cancer cells by dithiocarbamates.
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Affiliation(s)
- Marina Solovieva
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow region 142290, Russia
| | - Yuri Shatalin
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow region 142290, Russia.
| | - Irina Odinokova
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow region 142290, Russia
| | - Olga Krestinina
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow region 142290, Russia
| | - Yulia Baburina
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow region 142290, Russia
| | - Artem Mishukov
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow region 142290, Russia; Laboratory of Biorheology and Biomechanics, Center for Theoretical Problems of Physicochemical Pharmacology RAS, Moscow 109029, Russian Federation
| | - Yana Lomovskaya
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow region 142290, Russia
| | - Liubov Pavlik
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow region 142290, Russia
| | - Irina Mikheeva
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow region 142290, Russia
| | - Ekhson Holmuhamedov
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow region 142290, Russia; Department of Pharmacology, University of North Carolina at Chapel Hill, NC 27599, USA
| | - Vladimir Akatov
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow region 142290, Russia
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13
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Custodio MM, Sparks J, Long TE. Disulfiram: A Repurposed Drug in Preclinical and Clinical Development for the Treatment of Infectious Diseases. ANTI-INFECTIVE AGENTS 2022; 20:e040122199856. [PMID: 35782673 PMCID: PMC9245773 DOI: 10.2174/2211352520666220104104747] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 12/01/2021] [Accepted: 12/08/2021] [Indexed: 06/01/2023]
Abstract
This article reviews preclinical and clinical studies on the repurposed use of disulfiram (Antabuse) as an antimicrobial agent. Preclinical research covered on the alcohol sobriety aid includes uses as an anti-MRSA agent, a carbapenamase inhibitor, antifungal drug for candidiasis, and treatment for parasitic diseases due to protozoa (e.g., giardiasis, leishmaniasis, malaria) and helminthes (e.g., schistosomiasis, trichuriasis). Past, current, and pending clinical studies on disulfiram as a post-Lyme disease syndrome (PTLDS) therapy, an HIV latency reversal agent, and intervention for COVID-19 infections are also reviewed..
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Affiliation(s)
- Marco M. Custodio
- Chesapeake Regional Medical Center, 736 Battlefield Blvd. N Chesapeake, VA 23320, USA
| | - Jennifer Sparks
- Department of Pharmacy Practice, Administration and Research, Marshall University School of Pharmacy, One John Marshall Drive, Huntington WV 24755-0001, USA
| | - Timothy E. Long
- Department of Pharmaceutical Science and Research, Marshall University School of Pharmacy, One John Marshall, Drive Huntington WV 24755-0001, USA
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14
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Ta TM, Malik S, Anderson EM, Jones AD, Perchik J, Freylikh M, Sardo L, Klase ZA, Izumi T. Insights Into Persistent HIV-1 Infection and Functional Cure: Novel Capabilities and Strategies. Front Microbiol 2022; 13:862270. [PMID: 35572626 PMCID: PMC9093714 DOI: 10.3389/fmicb.2022.862270] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 02/21/2022] [Indexed: 12/23/2022] Open
Abstract
Although HIV-1 replication can be efficiently suppressed to undetectable levels in peripheral blood by combination antiretroviral therapy (cART), lifelong medication is still required in people living with HIV (PLWH). Life expectancies have been extended by cART, but age-related comorbidities have increased which are associated with heavy physiological and economic burdens on PLWH. The obstacle to a functional HIV cure can be ascribed to the formation of latent reservoir establishment at the time of acute infection that persists during cART. Recent studies suggest that some HIV reservoirs are established in the early acute stages of HIV infection within multiple immune cells that are gradually shaped by various host and viral mechanisms and may undergo clonal expansion. Early cART initiation has been shown to reduce the reservoir size in HIV-infected individuals. Memory CD4+ T cell subsets are regarded as the predominant cellular compartment of the HIV reservoir, but monocytes and derivative macrophages or dendritic cells also play a role in the persistent virus infection. HIV latency is regulated at multiple molecular levels in transcriptional and post-transcriptional processes. Epigenetic regulation of the proviral promoter can profoundly regulate the viral transcription. In addition, transcriptional elongation, RNA splicing, and nuclear export pathways are also involved in maintaining HIV latency. Although most proviruses contain large internal deletions, some defective proviruses may induce immune activation by expressing viral proteins or producing replication-defective viral-like particles. In this review article, we discuss the state of the art on mechanisms of virus persistence in the periphery and tissue and summarize interdisciplinary approaches toward a functional HIV cure, including novel capabilities and strategies to measure and eliminate the infected reservoirs and induce immune control.
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Affiliation(s)
- Tram M. Ta
- Department of Biological Sciences, Misher College of Arts and Sciences, University of the Sciences in Philadelphia, Philadelphia, PA, United States
| | - Sajjaf Malik
- Department of Biological Sciences, Misher College of Arts and Sciences, University of the Sciences in Philadelphia, Philadelphia, PA, United States
| | - Elizabeth M. Anderson
- Office of the Assistant Secretary for Health, Region 3, U.S. Department of Health and Human Services, Washington, DC, United States
| | - Amber D. Jones
- Department of Biological Sciences, Misher College of Arts and Sciences, University of the Sciences in Philadelphia, Philadelphia, PA, United States,Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, United States
| | - Jocelyn Perchik
- Department of Biological Sciences, Misher College of Arts and Sciences, University of the Sciences in Philadelphia, Philadelphia, PA, United States
| | - Maryann Freylikh
- Department of Biological Sciences, Misher College of Arts and Sciences, University of the Sciences in Philadelphia, Philadelphia, PA, United States
| | - Luca Sardo
- Department of Infectious Disease and Vaccines, Merck & Co., Inc., Kenilworth, NJ, United States
| | - Zackary A. Klase
- Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, United States,Center for Neuroimmunology and CNS Therapeutics, Institute of Molecular Medicine and Infectious Diseases, Drexel University of Medicine, Philadelphia, PA, United States
| | - Taisuke Izumi
- Department of Biological Sciences, Misher College of Arts and Sciences, University of the Sciences in Philadelphia, Philadelphia, PA, United States,*Correspondence: Taisuke Izumi,
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15
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Atindaana E, Kissi-Twum A, Emery S, Burnett C, Pitcher J, Visser M, Kidd JM, Telesnitsky A. Bimodal Expression Patterns, and Not Viral Burst Sizes, Predict the Effects of Vpr on HIV-1 Proviral Populations in Jurkat Cells. mBio 2022; 13:e0374821. [PMID: 35384697 PMCID: PMC9040753 DOI: 10.1128/mbio.03748-21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 02/28/2022] [Indexed: 11/29/2022] Open
Abstract
Integration site landscapes, clonal dynamics, and latency reversal with or without vpr were compared in HIV-1-infected Jurkat cell populations, and the properties of individual clones were defined. Clones differed in fractions of long terminal repeat (LTR)-active daughter cells, with some clones containing few to no LTR-active cells, while almost all cells were LTR active for others. Clones varied over 4 orders of magnitude in virus release per active cell. Proviruses in largely LTR-active clones were closer to preexisting enhancers and promoters than low-LTR-active clones. Unsurprisingly, major vpr+ clones contained fewer LTR-active cells than vpr- clones, and predominant vpr+ proviruses were farther from enhancers and promoters than those in vpr- pools. Distances to these marks among intact proviruses previously reported for antiretroviral therapy (ART)-suppressed patients revealed that patient integration sites were more similar to those in the vpr+ pool than to vpr- integrants. Complementing vpr-defective proviruses with vpr led to the rapid loss of highly LTR-active clones, indicating that the effect of Vpr on proviral populations occurred after integration. However, major clones in the complemented pool and its vpr- parent population did not differ in burst sizes. When the latency reactivation agents prostratin and JQ1 were applied separately or in combination, vpr+ and vpr- population-wide trends were similar, with dual-treatment enhancement being due in part to reactivated clones that did not respond to either drug applied separately. However, the expression signatures of individual clones differed between populations. These observations highlight how Vpr, exerting selective pressure on proviral epigenetic variation, can shape integration site landscapes, proviral expression patterns, and reactivation properties. IMPORTANCE A bedrock assumption in HIV-1 population modeling is that all active cells release the same amount of virus. However, the findings here revealed that when HIV-infected cells expand into clones, each clone differs in virus production. Reasoning that this variation in expression patterns constituted a population of clones from which differing subsets would prevail under differing environmental conditions, the cytotoxic HIV-1 protein Vpr was introduced, and population dynamics and expression properties were compared in the presence and absence of Vpr. The results showed that whereas most clones produced fairly continuous levels of virus in the absence of Vpr, its presence selected for a distinct subset of clones with properties reminiscent of persistent populations in patients, suggesting the possibility that the interclonal variation in expression patterns observed in culture may contribute to proviral persistence in vivo.
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Affiliation(s)
- Edmond Atindaana
- Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Abena Kissi-Twum
- West African Centre for Cell Biology of Infectious Pathogens (WACCBIP), University of Ghana, Legon, Greater Accra Region, Ghana
- Department of Biochemistry, Cell and Molecular Biology, University of Ghana, Legon, Greater Accra Region, Ghana
| | - Sarah Emery
- Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Cleo Burnett
- Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Jake Pitcher
- Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Myra Visser
- Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Jeffrey M. Kidd
- Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Alice Telesnitsky
- Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, USA
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16
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Bergstresser S, Kulpa DA. TGF-β Signaling Supports HIV Latency in a Memory CD4+ T Cell Based In Vitro Model. Methods Mol Biol 2022; 2407:69-79. [PMID: 34985658 DOI: 10.1007/978-1-0716-1871-4_6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
During antiretroviral therapy (ART), HIV-1 persists as a latent reservoir in CD4+ T cell subsets in central (TCM), transitional (TTM) and effector memory (TEM) CD4+ T cells. Understanding the mechanisms that support HIV-1 latency in each of these subsets is essential to the identification of cure strategies to eliminate them. Due to the very low frequency of latently infected cells in vivo, model systems that can accurately reflect the heterogenous population of HIV-1 infected cells are a critical component in HIV cure discoveries. Here, we describe a novel primary cell-based model of HIV-1 latency that recapitulates the complex dynamics of the establishment and maintenance of the latent reservoir in different memory T cell subsets. The latency and reversion assay (LARA ) culture conditions uniquely retain phenotypically and transcriptionally distinct memory CD4+ T cell subsets that allow in a single assay to assess LRA activity in each memory subset and differential examination of the dynamics of HIV latency reversal.
