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Guo Y, Liu H, Chen B, Zhang K, Meng L, Yan L, Niu Q, Zhang J, Yin G, Li Y. Dysregulated CD38 expression on T cells was associated with rapidly progressive interstitial lung disease in anti-melanoma differentiation-associated gene 5 positive dermatomyositis. Front Immunol 2024; 15:1455944. [PMID: 39588376 PMCID: PMC11586385 DOI: 10.3389/fimmu.2024.1455944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Accepted: 10/25/2024] [Indexed: 11/27/2024] Open
Abstract
Background Anti-melanoma differentiation-associated gene 5 positive dermatomyositis (MDA5+ DM) is a life-threatening disease due to rapidly progressive interstitial lung disease (RP-ILD). We aimed to investigate the expression profile of T cell subsets in MDA5+ DM patients, seeking for possible disease-causing T cell subsets and potential biomarkers to distinguish ILD, especially RP-ILD patients. Methods Peripheral blood T cell subpopulations were immunophenotyped in 24 MDA5+ DM patients and 21 healthy controls (HCs) by flow cytometry. The proportion of T cell subsets and clinical characteristics were analyzed. The quantitative determination of cytokines in the plasma was measured by using a microsphere-based immunofluorescence assaying kit. Results The proportion of naïve and CD38+ T cells were much higher, whereas the proportion of central memory T cells were lower in MDA5+ DM patients than in HCs. Notably, the proportion of CD38+CD4+ T cells and CD38+CD8+ T cells on T cells in in RP-ILD group were significantly elevated compared to C-ILD, non-ILD group and HCs. Moreover, serum IFN-α levels were significantly increased in MDA5+ DM patients with RP-ILD. Further, the frequencies of CD38+CD4+ T cells and CD38+CD8+ T cells were positively correlated with IFN-α levels. Finally, ROC analysis indicated that CD38+CD4+ T cells and CD38+CD8+ T cells could be potential biomarkers for predicting ILD/RP-ILD in MDA5+ DM patients. Conclusion Dysregulated CD38 expression on T cell subsets was associated with lung involvement, especially RP-ILD in MDA5+ DM patients. CD38+ T cell subsets could be used as potential biomarkers for predicting ILD/RP-ILD in MDA5+ DM patients.
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Affiliation(s)
- Yixue Guo
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
- Sichuan Clinical Research Center for Laboratory Medicine, Chengdu, China
- Clinical Laboratory Medicine Research Center of West China Hospital, Chengdu, China
| | - Hongjiang Liu
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, China
| | - Bo Chen
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, China
| | - Keyi Zhang
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
- Sichuan Clinical Research Center for Laboratory Medicine, Chengdu, China
- Clinical Laboratory Medicine Research Center of West China Hospital, Chengdu, China
| | - Liye Meng
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
- Sichuan Clinical Research Center for Laboratory Medicine, Chengdu, China
- Clinical Laboratory Medicine Research Center of West China Hospital, Chengdu, China
| | - Lin Yan
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
- Sichuan Clinical Research Center for Laboratory Medicine, Chengdu, China
- Clinical Laboratory Medicine Research Center of West China Hospital, Chengdu, China
| | - Qian Niu
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
- Sichuan Clinical Research Center for Laboratory Medicine, Chengdu, China
- Clinical Laboratory Medicine Research Center of West China Hospital, Chengdu, China
| | - Junlong Zhang
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
- Sichuan Clinical Research Center for Laboratory Medicine, Chengdu, China
- Clinical Laboratory Medicine Research Center of West China Hospital, Chengdu, China
| | - Geng Yin
- Health Management Center, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yi Li
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China
- Sichuan Clinical Research Center for Laboratory Medicine, Chengdu, China
- Clinical Laboratory Medicine Research Center of West China Hospital, Chengdu, China
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Basova LV, Lindsey A, McGovern A, Rosander A, Delorme-Walker V, ElShamy WM, Pendyala VV, Gaskill PJ, Ellis RJ, Cherner M, Iudicello JE, Marcondes MCG. MRP8/14 Is a Molecular Signature Triggered by Dopamine in HIV Latent Myeloid Targets That Increases HIV Transcription and Distinguishes HIV+ Methamphetamine Users with Detectable CSF Viral Load and Brain Pathology. Viruses 2023; 15:1363. [PMID: 37376663 PMCID: PMC10304659 DOI: 10.3390/v15061363] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 06/01/2023] [Accepted: 06/08/2023] [Indexed: 06/29/2023] Open
Abstract