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Affiliation(s)
- Sydney Bergstresser
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, and Yerkes National Primate Research Center, Atlanta, GA, USA
| | - Deanna A Kulpa
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, and Yerkes National Primate Research Center, Atlanta, GA, USA.
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17
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The antimicrobial and immunomodulatory effects of Ionophores for the treatment of human infection. J Inorg Biochem 2021; 227:111661. [PMID: 34896767 DOI: 10.1016/j.jinorgbio.2021.111661] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Revised: 10/27/2021] [Accepted: 11/03/2021] [Indexed: 12/18/2022]
Abstract
Ionophores are a diverse class of synthetic and naturally occurring ion transporter compounds which demonstrate both direct and in-direct antimicrobial properties against a broad panel of bacterial, fungal, viral and parasitic pathogens. In addition, ionophores can regulate the host-immune response during communicable and non-communicable disease states. Although the clinical use of ionophores such as Amphotericin B, Bedaquiline and Ivermectin highlight the utility of ionophores in modern medicine, for many other ionophore compounds issues surrounding toxicity, bioavailability or lack of in vivo efficacy studies have hindered clinical development. The antimicrobial and immunomodulating properties of a range of compounds with characteristics of ionophores remain largely unexplored. As such, ionophores remain a latent therapeutic avenue to address both the global burden of antimicrobial resistance, and the unmet clinical need for new antimicrobial therapies. This review will provide an overview of the broad-spectrum antimicrobial and immunomodulatory properties of ionophores, and their potential uses in clinical medicine for combatting infection.
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18
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Abstract
Combinatory antiretroviral therapy (cART) reduces human immunodeficiency virus type 1 (HIV-1) replication but is not curative because cART interruption almost invariably leads to a rapid rebound of viremia due to the persistence of stable HIV-1-infected cellular reservoirs. These reservoirs are mainly composed of CD4+ T cells harboring replication-competent latent proviruses. A broadly explored approach to reduce the HIV-1 reservoir size, the shock and kill strategy, consists of reactivating HIV-1 gene expression from the latently infected cellular reservoirs (the shock), followed by killing of the virus-producing infected cells (the kill). Based on improved understanding of the multiple molecular mechanisms controlling HIV-1 latency, distinct classes of latency reversing agents (LRAs) have been studied for their efficiency to reactivate viral gene expression in in vitro and ex vivo cell models. Here, we provide an up-to-date review of these different mechanistic classes of LRAs and discuss optimizations of the shock strategy by combining several LRAs simultaneously or sequentially.
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Affiliation(s)
- Anthony Rodari
- Service of Molecular Virology, Department of Molecular Biology, Université Libre de Bruxelles (ULB), 6041 Gosselies, Belgium;
| | - Gilles Darcis
- Infectious Diseases Department, Liège University Hospital, 4000 Liège, Belgium
| | - Carine M Van Lint
- Service of Molecular Virology, Department of Molecular Biology, Université Libre de Bruxelles (ULB), 6041 Gosselies, Belgium;
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19
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Mbonye U, Leskov K, Shukla M, Valadkhan S, Karn J. Biogenesis of P-TEFb in CD4+ T cells to reverse HIV latency is mediated by protein kinase C (PKC)-independent signaling pathways. PLoS Pathog 2021; 17:e1009581. [PMID: 34529720 PMCID: PMC8478230 DOI: 10.1371/journal.ppat.1009581] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 09/28/2021] [Accepted: 09/04/2021] [Indexed: 01/09/2023] Open
Abstract
The switch between HIV latency and productive transcription is regulated by an auto-feedback mechanism initiated by the viral trans-activator Tat, which functions to recruit the host transcription elongation factor P-TEFb to proviral HIV. A heterodimeric complex of CDK9 and one of three cyclin T subunits, P-TEFb is expressed at vanishingly low levels in resting memory CD4+ T cells and cellular mechanisms controlling its availability are central to regulation of the emergence of HIV from latency. Using a well-characterized primary T-cell model of HIV latency alongside healthy donor memory CD4+ T cells, we characterized specific T-cell receptor (TCR) signaling pathways that regulate the generation of transcriptionally active P-TEFb, defined as the coordinate expression of cyclin T1 and phospho-Ser175 CDK9. Protein kinase C (PKC) agonists, such as ingenol and prostratin, stimulated active P-TEFb expression and reactivated latent HIV with minimal cytotoxicity, even in the absence of intracellular calcium mobilization with an ionophore. Unexpectedly, inhibition-based experiments demonstrated that PKC agonists and TCR-mobilized diacylglycerol signal through MAP kinases ERK1/2 rather than through PKC to effect the reactivation of both P-TEFb and latent HIV. Single-cell and bulk RNA-seq analyses revealed that of the four known isoforms of the Ras guanine nucleotide exchange factor RasGRP, RasGRP1 is by far the predominantly expressed diacylglycerol-dependent isoform in CD4+ T cells. RasGRP1 should therefore mediate the activation of ERK1/2 via Ras-Raf signaling upon TCR co-stimulation or PKC agonist challenge. Combined inhibition of the PI3K-mTORC2-AKT-mTORC1 pathway and the ERK1/2 activator MEK prior to TCR co-stimulation abrogated active P-TEFb expression and substantially suppressed latent HIV reactivation. Therefore, contrary to prevailing models, the coordinate reactivation of P-TEFb and latent HIV in primary T cells following either TCR co-stimulation or PKC agonist challenge is independent of PKC but rather involves two complementary signaling arms of the TCR cascade, namely, RasGRP1-Ras-Raf-MEK-ERK1/2 and PI3K-mTORC2-AKT-mTORC1.
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Affiliation(s)
- Uri Mbonye
- Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America
- * E-mail: (UM); (JK)
| | - Konstantin Leskov
- Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America
| | - Meenakshi Shukla
- Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America
| | - Saba Valadkhan
- Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America
| | - Jonathan Karn
- Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America
- * E-mail: (UM); (JK)
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20
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Potential Utility of Natural Killer Cells for Eliminating Cells Harboring Reactivated Latent HIV-1 Following the Removal of CD8 + T Cell-Mediated Pro-Latency Effect(s). Viruses 2021; 13:v13081451. [PMID: 34452317 PMCID: PMC8402732 DOI: 10.3390/v13081451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 07/14/2021] [Accepted: 07/15/2021] [Indexed: 11/17/2022] Open
Abstract
An impediment to curing HIV-1 infection is the persistence of latently infected cells in ART-treated people living with HIV (PLWH). A key strategy for curing HIV-1 infection is to activate transcription and translation of latent virus using latency reversing agents (LRAs) and eliminate cells harboring reactivated virus via viral cytopathic effect or immune clearance. In this review, we provide an overview of available LRAs and their use in clinical trials. Furthermore, we describe recent data suggesting that CD8+ T cells promote HIV-1 latency in the context of ART, even in the presence of LRAs, which might at least partially explain the clinical inefficiency of previous “shock and kill” trials. Here, we propose a novel cure strategy called “unlock, shock, disarm, and kill”. The general premise of this strategy is to shut down the pro-latency function(s) of CD8+ T cells, use LRAs to reverse HIV-1 latency, counteract anti-apoptotic molecules, and engage natural killer (NK) cells to mediate the killing of cells harboring reactivated latent HIV-1.
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21
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The Combination of Venetoclax and Ixazomib Selectively and Efficiently Kills HIV-Infected Cell Lines but Has Unacceptable Toxicity in Primary Cell Models. J Virol 2021; 95:JVI.00138-21. [PMID: 33827940 DOI: 10.1128/jvi.00138-21] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 03/28/2021] [Indexed: 12/19/2022] Open
Abstract
The antiapoptotic protein BCL2 inhibits death of HIV-infected cells. Previously, we showed that the BCL2 inhibitor venetoclax selectively kills acutely HIV-infected cells and reduces HIV DNA in latently infected CD4 T cells ex vivo after reactivation with anti-CD3/anti-CD28. However, there is a need to identify a combination therapy with venetoclax and a clinically relevant latency reversal agent. Ixazomib is an oral proteasome inhibitor which we have shown reactivates latent HIV and predisposes reactivated cells to cell death. Here, we determined that the combination of venetoclax and ixazomib kills more latently HIV-infected cells and leads to greater reduction in HIV replication than either treatment alone in vitro in a T cell model. However, combination treatment of ex vivo CD4 T cells from antiretroviral therapy (ART)-suppressed, HIV-positive participants resulted in unanticipated and unacceptable nonspecific toxicity in primary cells. Therefore, while we show proof of concept that multiple agents can enhance selective killing of HIV-infected cells, the combination of venetoclax and ixazomib has unacceptable toxicity in primary cells, and so further investigation is needed to identify a clinically relevant latency reversal agent to combine with venetoclax as a novel strategy to reduce the size of the HIV reservoir.IMPORTANCE A cure for HIV would require eliminating cells that contain the virus in a latent form from the body. Current antiretroviral medications are unable to rid the body of latently infected cells. Here, we show that a combination of investigational agents-ixazomib plus venetoclax-which reactivate latent virus and predispose infected cells to apoptosis may reduce latent virus in a T cell model, but at the expense of nonspecific toxicity in primary cells.
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22
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Schnell AP, Kohrt S, Thoma-Kress AK. Latency Reversing Agents: Kick and Kill of HTLV-1? Int J Mol Sci 2021; 22:ijms22115545. [PMID: 34073995 PMCID: PMC8197370 DOI: 10.3390/ijms22115545] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 05/19/2021] [Accepted: 05/20/2021] [Indexed: 12/14/2022] Open
Abstract
Human T-cell leukemia virus type 1 (HTLV-1), the cause of adult T-cell leukemia/lymphoma (ATLL), is a retrovirus, which integrates into the host genome and persistently infects CD4+ T-cells. Virus propagation is stimulated by (1) clonal expansion of infected cells and (2) de novo infection. Viral gene expression is induced by the transactivator protein Tax, which recruits host factors like positive transcription elongation factor b (P-TEFb) to the viral promoter. Since HTLV-1 gene expression is repressed in vivo by viral, cellular, and epigenetic mechanisms in late phases of infection, HTLV-1 avoids an efficient CD8+ cytotoxic T-cell (CTL) response directed against the immunodominant viral Tax antigen. Hence, therapeutic strategies using latency reversing agents (LRAs) sought to transiently activate viral gene expression and antigen presentation of Tax to enhance CTL responses towards HTLV-1, and thus, to expose the latent HTLV-1 reservoir to immune destruction. Here, we review strategies that aimed at enhancing Tax expression and Tax-specific CTL responses to interfere with HTLV-1 latency. Further, we provide an overview of LRAs including (1) histone deacetylase inhibitors (HDACi) and (2) activators of P-TEFb, that have mainly been studied in context of human immunodeficiency virus (HIV), but which may also be powerful in the context of HTLV-1.
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23
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Gao H, Ozantürk AN, Wang Q, Harlan GH, Schmitz AJ, Presti RM, Deng K, Shan L. Evaluation of HIV-1 latency reversal and antibody-dependent viral clearance by quantification of singly spliced HIV-1 vpu/ env mRNA. J Virol 2021; 95:JVI.02124-20. [PMID: 33762408 PMCID: PMC8139706 DOI: 10.1128/jvi.02124-20] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Accepted: 03/13/2021] [Indexed: 11/20/2022] Open
Abstract
The latent reservoir of HIV-1 is a major barrier for viral eradication. Potent HIV-1 broadly neutralizing antibodies (bNabs) have been used to prevent and treat HIV-1 infections in animal models and clinical trials. Combination of bNabs and latency-reversing agents (LRAs) is considered a promising approach for HIV-1 eradication. PCR-based assays that can rapidly and specifically measure singly spliced HIV-1 vpu/env mRNA are needed to evaluate the induction of the viral envelope production at the transcription level and bNab-mediated reservoir clearance. Here we reported a PCR-based method to accurately quantify the production of intracellular HIV-1 vpu/env mRNA. With the vpu/env assay, we determined the LRA combinations that could effectively induce vpu/env mRNA production in CD4+ T cells from ART-treated individuals. None of the tested LRAs were effective alone. A comparison between the quantitative viral outgrowth assay (Q-VOA) and the vpu/env assay showed that vpu/env mRNA production was closely associated with the reactivation of replication-competent HIV-1, suggesting that vpu/env mRNA was mainly produced by intact viruses. Finally, antibody-mediated in vitro killing in HIV-1-infected humanized mice demonstrated that the vpu/env assay could be used to measure the reduction of infected cells in tissues and was more accurate than the commonly used gag-based PCR assay which measured unspliced viral genomic RNA. In conclusion, the vpu/env assay allows convenient and accurate assessment of HIV-1 latency reversal and bNab-mediated therapeutic strategies.ImportanceHIV-1 persists in individuals on antiretroviral therapy (ART) due to the long-lived cellular reservoirs that contain dormant viruses. Recent discoveries of HIV-1-specific broadly neutralizing antibodies (bNabs) targeting HIV-1 Env protein rekindled the interest in antibody-mediated elimination of latent HIV-1. Latency-reversing agents (LRAs) together with HIV-1 bNabs is a possible strategy to clear residual viral reservoirs, which makes the evaluation of HIV-1 Env expression upon LRA treatment critical. We developed a PCR-based assay to quantify the production of intracellular HIV-1 vpu/env mRNA. Using patient CD4+ T cells, we found that induction of HIV-1 vpu/env mRNA required a combination of different LRAs. Using in vitro, ex vivo and humanized mouse models, we showed that the vpu/env assay could be used to measure antibody efficacy in clearing HIV-1 infection. These results suggest that the vpu/env assay can accurately evaluate HIV-1 reactivation and bNab-based therapeutic interventions.
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Affiliation(s)
- Hongbo Gao
- Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
- Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA
| | - Ayşe N Ozantürk
- Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA
| | - Qiankun Wang
- Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA
| | - Gray H Harlan
- Department of Chemistry, Washington University, St Louis, MO, USA
| | - Aaron J Schmitz
- Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA
| | - Rachel M Presti
- Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA
| | - Kai Deng
- Institute of Human Virology, Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Liang Shan
- Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA
- The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, Saint Louis, MO, USA
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24
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HIV latency reversal agents: A potential path for functional cure? Eur J Med Chem 2021; 213:113213. [PMID: 33540228 DOI: 10.1016/j.ejmech.2021.113213] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 11/16/2020] [Accepted: 01/12/2021] [Indexed: 12/28/2022]
Abstract
Despite the advances in Human Immunodeficiency Virus (HIV) treatment, the cure for all HIV patients still poses a major challenge, which needs to be surpassed in the coming years. Among the strategies pursuing this aim, the 'kick-and-kill' approach, which involves the reactivation and elimination of a latent HIV reservoir that resides in some CD4+ T cells, appears promising. The first step of this approach requires the use of latency reversal agents (LRAs) that induce the reactivation of the latent virus. Although several classes of LRAs have been reported so far, some limitations of these compounds still need to be overcome before their clinical use. The complete exhaustion of the reservoir of latent virus will contribute to promote the second step of this approach, facilitating the elimination of the reactivated HIV. Therefore, potent, safe, and non-toxic LRAs are necessary to promote efficient elimination of the HIV-1 virus from its reservoir. In this review article, we focus on the promising LRAs that have been described in the literature over the past few years, highlighting the advantages and disadvantages of their use in the 'kick and kill' approach, thus opening a new avenue in the development of a potential cure.
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25
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TELWATTE S, KIM P, CHEN TH, MILUSH JM, SOMSOUK M, DEEKS SG, HUNT PW, WONG JK, YUKL SA. Mechanistic differences underlying HIV latency in the gut and blood contribute to differential responses to latency-reversing agents. AIDS 2020; 34:2013-2024. [PMID: 32910065 PMCID: PMC7990078 DOI: 10.1097/qad.0000000000002684] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVE While latently HIV-infected cells have been described in the blood, it is unclear whether a similar inducible reservoir exists in the gut, where most HIV-infected cells reside. Tissue-specific environments may contribute to differences in the mechanisms that govern latent HIV infection and amenability to reactivation. We sought to determine whether HIV-infected cells from the blood and gut differ in their responses to T-cell activation and mechanistically distinct latency reversing agents (LRAs). DESIGN Cross sectional study using samples from HIV-infected individuals (n = 11). METHODS Matched peripheral blood mononuclear cells (PBMC) and dissociated total cells from rectum ± ileum were treated ex vivo for 24 h with anti-CD3/CD28 or LRAs in the presence of antiretrovirals. HIV DNA and 'read-through', initiated, 5' elongated, completed, and multiply-spliced HIV transcripts were quantified using droplet digital PCR. RESULTS T-cell activation increased levels of all HIV transcripts in PBMC and gut cells, and was the only treatment that increased multiply-spliced HIV RNA. Disulfiram increased initiated HIV transcripts in PBMC but not gut cells, while ingenol mebutate increased HIV transcription more in gut cells. Romidepsin increased HIV transcription in PBMC and gut cells, but the increase in transcription initiation was greater in PBMC. CONCLUSION The gut harbors HIV-infected cells in a latent-like state that can be reversed by T-cell activation involving CD3/CD28 signaling. Histone deacetylation and protein kinase B may contribute less to HIV transcriptional initiation in the gut, whereas protein kinase C may contribute more. New LRAs or combinations are needed to induce multiply-spliced HIV and should be tested on both blood and gut.
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Affiliation(s)
- Sushama TELWATTE
- Department of Medicine, University of California San Francisco (UCSF), San Francisco, CA, 94110, USA
- Department of Medicine, San Francisco VA Medical Center, San Francisco, CA, 94121, USA
| | - Peggy KIM
- Department of Medicine, San Francisco VA Medical Center, San Francisco, CA, 94121, USA
| | - Tsui-Hua CHEN
- Department of Medicine, University of California San Francisco (UCSF), San Francisco, CA, 94110, USA
| | - Jeffrey M. MILUSH
- Department of Medicine, University of California San Francisco (UCSF), San Francisco, CA, 94110, USA
| | - Ma SOMSOUK
- Department of Medicine, University of California San Francisco (UCSF), San Francisco, CA, 94110, USA
| | - Steven G. DEEKS
- Department of Medicine, University of California San Francisco (UCSF), San Francisco, CA, 94110, USA
| | - Peter W. HUNT
- Department of Medicine, University of California San Francisco (UCSF), San Francisco, CA, 94110, USA
| | - Joseph K. WONG
- Department of Medicine, University of California San Francisco (UCSF), San Francisco, CA, 94110, USA
- Department of Medicine, San Francisco VA Medical Center, San Francisco, CA, 94121, USA
| | - Steven A. YUKL
- Department of Medicine, University of California San Francisco (UCSF), San Francisco, CA, 94110, USA
- Department of Medicine, San Francisco VA Medical Center, San Francisco, CA, 94121, USA
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Fujinaga K, Cary DC. Experimental Systems for Measuring HIV Latency and Reactivation. Viruses 2020; 12:v12111279. [PMID: 33182414 PMCID: PMC7696534 DOI: 10.3390/v12111279] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Revised: 11/02/2020] [Accepted: 11/05/2020] [Indexed: 02/07/2023] Open
Abstract
The final obstacle to achieving a cure to HIV/AIDS is the presence of latent HIV reservoirs scattered throughout the body. Although antiretroviral therapy maintains plasma viral loads below the levels of detection, upon cessation of therapy, the latent reservoir immediately produces infectious progeny viruses. This results in elevated plasma viremia, which leads to clinical progression to AIDS. Thus, if a HIV cure is ever to become a reality, it will be necessary to target and eliminate the latent reservoir. To this end, tremendous effort has been dedicated to locate the viral reservoir, understand the mechanisms contributing to latency, find optimal methods to reactivate HIV, and specifically kill latently infected cells. Although we have not yet identified a therapeutic approach to completely eliminate HIV from patients, these efforts have provided many technological breakthroughs in understanding the underlying mechanisms that regulate HIV latency and reactivation in vitro. In this review, we summarize and compare experimental systems which are frequently used to study HIV latency. While none of these models are a perfect proxy for the complex systems at work in HIV+ patients, each aim to replicate HIV latency in vitro.