There is a significant overlap between HIV infection and substance-use disorders. Dopamine (DA) is the most abundantly upregulated neurotransmitter in methamphetamine abuse, with receptors (DRD1-5) that are expressed by neurons as well as by a large diversity of cell types, including innate immune cells that are the targets of HIV infection, making them responsive to the hyperdopaminergic environment that is characteristic of stimulant drugs. Therefore, the presence of high levels of dopamine may affect the pathogenesis of HIV, particularly in the brain. The stimulation of HIV latently infected U1 promonocytes with DA significantly increased viral p24 levels in the supernatant at 24 h, suggesting effects on activation and replication. Using selective agonists to different DRDs, we found that DRD1 played a major role in activating viral transcription, followed by DRD4, which increased p24 with a slower kinetic rate compared to DRD1. Transcriptome and systems biology analyses led to the identification of a cluster of genes responsive to DA, where S100A8 and S100A9 were most significantly correlated with the early increase in p24 levels following DA stimulation. Conversely, DA increased the expression of these genes' transcripts at the protein level, MRP8 and MRP14, respectively, which form a complex also known as calprotectin. Interestingly, MRP8/14 was able to stimulate HIV transcription in latent U1 cells, and this occurred via binding of the complex to the receptor for an advanced glycosylation end-product (RAGE). Using selective agonists, both DRD1 and DRD4 increased MRP8/14 on the surface, in the cytoplasm, as well as secreted in the supernatants. On the other hand, while DRD1/5 did not affect the expression of RAGE, DRD4 stimulation caused its downregulation, offering a mechanism for the delayed effect via DRD4 on the p24 increase. To cross-validate MRP8/14 as a DA signature with a biomarker value, we tested its expression in HIV+ Meth users' postmortem brain specimens and peripheral cells. MRP8/14+ cells were more frequently identified in mesolimbic areas such as the basal ganglia of HIV+ Meth+ cases compared to HIV+ non-Meth users or to controls. Likewise, MRP8/14+ CD11b+ monocytes were more frequent in HIV+ Meth users, particularly in specimens from participants with a detectable viral load in the CSF. Overall, our results suggest that the MRP8 and MRP14 complex may serve as a signature to distinguish subjects using addictive substances in the context of HIV, and that this may play a role in aggravating HIV pathology by promoting viral replication in people with HIV who use Meth.
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Affiliation(s)
- Liana V. Basova
- San Diego Biomedical Research Institute, San Diego, CA 92121, USA
| | | | | | - Ashley Rosander
- San Diego Biomedical Research Institute, San Diego, CA 92121, USA
- Human Biology Program BISP, University of California San Diego, San Diego, CA 92037, USA
| | | | - Wael M. ElShamy
- San Diego Biomedical Research Institute, San Diego, CA 92121, USA
| | | | | | - Ronald J. Ellis
- HIV Neurobehavioral Research Program, University of California San Diego, San Diego, CA 92103, USA
| | - Mariana Cherner
- HIV Neurobehavioral Research Program, University of California San Diego, San Diego, CA 92103, USA
| | - Jennifer E. Iudicello
- HIV Neurobehavioral Research Program, University of California San Diego, San Diego, CA 92103, USA
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CD38: An important regulator of T cell function. Biomed Pharmacother 2022; 153:113395. [PMID: 35834988 DOI: 10.1016/j.biopha.2022.113395] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 07/03/2022] [Accepted: 07/07/2022] [Indexed: 11/23/2022] Open
Abstract
Cluster of differentiation 38 (CD38) is a multifunctional extracellular enzyme on the cell surface with NADase and cyclase activities. CD38 is not only expressed in human immune cells, such as lymphocytes and plasma cells, but also is abnormally expressed in a variety of tumor cells, which is closely related to the occurrence and development of tumors. T cells are one of the important immune cells in the body. As NAD consuming enzymes, CD38, ART2, SIRT1 and PARP1 are closely related to the number and function of T cells. CD38 may also influence the activity of ART2, SIRT1 and PARP1 through the CD38-NAD+ axis to indirectly affect the number and function of T cells. Thus, CD38-NAD+ axis has a profound effect on T cell activity. In this paper, we reviewed the role and mechanism of CD38+ CD4+ T cells / CD38+ CD8+ T cells in cellular immunity and the effects of the CD38-NAD+ axis on T cell activity. We also summarized the relationship between the CD38 expression level on T cell surface and disease prediction and prognosis, the effects of anti-CD38 monoclonal antibodies on T cell activity and function, and the role of anti-CD38 chimeric antigen receptor (CAR) T cell therapy in tumor immunity. This will provide an important theoretical basis for a comprehensive understanding of the relationship between CD38 and T cells.