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Affiliation(s)
- Koh Fujinaga
- Division of Rheumatology, Department of Medicine, School of Medicine, University of California, San Francisco, CA 94143-0703, USA
- Correspondence: ; Tel.: +1-415-502-1908
| | - Daniele C. Cary
- Department of Medicine, Microbiology, and Immunology, School of Medicine, University of California, San Francisco, CA 94143-0703, USA;
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Sahay B, Mergia A. The Potential Contribution of Caveolin 1 to HIV Latent Infection. Pathogens 2020; 9:pathogens9110896. [PMID: 33121153 PMCID: PMC7692328 DOI: 10.3390/pathogens9110896] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 10/22/2020] [Accepted: 10/23/2020] [Indexed: 12/25/2022] Open
Abstract
Combinatorial antiretroviral therapy (cART) suppresses HIV replication to undetectable levels and has been effective in prolonging the lives of HIV infected individuals. However, cART is not capable of eradicating HIV from infected individuals mainly due to HIV’s persistence in small reservoirs of latently infected resting cells. Latent infection occurs when the HIV-1 provirus becomes transcriptionally inactive and several mechanisms that contribute to the silencing of HIV transcription have been described. Despite these advances, latent infection remains a major hurdle to cure HIV infected individuals. Therefore, there is a need for more understanding of novel mechanisms that are associated with latent infection to purge HIV from infected individuals thoroughly. Caveolin 1(Cav-1) is a multifaceted functional protein expressed in many cell types. The expression of Cav-1 in lymphocytes has been controversial. Recent evidence, however, convincingly established the expression of Cav-1 in lymphocytes. In lieu of this finding, the current review examines the potential role of Cav-1 in HIV latent infection and provides a perspective that helps uncover new insights to understand HIV latent infection.
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Affiliation(s)
| | - Ayalew Mergia
- Correspondence: ; Tel.: +352-294-4139; Fax: +352-392-9704
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28
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López-Huertas MR, Jiménez-Tormo L, Madrid-Elena N, Gutiérrez C, Vivancos MJ, Luna L, Moreno S. Maraviroc reactivates HIV with potency similar to that of other latency reversing drugs without inducing toxicity in CD8 T cells. Biochem Pharmacol 2020; 182:114231. [PMID: 32979351 DOI: 10.1016/j.bcp.2020.114231] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Accepted: 09/21/2020] [Indexed: 01/12/2023]
Abstract
Human immunodeficiency virus (HIV) remains incurable due to latent reservoirs established in non-activated CD4 T cells. Current efforts to achieve a functional cure rely on immunomodulatory strategies focused on enhancing the functions of cytotoxic cells. Implementation of these actions requires a coordinated activation of the viral transcription in latently infected cells so that the reservoir became visible and accessible to cytotoxic cells. As no latency reversing agent (LRA) has been shown to be completely effective, new combinations are of increasing importance. Recent data have shown that maraviroc is a new LRA. In this work, we have explored how the combination of maraviroc with other LRAs influences on HIV reactivation using in vitro latency models as well as on the cell viability of CD8 T cells from ART-treated patients. Maraviroc reactivated HIV with a potency similar to other LRAs. Triple combinations resulted toxic and were rejected. No dual combination was synergistic. The combination with panobinostat or disulfiram maintained the effect of both drugs without inducing cell proliferation or toxicity. Maraviroc does not alter the viability of CD8 T cells isolated from patients under antiretroviral treatment. This finding enhances the properties of maraviroc as a LRA.
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Affiliation(s)
- María Rosa López-Huertas
- Servicio de Enfermedades Infecciosas, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS) and Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain.
| | - Laura Jiménez-Tormo
- Servicio de Enfermedades Infecciosas, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS) and Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain
| | - Nadia Madrid-Elena
- Servicio de Enfermedades Infecciosas, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS) and Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain
| | - Carolina Gutiérrez
- Servicio de Enfermedades Infecciosas, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS) and Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain
| | - María Jesús Vivancos
- Servicio de Enfermedades Infecciosas, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS) and Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain
| | - Laura Luna
- Servicio de Enfermedades Infecciosas, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS) and Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain
| | - Santiago Moreno
- Servicio de Enfermedades Infecciosas, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS) and Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain; Facultad de Medicina y Ciencias de la Salud, Universidad de Alcalá de Henares, 28871 Alcalá de Henares, Spain
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Hayes AML. Future approaches to clearing the latent human immunodeficiency virus reservoir: Beyond latency reversal. South Afr J HIV Med 2020; 21:1089. [PMID: 32934831 PMCID: PMC7479387 DOI: 10.4102/sajhivmed.v21i1.1089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Accepted: 05/12/2020] [Indexed: 11/01/2022] Open
Abstract
Background While combined antiretroviral therapy (cART) allows near-normal life expectancy for people living with human immunodeficiency virus (HIV), it is unable to cure the infection and so life long treatment is required. Objectives The main barrier to curing HIV is the latent reservoir of cells, which is stable and resistant to cART. Method Current approaches under investigation for clearing this reservoir propose a 'Shock and Kill' mechanism, in which active replication is induced in latent cells by latency reversal agents, theoretically allowing killing of the newly active cells. Results However, previous studies have failed to achieve depletion of the T central memory cell reservoir, are unable to target other latent reservoirs and may be causing neurological damage to participants. Conclusion Future approaches to clearing the latent reservoir may bypass latency reversal through the use of drugs that selectively induce apoptosis in infected cells. Several classes of these pro-apoptotic drugs have shown promise in in vitro and ex vivo studies, and may represent the basis of a future functional cure for HIV.
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Affiliation(s)
- Alexander M L Hayes
- Medical Sciences Division, Faculty of Clinical Medicine, University of Oxford, Oxford, United Kingdom
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30
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Hashemi P, Sadowski I. Diversity of small molecule HIV-1 latency reversing agents identified in low- and high-throughput small molecule screens. Med Res Rev 2020; 40:881-908. [PMID: 31608481 PMCID: PMC7216841 DOI: 10.1002/med.21638] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 08/26/2019] [Accepted: 09/16/2019] [Indexed: 12/12/2022]
Abstract
The latency phenomenon produced by human immunodeficiency virus (HIV-1) prevents viral clearance by current therapies, and consequently development of a cure for HIV-1 disease represents a formidable challenge. Research over the past decade has resulted in identification of small molecules that are capable of exposing HIV-1 latent reservoirs, by reactivation of viral transcription, which is intended to render these infected cells sensitive to elimination by immune defense recognition or apoptosis. Molecules with this capability, known as latency-reversing agents (LRAs) could lead to realization of proposed HIV-1 cure strategies collectively termed "shock and kill," which are intended to eliminate the latently infected population by forced reactivation of virus replication in combination with additional interventions that enhance killing by the immune system or virus-mediated apoptosis. Here, we review efforts to discover novel LRAs via low- and high-throughput small molecule screens, and summarize characteristics and biochemical properties of chemical structures with this activity. We expect this analysis will provide insight toward further research into optimized designs for new classes of more potent LRAs.
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Affiliation(s)
- Pargol Hashemi
- Biochemistry and Molecular Biology, Molecular Epigenetics, Life Sciences InstituteUniversity of British ColumbiaVancouverBritish ColumbiaCanada
| | - Ivan Sadowski
- Biochemistry and Molecular Biology, Molecular Epigenetics, Life Sciences InstituteUniversity of British ColumbiaVancouverBritish ColumbiaCanada
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31
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Thomas J, Ruggiero A, Paxton WA, Pollakis G. Measuring the Success of HIV-1 Cure Strategies. Front Cell Infect Microbiol 2020; 10:134. [PMID: 32318356 PMCID: PMC7154081 DOI: 10.3389/fcimb.2020.00134] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Accepted: 03/13/2020] [Indexed: 01/10/2023] Open
Abstract
HIV-1 eradication strategies aim to achieve viral remission in the absence of antiretroviral therapy (ART). The development of an HIV-1 cure remains challenging due to the latent reservoir (LR): long-lived CD4 T cells that harbor transcriptionally silent HIV-1 provirus. The LR is stable despite years of suppressive ART and is the source of rebound viremia following therapy interruption. Cure strategies such as "shock and kill" aim to eliminate or reduce the LR by reversing latency, exposing the infected cells to clearance via the immune response or the viral cytopathic effect. Alternative strategies include therapeutic vaccination, which aims to prime the immune response to facilitate control of the virus in the absence of ART. Despite promising advances, these strategies have been unable to significantly reduce the LR or increase the time to viral rebound but have provided invaluable insight in the field of HIV-1 eradication. The development and assessment of an HIV-1 cure requires robust assays that can measure the LR with sufficient sensitivity to detect changes that may occur following treatment. The viral outgrowth assay (VOA) is considered the gold standard method for LR quantification due to its ability to distinguish intact and defective provirus. However, the VOA is time consuming and resource intensive, therefore several alternative assays have been developed to bridge the gap between practicality and accuracy. Whilst a cure for HIV-1 infection remains elusive, recent advances in our understanding of the LR and methods for its eradication have offered renewed hope regarding achieving ART free viral remission.
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Affiliation(s)
- Jordan Thomas
- Department of Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom
| | - Alessandra Ruggiero
- Department of Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom.,Immune and Infectious Disease Division, Academic Department of Pediatrics (DPUO), Bambino Gesù Children's Hospital, Rome, Italy
| | - William A Paxton
- Department of Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom
| | - Georgios Pollakis
- Department of Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom
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32
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Ait-Ammar A, Kula A, Darcis G, Verdikt R, De Wit S, Gautier V, Mallon PWG, Marcello A, Rohr O, Van Lint C. Current Status of Latency Reversing Agents Facing the Heterogeneity of HIV-1 Cellular and Tissue Reservoirs. Front Microbiol 2020; 10:3060. [PMID: 32038533 PMCID: PMC6993040 DOI: 10.3389/fmicb.2019.03060] [Citation(s) in RCA: 112] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Accepted: 12/18/2019] [Indexed: 12/15/2022] Open
Abstract
One of the most explored therapeutic approaches aimed at eradicating HIV-1 reservoirs is the "shock and kill" strategy which is based on HIV-1 reactivation in latently-infected cells ("shock" phase) while maintaining antiretroviral therapy (ART) in order to prevent spreading of the infection by the neosynthesized virus. This kind of strategy allows for the "kill" phase, during which latently-infected cells die from viral cytopathic effects or from host cytolytic effector mechanisms following viral reactivation. Several latency reversing agents (LRAs) with distinct mechanistic classes have been characterized to reactivate HIV-1 viral gene expression. Some LRAs have been tested in terms of their potential to purge latent HIV-1 in vivo in clinical trials, showing that reversing HIV-1 latency is possible. However, LRAs alone have failed to reduce the size of the viral reservoirs. Together with the inability of the immune system to clear the LRA-activated reservoirs and the lack of specificity of these LRAs, the heterogeneity of the reservoirs largely contributes to the limited success of clinical trials using LRAs. Indeed, HIV-1 latency is established in numerous cell types that are characterized by distinct phenotypes and metabolic properties, and these are influenced by patient history. Hence, the silencing mechanisms of HIV-1 gene expression in these cellular and tissue reservoirs need to be better understood to rationally improve this cure strategy and hopefully reach clinical success.
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Affiliation(s)
- Amina Ait-Ammar
- Service of Molecular Virology, Department of Molecular Virology (DBM), Université Libre de Bruxelles (ULB), Gosselies, Belgium
| | - Anna Kula
- Malopolska Centre of Biotechnology, Laboratory of Virology, Jagiellonian University, Krakow, Poland
| | - Gilles Darcis
- Infectious Diseases Department, Liège University Hospital, Liège, Belgium
| | - Roxane Verdikt
- Service of Molecular Virology, Department of Molecular Virology (DBM), Université Libre de Bruxelles (ULB), Gosselies, Belgium
| | - Stephane De Wit
- Service des Maladies Infectieuses, CHU Saint-Pierre, Université Libre de Bruxelles, Bruxelles, Belgium
| | - Virginie Gautier
- UCD Centre for Experimental Pathogen Host Research (CEPHR), School of Medicine, University College Dublin, Dublin, Ireland
| | - Patrick W G Mallon
- UCD Centre for Experimental Pathogen Host Research (CEPHR), School of Medicine, University College Dublin, Dublin, Ireland
| | - Alessandro Marcello
- Laboratory of Molecular Virology, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy
| | - Olivier Rohr
- Université de Strasbourg, EA7292, FMTS, IUT Louis Pasteur, Schiltigheim, France
| | - Carine Van Lint
- Service of Molecular Virology, Department of Molecular Virology (DBM), Université Libre de Bruxelles (ULB), Gosselies, Belgium
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Heterogeneous HIV-1 Reactivation Patterns of Disulfiram and Combined Disulfiram+Romidepsin Treatments. J Acquir Immune Defic Syndr 2019; 80:605-613. [PMID: 30768485 DOI: 10.1097/qai.0000000000001958] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
OBJECTIVES Few single latency-reversing agents (LRAs) have been tested in vivo, and only some of them have demonstrated an effect, albeit weak, on the decrease of latent reservoir. Therefore, other LRAs and combinations of LRAs need to be assessed. Here, we evaluated the potential of combined treatments of therapeutically promising LRAs, disulfiram and romidepsin. SETTING AND METHODS We assessed the reactivation potential of individual disulfiram or simultaneous or sequential combined treatments with romidepsin in vitro in latently infected cell lines of T-lymphoid and myeloid origins and in ex vivo cultures of CD8-depleted peripheral blood mononuclear cells isolated from 18 HIV-1 combination antiretroviral therapy-treated individuals. RESULTS We demonstrated heterogeneous reactivation effects of disulfiram in vitro in various cell lines of myeloid origin and no latency reversal neither in vitro in T-lymphoid cells nor ex vivo, even if doses corresponding to maximal plasmatic concentration or higher were tested. Disulfiram+romidepsin combined treatments produced distinct reactivation patterns in vitro. Ex vivo, the combined treatments showed a modest reactivation effect when used simultaneously as opposed to no viral reactivation for the corresponding sequential treatment. CONCLUSIONS Exclusive reactivation effects of disulfiram in myeloid latency cell lines suggest that disulfiram could be a potential LRA for this neglected reservoir. Moreover, distinct reactivation profiles pinpoint heterogeneity of the latent reservoir and confirm that the mechanisms that contribute to HIV latency are diverse. Importantly, disulfiram+romidepsin treatments are not potent ex vivo and most likely do not represent an effective drug combination to achieve high levels of latency reversal in vivo.
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Palermo E, Acchioni C, Di Carlo D, Zevini A, Muscolini M, Ferrari M, Castiello L, Virtuoso S, Borsetti A, Antonelli G, Turriziani O, Sgarbanti M, Hiscott J. Activation of Latent HIV-1 T Cell Reservoirs with a Combination of Innate Immune and Epigenetic Regulators. J Virol 2019; 93:e01194-19. [PMID: 31413127 PMCID: PMC6803272 DOI: 10.1128/jvi.01194-19] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Accepted: 08/03/2019] [Indexed: 02/07/2023] Open
Abstract
The presence of T cell reservoirs in which human immunodeficiency virus (HIV) establishes latency by integrating into the host genome represents a major obstacle to an HIV cure and has prompted the development of strategies aimed at the eradication of HIV from latently infected cells. The "shock-and-kill" strategy is one of the most pursued approaches to the elimination of viral reservoirs. Although several latency-reversing agents (LRAs) have shown promising reactivation activity, they have failed to eliminate the cellular reservoir. In this study, we evaluated a novel immune system-mediated approach to clearing the HIV reservoir, based on a combination of innate immune stimulation and epigenetic reprogramming. The combination of the STING agonist cGAMP (cyclic GMP-AMP) and the FDA-approved histone deacetylase inhibitor resminostat resulted in a significant increase in HIV proviral reactivation and specific apoptosis in HIV-infected cells in vitro Reductions in the proportion of HIV-harboring cells and the total amount of HIV DNA were also observed in CD4+ central memory T (TCM) cells, a primary cell model of latency, where resminostat alone or together with cGAMP induced high levels of selective cell death. Finally, high levels of cell-associated HIV RNA were detected ex vivo in peripheral blood mononuclear cells (PBMCs) and CD4+ T cells from individuals on suppressive antiretroviral therapy (ART). Although synergism was not detected in PBMCs with the combination, viral RNA expression was significantly increased in CD4+ T cells. Collectively, these results represent a promising step toward HIV eradication by demonstrating the potential of innate immune activation and epigenetic modulation for reducing the viral reservoir and inducing specific death of HIV-infected cells.IMPORTANCE One of the challenges associated with HIV-1 infection is that despite antiretroviral therapies that reduce HIV-1 loads to undetectable levels, proviral DNA remains dormant in a subpopulation of T lymphocytes. Numerous strategies to clear residual virus by reactivating latent virus and eliminating the reservoir of HIV-1 (so-called "shock-and-kill" strategies) have been proposed. In the present study, we use a combination of small molecules that activate the cGAS-STING antiviral innate immune response (the di-cyclic nucleotide cGAMP) and epigenetic modulators (histone deacetylase inhibitors) that induce reactivation and HIV-infected T cell killing in cell lines, primary T lymphocytes, and patient samples. These studies represent a novel strategy for HIV eradication by reducing the viral reservoir and inducing specific death of HIV-infected cells.
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Affiliation(s)
- Enrico Palermo
- Pasteur Institute-Italy, Istituto Pasteur-Fondazione Cenci Bolognetti, Rome, Italy
| | - Chiara Acchioni
- Department of Infectious, Parasitic and Immune-Mediated Diseases, Istituto Superiore di Sanità, Rome, Italy
| | - Daniele Di Carlo
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Alessandra Zevini
- Pasteur Institute-Italy, Istituto Pasteur-Fondazione Cenci Bolognetti, Rome, Italy
| | - Michela Muscolini
- Pasteur Institute-Italy, Istituto Pasteur-Fondazione Cenci Bolognetti, Rome, Italy
| | - Matteo Ferrari
- Pasteur Institute-Italy, Istituto Pasteur-Fondazione Cenci Bolognetti, Rome, Italy
| | - Luciano Castiello
- Pasteur Institute-Italy, Istituto Pasteur-Fondazione Cenci Bolognetti, Rome, Italy
| | - Sara Virtuoso
- National HIV/AIDS Research Center, Istituto Superiore di Sanità, Rome, Italy
| | - Alessandra Borsetti
- National HIV/AIDS Research Center, Istituto Superiore di Sanità, Rome, Italy
| | - Guido Antonelli
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | | | - Marco Sgarbanti
- Department of Infectious, Parasitic and Immune-Mediated Diseases, Istituto Superiore di Sanità, Rome, Italy
| | - John Hiscott
- Pasteur Institute-Italy, Istituto Pasteur-Fondazione Cenci Bolognetti, Rome, Italy
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Sadowski I, Hashemi FB. Strategies to eradicate HIV from infected patients: elimination of latent provirus reservoirs. Cell Mol Life Sci 2019; 76:3583-3600. [PMID: 31129856 PMCID: PMC6697715 DOI: 10.1007/s00018-019-03156-8] [Citation(s) in RCA: 80] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 04/29/2019] [Accepted: 05/20/2019] [Indexed: 02/06/2023]
Abstract
35 years since identification of HIV as the causative agent of AIDS, and 35 million deaths associated with this disease, significant effort is now directed towards the development of potential cures. Current anti-retroviral (ART) therapies for HIV/AIDS can suppress virus replication to undetectable levels, and infected individuals can live symptom free so long as treatment is maintained. However, removal of therapy allows rapid re-emergence of virus from a highly stable reservoir of latently infected cells that exist as a barrier to elimination of the infection with current ART. Prospects of a cure for HIV infection are significantly encouraged by two serendipitous cases where individuals have entered remission following stem cell transplantation from compatible HIV-resistant donors. However, development of a routine cure that could become available to millions of infected individuals will require a means of specifically purging cells harboring latent HIV, preventing replication of latent provirus, or destruction of provirus genomes by gene editing. Elimination of latently infected cells will require a means of exposing this population, which may involve identification of a natural specific biomarker or therapeutic intervention to force their exposure by reactivation of virus expression. Accordingly, the proposed "Shock and Kill" strategy involves treatment with latency-reversing agents (LRA) to induce HIV provirus expression thus exposing these cells to killing by cellular immunity or apoptosis. Current efforts to enable this strategy are directed at developing improved combinations of LRA to produce broad and robust induction of HIV provirus and enhancing the elimination of cells where replication has been reactivated by targeted immune modulation. Alternative strategies may involve preventing re-emergence virus from latently infected cells by "Lock and Block" intervention, where transcription of provirus is inhibited to prevent virus spread or disruption of the HIV provirus genome by genome editing.