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Glaría E, Valledor AF. Roles of CD38 in the Immune Response to Infection. Cells 2020; 9:cells9010228. [PMID: 31963337 PMCID: PMC7017097 DOI: 10.3390/cells9010228] [Citation(s) in RCA: 93] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 01/12/2020] [Accepted: 01/14/2020] [Indexed: 12/13/2022] Open
Abstract
CD38 is a multifunctional protein widely expressed in cells from the immune system and as a soluble form in biological fluids. CD38 expression is up-regulated by an array of inflammatory mediators, and it is frequently used as a cell activation marker. Studies in animal models indicate that CD38 functional expression confers protection against infection by several bacterial and parasitic pathogens. In addition, infectious complications are associated with anti-CD38 immunotherapy. Although CD38 displays receptor and enzymatic activities that contribute to the establishment of an effective immune response, recent work raises the possibility that CD38 might also enhance the immunosuppressive potential of regulatory leukocytes. This review integrates the current knowledge on the diversity of functions mediated by CD38 in the host defense to infection.
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Vitamin D treatment of peripheral blood mononuclear cells modulated immune activation and reduced susceptibility to HIV-1 infection of CD4+ T lymphocytes. PLoS One 2019; 14:e0222878. [PMID: 31550271 PMCID: PMC6759150 DOI: 10.1371/journal.pone.0222878] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Accepted: 09/09/2019] [Indexed: 01/16/2023] Open
Abstract
INTRODUCTION Mucosal immune activation, in the context of sexual transmission of HIV-1 infection, is crucial, as the increased presence of activated T cells enhance susceptibility to infection. In this regard, it has been proposed that immunomodulatory compounds capable of modulating immune activation, such as Vitamin D (VitD) may reduce HIV-1 transmission and might be used as a safe and cost-effective strategy for prevention. Considering this, we examined the in vitro effect of the treatment of peripheral blood mononuclear cells (PBMCs) with the active form of VitD, calcitriol, on cellular activation, function and susceptibility of CD4+ T cells to HIV-1 infection. METHODS We treated PBMCs from healthy HIV unexposed individuals (Co-HC) and frequently exposed, HIV-1 seronegative individuals (HESNs) from Colombia and from healthy non-exposed individuals from Canada (Ca-HC) with calcitriol and performed in vitro HIV-1 infection assays using X4- and R5-tropic HIV-1 strains respectively. In addition, we evaluated the activation and function of T cells and the expression of viral co-receptors, and select antiviral genes following calcitriol treatment. RESULTS Calcitriol reduced the frequency of infected CD4+ T cells and the number of viral particles per cell, for both, X4- and R5-tropic viruses tested in the Co-HC and the Ca-HC, respectively, but not in HESNs. Furthermore, in the Co-HC, calcitriol reduced the frequency of polyclonally activated T cells expressing the activation markers HLA-DR and CD38, and those HLA-DR+CD38-, whereas increased the subpopulation HLA-DR-CD38+. Calcitriol treatment also decreased production of granzyme, IL-2 and MIP-1β by T cells and increased the transcriptional expression of the inhibitor of NF-kB and the antiviral genes cathelicidin (CAMP) and APOBEC3G in PBMCs from Co-HC. CONCLUSION Our in vitro findings suggest that VitD treatment could reduce HIV-1 transmission through a specific modulation of the activation levels and function of T cells, and the production of antiviral factors. In conclusion, VitD remains as an interesting potential strategy to prevent HIV-1 transmission that should be further explored.
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Wagner DR, Karnik S, Gunderson ZJ, Nielsen JJ, Fennimore A, Promer HJ, Lowery JW, Loghmani MT, Low PS, McKinley TO, Kacena MA, Clauss M, Li J. Dysfunctional stem and progenitor cells impair fracture healing with age. World J Stem Cells 2019; 11:281-296. [PMID: 31293713 PMCID: PMC6600851 DOI: 10.4252/wjsc.v11.i6.281] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 04/26/2019] [Accepted: 06/13/2019] [Indexed: 02/06/2023] Open
Abstract
Successful fracture healing requires the simultaneous regeneration of both the bone and vasculature; mesenchymal stem cells (MSCs) are directed to replace the bone tissue, while endothelial progenitor cells (EPCs) form the new vasculature that supplies blood to the fracture site. In the elderly, the healing process is slowed, partly due to decreased regenerative function of these stem and progenitor cells. MSCs from older individuals are impaired with regard to cell number, proliferative capacity, ability to migrate, and osteochondrogenic differentiation potential. The proliferation, migration and function of EPCs are also compromised with advanced age. Although the reasons for cellular dysfunction with age are complex and multidimensional, reduced expression of growth factors, accumulation of oxidative damage from reactive oxygen species, and altered signaling of the Sirtuin-1 pathway are contributing factors to aging at the cellular level of both MSCs and EPCs. Because of these geriatric-specific issues, effective treatment for fracture repair may require new therapeutic techniques to restore cellular function. Some suggested directions for potential treatments include cellular therapies, pharmacological agents, treatments targeting age-related molecular mechanisms, and physical therapeutics. Advanced age is the primary risk factor for a fracture, due to the low bone mass and inferior bone quality associated with aging; a better understanding of the dysfunctional behavior of the aging cell will provide a foundation for new treatments to decrease healing time and reduce the development of complications during the extended recovery from fracture healing in the elderly.