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Affiliation(s)
- Ivan Sadowski
- Department of Biochemistry and Molecular Biology, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada.
| | - Farhad B Hashemi
- Department of Microbiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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36
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Cao S, Woodrow KA. Nanotechnology approaches to eradicating HIV reservoirs. Eur J Pharm Biopharm 2019; 138:48-63. [PMID: 29879528 PMCID: PMC6279622 DOI: 10.1016/j.ejpb.2018.06.002] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Revised: 05/29/2018] [Accepted: 06/02/2018] [Indexed: 02/06/2023]
Abstract
The advent of combination antiretroviral therapy (cART) has transformed HIV-1 infection into a controllable chronic disease, but these therapies are incapable of eradicating the virus to bring about an HIV cure. Multiple strategies have been proposed and investigated to eradicate latent viral reservoirs from various biological sanctuaries. However, due to the complexity of HIV infection and latency maintenance, a single drug is unlikely to eliminate all HIV reservoirs and novel strategies may be needed to achieve better efficacy while limiting systemic toxicity. In this review, we describe HIV latency in cellular and anatomical reservoirs, and present an overview of current strategies for HIV cure with a focus on their challenges for clinical translation. Then we provide a summary of nanotechnology solutions that have been used to address challenges in HIV cure by delivering physicochemically diverse agents for combination therapy or targeting HIV reservoir sites. We also review nanocarrier-based gene delivery and immunotherapy used in cancer treatment but may have potential applications in HIV cure.
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Affiliation(s)
- Shijie Cao
- Department of Bioengineering, University of Washington, Seattle, WA 98105, USA
| | - Kim A Woodrow
- Department of Bioengineering, University of Washington, Seattle, WA 98105, USA.
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Nehme Z, Pasquereau S, Herbein G. Control of viral infections by epigenetic-targeted therapy. Clin Epigenetics 2019; 11:55. [PMID: 30917875 PMCID: PMC6437953 DOI: 10.1186/s13148-019-0654-9] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Accepted: 03/13/2019] [Indexed: 12/13/2022] Open
Abstract
Epigenetics is defined as the science that studies the modifications of gene expression that are not owed to mutations or changes in the genetic sequence. Recently, strong evidences are pinpointing toward a solid interplay between such epigenetic alterations and the outcome of human cytomegalovirus (HCMV) infection. Guided by the previous possibly promising experimental trials of human immunodeficiency virus (HIV) epigenetic reprogramming, the latter is paving the road toward two major approaches to control viral gene expression or latency. Reactivating HCMV from the latent phase ("shock and kill" paradigm) or alternatively repressing the virus lytic and reactivation phases ("block and lock" paradigm) by epigenetic-targeted therapy represent encouraging options to overcome latency and viral shedding or otherwise replication and infectivity, which could lead eventually to control the infection and its complications. Not limited to HIV and HCMV, this concept is similarly studied in the context of hepatitis B and C virus, herpes simplex virus, and Epstein-Barr virus. Therefore, epigenetic manipulations stand as a pioneering research area in modern biology and could constitute a curative methodology by potentially consenting the development of broad-spectrum antivirals to control viral infections in vivo.
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Affiliation(s)
- Zeina Nehme
- Department Pathogens & Inflammation-EPILAB, UPRES EA4266, University of Franche-Comté, University of Bourgogne Franche-Comté, 16 route de Gray, F-25030 Besançon cedex, France
- Université Libanaise, Beirut, Lebanon
| | - Sébastien Pasquereau
- Department Pathogens & Inflammation-EPILAB, UPRES EA4266, University of Franche-Comté, University of Bourgogne Franche-Comté, 16 route de Gray, F-25030 Besançon cedex, France
| | - Georges Herbein
- Department Pathogens & Inflammation-EPILAB, UPRES EA4266, University of Franche-Comté, University of Bourgogne Franche-Comté, 16 route de Gray, F-25030 Besançon cedex, France
- Department of Virology, CHRU Besancon, F-25030 Besançon, France
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Abstract
Current primary cell models for HIV latency correlate poorly with the reactivation behavior of patient cells. We have developed a new model, called QUECEL, which generates a large and homogenous population of latently infected CD4+ memory cells. By purifying HIV-infected cells and inducing cell quiescence with a defined cocktail of cytokines, we have eliminated the largest problems with previous primary cell models of HIV latency: variable infection levels, ill-defined polarization states, and inefficient shutdown of cellular transcription. Latency reversal in the QUECEL model by a wide range of agents correlates strongly with RNA induction in patient samples. This scalable and highly reproducible model of HIV latency will permit detailed analysis of cellular mechanisms controlling HIV latency and reactivation. The latent HIV reservoir is generated following HIV infection of activated effector CD4 T cells, which then transition to a memory phenotype. Here, we describe an ex vivo method, called QUECEL (quiescent effector cell latency), that mimics this process efficiently and allows production of large numbers of latently infected CD4+ T cells. Naïve CD4+ T cells were polarized into the four major T cell subsets (Th1, Th2, Th17, and Treg) and subsequently infected with a single-round reporter virus which expressed GFP/CD8a. The infected cells were purified and coerced into quiescence using a defined cocktail of cytokines, including tumor growth factor beta, interleukin-10 (IL-10), and IL-8, producing a homogeneous population of latently infected cells. Flow cytometry and transcriptome sequencing (RNA-Seq) demonstrated that the cells maintained the correct polarization phenotypes and had withdrawn from the cell cycle. Key pathways and gene sets enriched during transition from quiescence to reactivation include E2F targets, G2M checkpoint, estrogen response late gene expression, and c-myc targets. Reactivation of HIV by latency-reversing agents (LRAs) closely mimics RNA induction profiles seen in cells from well-suppressed HIV patient samples using the envelope detection of in vitro transcription sequencing (EDITS) assay. Since homogeneous populations of latently infected cells can be recovered, the QUECEL model has an excellent signal-to-noise ratio and has been extremely consistent and reproducible in numerous experiments performed during the last 4 years. The ease, efficiency, and accuracy of the mimicking of physiological conditions make the QUECEL model a robust and reproducible tool to study the molecular mechanisms underlying HIV latency.
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Abner E, Jordan A. HIV "shock and kill" therapy: In need of revision. Antiviral Res 2019; 166:19-34. [PMID: 30914265 DOI: 10.1016/j.antiviral.2019.03.008] [Citation(s) in RCA: 124] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2018] [Revised: 03/08/2019] [Accepted: 03/17/2019] [Indexed: 01/05/2023]
Abstract
The implementation of antiretroviral therapy 23 years ago has rendered HIV infection clinically manageable. However, the disease remains incurable, since it establishes latent proviral reservoirs, which in turn can stochastically begin reproducing viral particles throughout the patient's lifetime. Viral latency itself depends in large part on the silencing environment of the infected host cell, which can be chemically manipulated. "Shock and kill" therapy intends to reverse proviral quiescence by inducing transcription with pharmaceuticals and allowing a combination of antiretroviral therapy, host immune clearance and HIV-cytolysis to remove latently infected cells, leading to a complete cure. Over 160 compounds functioning as latency-reversing agents (LRAs) have been identified to date, but none of the candidates has yet led to a promising functional cure. Furthermore, fundamental bioinformatic and clinical research from the past decade has highlighted the complexity and highly heterogeneous nature of the proviral reservoirs, shedding doubt on the "shock and kill" concept. Alternative therapies such as the HIV transcription-inhibiting "block and lock" strategy are therefore being considered. In this review we describe the variety of existing classes of LRAs, discuss their current drawbacks and highlight the potential for combinatorial "shocktail" therapies for potent proviral reactivation. We also suggest investigating LRAs with lesser-known mechanisms of action, and examine the feasibility of "block and lock" therapy.
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Affiliation(s)
- Erik Abner
- Molecular Biology Institute of Barcelona (IBMB-CSIC), Barcelona, Spain
| | - Albert Jordan
- Molecular Biology Institute of Barcelona (IBMB-CSIC), Barcelona, Spain.
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Lee SA, Elliott JH, McMahon J, Hartogenesis W, Bumpus NN, Lifson JD, Gorelick RJ, Bacchetti P, Deeks SG, Lewin SR, Savic RM. Population Pharmacokinetics and Pharmacodynamics of Disulfiram on Inducing Latent HIV-1 Transcription in a Phase IIb Trial. Clin Pharmacol Ther 2019; 105:692-702. [PMID: 30137649 PMCID: PMC6379104 DOI: 10.1002/cpt.1220] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Revised: 07/23/2018] [Accepted: 07/30/2018] [Indexed: 11/09/2022]
Abstract
Disulfiram (DSF) was well tolerated and activated viral transcription (cell-associated unspliced (CA-US) and plasma human immunodeficiency virus (HIV) RNA) in a phase II dose-escalation trial in HIV+ antiretroviral therapy (ART)-suppressed participants. Here, we investigated whether exposure to DSF and its metabolites predicted these changes in HIV transcription. Participants were administered 500 (N = 10), 1,000 (N = 10), or 2,000 (N = 10) mg of DSF for 3 consecutive days. DSF and four metabolites were measured by ultraperformance liquid chromatography-tandem mass spectrometry. Changes in CA-US and plasma HIV RNA were quantified by polymerase chain reaction (PCR) and analyzed in NONMEM. A seven-compartment pharmacokinetic (PK) model demonstrated nonlinear elimination kinetics. The fitted median area under the curve values for 72 hours (AUC0-72 ) were 3,816, 8,386, and 22,331 mg*hour/L, respectively. Higher exposure predicted greater increases in CA-US (maximum effect (Emax ) = 78%, AUC50 = 1,600 μg*hour/L, P = 0.013) but not plasma HIV RNA. These results provide support for further development of DSF as an important drug for future HIV cure strategies.
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Affiliation(s)
- Sulggi A. Lee
- University of California San Francisco, Department of Medicine, Division of HIV/AIDS
| | - Julian H. Elliott
- Department of Infectious Diseases, Alfred Hospital and Monash University
| | - James McMahon
- Department of Infectious Diseases, Alfred Hospital and Monash University
| | - Wendy Hartogenesis
- University of California San Francisco, Department of Medicine, Division of HIV/AIDS
| | - Namandje N. Bumpus
- Johns Hopkins University, Department of Pharmacology and Molecular Sciences
| | - Jeffrey D. Lifson
- AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland
| | - Robert J. Gorelick
- AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland
| | - Peter Bacchetti
- University of California San Francisco, Department of Epidemiology and Biostatistics
| | - Steven G. Deeks
- University of California San Francisco, Department of Medicine, Division of HIV/AIDS
| | - Sharon R. Lewin
- Department of Infectious Diseases, Alfred Hospital and Monash University
- The Peter Doherty Institute for Infection and Immunity, The University of Melbourne
| | - Radojka M. Savic
- University of California San Francisco, Department of Bioengineering and Therapeutic Sciences
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Giacomelli A, de Rose S, Rusconi S. Clinical pharmacology in HIV cure research - what impact have we seen? Expert Rev Clin Pharmacol 2019; 12:17-29. [PMID: 30570410 DOI: 10.1080/17512433.2019.1561272] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Introduction: Combined antiretroviral therapy (cART) has transformed an inexorably fatal disease into a chronic pathology, shifting the focus of research from the control of viral replication to the possibility of HIV cure. Areas covered: The present review assesses the principal pharmacological strategies that have been tested for an HIV cure starting from the in vitro proof of concept and the potential rationale of their in vivo applicability. We evaluated the possible pharmacological procedures employed during the early-stage HIV infection and the possibility of cART-free remission. We then analyzed the shock and kill approach from the single compounds in vitro mechanism of action, to the in vivo application of single or combined actions. Finally, we briefly considered the novel immunological branch through the discovery and development of broadly neutralizing antibodies in regard to the current and future in vivo therapeutic strategies aiming to verify the clinical applicability of these compounds. Expert opinion: Despite an incredible effort in HIV research cure, the likelihood of completely eradicating HIV is unreachable within our current knowledge. A better understanding of the mechanism of viral latency and the full characterization of HIV reservoir are crucial for the discovery of new therapeutic targets and novel pharmacological entities.
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Affiliation(s)
- Andrea Giacomelli
- a Infectious Diseases Unit, DIBIC Luigi Sacco , University of Milan , Milan , Italy
| | - Sonia de Rose
- a Infectious Diseases Unit, DIBIC Luigi Sacco , University of Milan , Milan , Italy
| | - Stefano Rusconi
- a Infectious Diseases Unit, DIBIC Luigi Sacco , University of Milan , Milan , Italy
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The BET bromodomain inhibitor apabetalone induces apoptosis of latent HIV-1 reservoir cells following viral reactivation. Acta Pharmacol Sin 2019; 40:98-110. [PMID: 29789664 DOI: 10.1038/s41401-018-0027-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Accepted: 04/06/2018] [Indexed: 12/17/2022]
Abstract
The persistence of latent HIV-1 reservoirs throughout combination antiretroviral therapy (cART) is a major barrier on the path to achieving a cure for AIDS. It has been shown that bromodomain and extra-terminal (BET) inhibitors could reactivate HIV-1 latency, but restrained from clinical application due to their toxicity and side effects. Thus, identifying a new type of BET inhibitor with high degrees of selectivity and safety is urgently needed. Apabetalone is a small-molecule selective BET inhibitor specific for second bromodomains, and has been evaluated in phase III clinical trials that enrolled patients with high-risk cardiovascular disorders, dyslipidemia, and low HDL cholesterol. In the current study, we examined the impact of apabetalone on HIV-1 latency. We showed that apabetalone (10-50 μmol/L) dose-dependently reactivated latent HIV-1 in 4 types of HIV-1 latency cells in vitro and in primary human CD4+ T cells ex vivo. In ACH2 cells, we further demonstrated that apabetalone activated latent HIV-1 through Tat-dependent P-TEFB pathway, i.e., dissociating bromodomain 4 (BDR4) from the HIV-1 promoter and recruiting Tat for stimulating HIV-1 elongation. Furthermore, we showed that apabetalone (10-30 μmol/L) caused dose-dependent cell cycle arrest at the G1/G0 phase in ACH2 cells, and thereby induced the preferential apoptosis of HIV-1 latent cells to promote the death of reactivated reservoir cells. Notably, cardiovascular diseases and low HDL cholesterol are known as the major side effects of cART, which should be prevented by apabetalone. In conclusion, apabetalone should be an ideal bifunctional latency-reversing agent for advancing HIV-1 eradication and reducing the side effects of BET inhibitors.
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Jean MJ, Fiches G, Hayashi T, Zhu J. Current Strategies for Elimination of HIV-1 Latent Reservoirs Using Chemical Compounds Targeting Host and Viral Factors. AIDS Res Hum Retroviruses 2019; 35:1-24. [PMID: 30351168 DOI: 10.1089/aid.2018.0153] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Since the implementation of combination antiretroviral therapy (cART), rates of HIV type 1 (HIV-1) mortality, morbidity, and newly acquired infections have decreased dramatically. In fact, HIV-1-infected individuals under effective suppressive cART approach normal life span and quality of life. However, long-term therapy is required because the virus establish a reversible state of latency in memory CD4+ T cells. Two principle strategies, namely "shock and kill" approach and "block and lock" approach, are currently being investigated for the eradication of these HIV-1 latent reservoirs. Actually, both of these contrasting approaches are based on the use of small-molecule compounds to achieve the cure for HIV-1. In this review, we discuss the recent progress that has been made in designing and developing small-molecule compounds for both strategies.
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Affiliation(s)
- Maxime J. Jean
- Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York
| | - Guillaume Fiches
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, Ohio
| | - Tsuyoshi Hayashi
- National Institute of Biomedical Innovation, Health and Nutrition, Osaka, Japan
| | - Jian Zhu
- Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, Ohio
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Ke R, Conway JM, Margolis DM, Perelson AS. Determinants of the efficacy of HIV latency-reversing agents and implications for drug and treatment design. JCI Insight 2018; 3:123052. [PMID: 30333308 DOI: 10.1172/jci.insight.123052] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Accepted: 08/30/2018] [Indexed: 11/17/2022] Open
Abstract
HIV eradication studies have focused on developing latency-reversing agents (LRAs). However, it is not understood how the rate of latent reservoir reduction is affected by different steps in the process of latency reversal. Furthermore, as current LRAs are host-directed, LRA treatment is likely to be intermittent to avoid host toxicities. Few careful studies of the serial effects of pulsatile LRA treatment have yet been done. This lack of clarity makes it difficult to evaluate the efficacy of candidate LRAs or predict long-term treatment outcomes. We constructed a mathematical model that describes the dynamics of latently infected cells under LRA treatment. Model analysis showed that, in addition to increasing the immune recognition and clearance of infected cells, the duration of HIV antigen expression (i.e., the period of vulnerability) plays an important role in determining the efficacy of LRAs, especially if effective clearance is achieved. Patients may benefit from pulsatile LRA exposures compared with continuous LRA exposures if the period of vulnerability is long and the clearance rate is high, both in the presence and absence of an LRA. Overall, the model framework serves as a useful tool to evaluate the efficacy and the rational design of LRAs and combination strategies.
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Affiliation(s)
- Ruian Ke
- Department of Mathematics, North Carolina State University, Raleigh, North Carolina, USA.,Theoretical Biology and Biophysics Group, MS-K710, Los Alamos National Laboratory, Los Alamos, New Mexico, USA
| | - Jessica M Conway
- Department of Mathematics and Center for Infectious Disease Dynamics, Pennsylvania State University, State College, Pennsylvania, USA
| | - David M Margolis
- University of North Carolina (UNC) HIV Cure Center, UNC Institute of Global Health and Infectious Diseases.,Departments of Medicine, Microbiology and Immunology, UNC Chapel Hill School of Medicine, and.,Department of Epidemiology, UNC Chapel Hill School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Alan S Perelson
- Theoretical Biology and Biophysics Group, MS-K710, Los Alamos National Laboratory, Los Alamos, New Mexico, USA
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Castro-Gonzalez S, Colomer-Lluch M, Serra-Moreno R. Barriers for HIV Cure: The Latent Reservoir. AIDS Res Hum Retroviruses 2018; 34:739-759. [PMID: 30056745 PMCID: PMC6152859 DOI: 10.1089/aid.2018.0118] [Citation(s) in RCA: 78] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Thirty-five years after the identification of HIV-1 as the causative agent of AIDS, we are still in search of vaccines and treatments to eradicate this devastating infectious disease. Progress has been made in understanding the molecular pathogenesis of this infection, which has been crucial for the development of the current therapy regimens. However, despite their efficacy at limiting active viral replication, these drugs are unable to purge the latent reservoir: a pool of cells that harbor transcriptionally inactive, but replication-competent HIV-1 proviruses, and that represent the main barrier to eradicate HIV-1 from affected individuals. In this review, we discuss advances in the field that have allowed a better understanding of HIV-1 latency, including the diverse cell types that constitute the latent reservoir, factors influencing latency, tools to study HIV-1 latency, as well as current and prospective therapeutic approaches to target these latently infected cells, so a functional cure for HIV/AIDS can become a reality.
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Affiliation(s)
- Sergio Castro-Gonzalez
- Department of Biological Sciences, College of Arts and Sciences, Texas Tech University, Lubbock, Texas
| | - Marta Colomer-Lluch
- IrsiCaixa AIDS Research Institute, Hospital Germans Trias i Pujol, Badalona, Spain
| | - Ruth Serra-Moreno
- Department of Biological Sciences, College of Arts and Sciences, Texas Tech University, Lubbock, Texas
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46
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Abstract
Despite the success of antiretroviral therapy (ART), there is currently no HIV cure and treatment is life long. HIV persists during ART due to long-lived and proliferating latently infected CD4+ T cells. One strategy to eliminate latency is to activate virus production using latency reversing agents (LRAs) with the goal of triggering cell death through virus-induced cytolysis or immune-mediated clearance. However, multiple studies have demonstrated that activation of viral transcription alone is insufficient to induce cell death and some LRAs may counteract cell death by promoting cell survival. Here, we review new approaches to induce death of latently infected cells through apoptosis and inhibition of pathways critical for cell survival, which are often hijacked by HIV proteins. Given advances in the commercial development of compounds that induce apoptosis in cancer chemotherapy, these agents could move rapidly into clinical trials, either alone or in combination with LRAs, to eliminate latent HIV infection.
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47
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Jin S, Liao Q, Chen J, Zhang L, He Q, Zhu H, Zhang X, Xu J. TSC1 and DEPDC5 regulate HIV-1 latency through the mTOR signaling pathway. Emerg Microbes Infect 2018; 7:138. [PMID: 30087333 PMCID: PMC6081400 DOI: 10.1038/s41426-018-0139-5] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2018] [Revised: 06/14/2018] [Accepted: 06/23/2018] [Indexed: 01/10/2023]
Abstract
The latent reservoir of HIV-1 presents a major barrier to viral eradication. The mechanism of the establishment and maintenance of the latent viral reservoir is not yet fully understood, which hinders the development of effective curative strategies. In this study, we identified two inhibitory genes, TSC1 and DEPDC5, that maintained HIV-1 latency by suppressing the mTORC1 pathway. We first adapted a genome-wide CRISPR screening approach to identify host factors required for HIV latency in a T-cell-based latency model and discovered two inhibitory genes, TSC1 and DEPDC5, which are potentially involved in HIV-1 latency. Knockout of either TSC1 or DEPDC5 led to enhanced HIV-1 reactivation in both a T-cell line (C11) and a monocyte cell line (U1), and this enhancement could be antagonized by the mTORC1 inhibitor rapamycin. Further evaluation of the mechanism revealed that TSC1 suppresses AKT-mTORC1-S6 via downregulation of Rheb, whereas DEPDC5 inhibits AKT-mTORC1-S6 through RagA. Overall, both TSC1 and DEPDC5 negatively regulate the AKT-mTORC1 pathway, and thus their agonists could be used in the development of new therapeutic approaches for activating HIV-1 latency.
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Affiliation(s)
- Shan Jin
- Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Key Laboratory of Medical Molecular Virology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Qibin Liao
- Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Key Laboratory of Medical Molecular Virology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jian Chen
- Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Key Laboratory of Medical Molecular Virology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Linxia Zhang
- Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Key Laboratory of Medical Molecular Virology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Qian He
- Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Key Laboratory of Medical Molecular Virology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Huanzhang Zhu
- State Key Laboratory of Genetic Engineering and Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, School of Life Sciences, Fudan University, Shanghai, China
| | - Xiaoyan Zhang
- Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Key Laboratory of Medical Molecular Virology, Shanghai Medical College, Fudan University, Shanghai, China.
| | - Jianqing Xu
- Shanghai Public Health Clinical Center and Institutes of Biomedical Sciences, Key Laboratory of Medical Molecular Virology, Shanghai Medical College, Fudan University, Shanghai, China. .,State Key Laboratory for Infectious Disease Prevention and Control, China Centers for Disease Control and Prevention, Beijing, China.
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48
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Lim SY, Osuna CE, Hraber PT, Hesselgesser J, Gerold JM, Barnes TL, Sanisetty S, Seaman MS, Lewis MG, Geleziunas R, Miller MD, Cihlar T, Lee WA, Hill AL, Whitney JB. TLR7 agonists induce transient viremia and reduce the viral reservoir in SIV-infected rhesus macaques on antiretroviral therapy. Sci Transl Med 2018; 10:eaao4521. [PMID: 29720451 PMCID: PMC5973480 DOI: 10.1126/scitranslmed.aao4521] [Citation(s) in RCA: 124] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Accepted: 12/19/2017] [Indexed: 12/18/2022]
Abstract
Antiretroviral therapy (ART) can halt HIV-1 replication but fails to target the long-lived latent viral reservoir. Several pharmacological compounds have been evaluated for their ability to reverse HIV-1 latency, but none has demonstrably reduced the latent HIV-1 reservoir or affected viral rebound after the interruption of ART. We evaluated orally administered selective Toll-like receptor 7 (TLR7) agonists GS-986 and GS-9620 for their ability to induce transient viremia in rhesus macaques infected with simian immunodeficiency virus (SIV) and treated with suppressive ART. In an initial dose-escalation study, and a subsequent dose-optimization study, we found that TLR7 agonists activated multiple innate and adaptive immune cell populations in addition to inducing expression of SIV RNA. We also observed TLR7 agonist-induced reductions in SIV DNA and measured inducible virus from treated animals in ex vivo cell cultures. In a second study, after stopping ART, two of nine treated animals remained aviremic for more than 2 years, even after in vivo CD8+ T cell depletion. Moreover, adoptive transfer of cells from aviremic animals could not induce de novo infection in naïve recipient macaques. These findings suggest that TLR7 agonists may facilitate reduction of the viral reservoir in a subset of SIV-infected rhesus macaques.
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Affiliation(s)
- So-Yon Lim
- Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Christa E Osuna
- Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Peter T Hraber
- Los Alamos National Laboratory, Los Alamos, NM 87545, USA
| | | | - Jeffrey M Gerold
- Program for Evolutionary Dynamics, Harvard University, Cambridge, MA 02138, USA
| | | | - Srisowmya Sanisetty
- Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Michael S Seaman
- Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | | | | | | | - Tomas Cihlar
- Gilead Sciences Inc., Foster City, CA 94404, USA
| | | | - Alison L Hill
- Program for Evolutionary Dynamics, Harvard University, Cambridge, MA 02138, USA
| | - James B Whitney
- Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
- Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Cambridge, MA 02139, USA
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49
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Tang X, Lu H, Dooner M, Chapman S, Quesenberry PJ, Ramratnam B. Exosomal Tat protein activates latent HIV-1 in primary, resting CD4+ T lymphocytes. JCI Insight 2018; 3:95676. [PMID: 29618654 DOI: 10.1172/jci.insight.95676] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Accepted: 02/28/2018] [Indexed: 01/19/2023] Open
Abstract
Replication competent HIV-1 persists in a subpopulation of CD4+ T lymphocytes despite prolonged antiretroviral treatment. This residual reservoir of infected cells harbors transcriptionally silent provirus capable of reigniting productive infection upon discontinuation of antiretroviral therapy. Certain classes of drugs can activate latent virus but not at levels that lead to reductions in HIV-1 reservoir size in vivo. Here, we show the utility of CD4+ receptor targeting exosomes as an HIV-1 latency reversal agent (LRA). We engineered human cellular exosomes to express HIV-1 Tat, a protein that is a potent transactivator of viral transcription. Preparations of exosomal Tat-activated HIV-1 in primary, resting CD4+ T lymphocytes isolated from antiretroviral-treated individuals with prolonged periods of viral suppression and led to the production of replication competent HIV-1. Furthermore, exosomal Tat increased the potency of selected LRA by over 30-fold in terms of HIV-1 mRNA expression, thereby establishing it as a potentially new class of biologic product with possible combinatorial utility in targeting latent HIV-1.
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Affiliation(s)
| | | | - Mark Dooner
- Division of Hematology and Oncology, Department of Medicine, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA
| | - Stacey Chapman
- Center for AIDS Research, The Miriam Hospital, Providence, Rhode Island, USA
| | - Peter J Quesenberry
- Division of Hematology and Oncology, Department of Medicine, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA
| | - Bharat Ramratnam
- Division of Infectious Diseases and.,Lifespan Clinical Research Center, Providence, Rhode Island, USA.,COBRE Center for Cancer Research Development, Rhode Island Hospital, Providence, Rhode Island, USA
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The role of latency reversal agents in the cure of HIV: A review of current data. Immunol Lett 2018; 196:135-139. [PMID: 29427743 DOI: 10.1016/j.imlet.2018.02.004] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Accepted: 02/06/2018] [Indexed: 02/05/2023]
Abstract
The definitive cure for human immunodeficiency virus type-1 (HIV) infection is represented by the eradication of the virus from the patient's body. To reach this result, cells that are infected but do not produce the virus must become recognizable to be killed by the immune system. For this purpose, drugs defined "latency reverting agents" (LRA) that reactivate viral production are under investigation. A few clinical studies have been performed in HIV-infected patients treated with LRA and combined antiretroviral therapy (cART). The strategy is thus to combine cART and LRA to reactivate the virus and unmask latently infected cells that, because of cART, cannot produce a fully competent form of the virus. Unmasked cells can present viral antigens to the immune system, that ultimately recognizes and kills such latently infected cells. This review reports and discusses recent studies that have been published on this topic.
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