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Affiliation(s)
- Diane R Wagner
- Department of Mechanical and Energy Engineering, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, United States
| | - Sonali Karnik
- Department of Mechanical and Energy Engineering, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, United States
| | - Zachary J Gunderson
- Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Jeffery J Nielsen
- Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, United States
| | - Alanna Fennimore
- Department of Physical Therapy, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, United States
| | - Hunter J Promer
- Division of Biomedical Science, Marian University College of Osteopathic Medicine, Indianapolis, IN 46222, United States
| | - Jonathan W Lowery
- Division of Biomedical Science, Marian University College of Osteopathic Medicine, Indianapolis, IN 46222, United States
| | - M Terry Loghmani
- Department of Physical Therapy, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, United States
| | - Philip S Low
- Department of Chemistry, Purdue University, West Lafayette, IN 47907 United States
| | - Todd O McKinley
- Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Melissa A Kacena
- Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, United States
- Richard L. Roudebush VA Medical Center, Indianapolis, IN 46202, United States
| | - Matthias Clauss
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Jiliang Li
- Department of Biology, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, United States
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Ge Y, Long Y, Xiao S, Liang L, He Z, Yue C, Wei X, Zhou Y. CD38 affects the biological behavior and energy metabolism of nasopharyngeal carcinoma cells. Int J Oncol 2018; 54:585-599. [PMID: 30535454 PMCID: PMC6317656 DOI: 10.3892/ijo.2018.4651] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Accepted: 10/12/2018] [Indexed: 02/07/2023] Open
Abstract
Nasopharyngeal carcinoma (NPC) is the most common malignant tumor type in Southern China and South-East Asia. Cluster of differentiation (CD)38 is highly expressed in the human immune system and participates in the activation of T, natural killer and plasma cells mediated by CD2 and CD3 through synergistic action. CD38 is a type II transmembrane glycoprotein, which was observed to mediate diverse activities, including signal transduction, cell adhesion and cyclic ADP-ribose synthesis. However, the significance of CD38 in NPC biological behavior and cellular energy metabolism has not been examined. In order to elucidate the effect of CD38 on the biological behavior of NPC cells, stable CD38-overexpressed NPC cell lines were established. It was demonstrated that CD38 promoted NPC cell proliferation with Cell Counting Kit-8 and colony formation assays. It was also indicated that CD38 inhibited cell senescence, and promoted cell metastasis. Furthermore, it was determined that CD38 promoted the conversion of cells to the S phase and decreased the content of reactive oxygen species and Ca2+. Additionally, cell metabolism assays demonstrated that CD38 increased the concentration of ATP, lactic acid, cyclic adenosine monophosphate and human ADP/acrp30 concentration in NPC cells. To investigate the possible mechanism, bioinformatics analysis and mass spectrometry technology was used to determine the most notably changing molecule and signaling pathways, and it was determined and verified that CD38 regulated the metabolic-associated signaling pathways associated with tumor protein 53, hypoxia inducible factor-1α and sirtuin 1. The present results indicated that CD38 may serve a carcinogenic role in NPC by regulating metabolic-associated signaling pathways.
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Affiliation(s)
- Yanshan Ge
- Department of Oncology, Hunan Provincial Tumor Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan 410006, P.R. China
| | - Yuehua Long
- Department of Oncology, Hunan Provincial Tumor Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan 410006, P.R. China
| | - Songshu Xiao
- Department of Gynecology and Obstetrics, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410078, P.R. China
| | - Lin Liang
- Department of Oncology, Hunan Provincial Tumor Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan 410006, P.R. China
| | - Zhengxi He
- Department of Oncology, Hunan Provincial Tumor Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan 410006, P.R. China
| | - Chunxue Yue
- Department of Oncology, Hunan Provincial Tumor Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan 410006, P.R. China
| | - Xiong Wei
- Department of Oncology, Hunan Provincial Tumor Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan 410006, P.R. China
| | - Yanhong Zhou
- Department of Oncology, Hunan Provincial Tumor Hospital, Xiangya School of Medicine, Central South University, Changsha, Hunan 410006, P.R. China
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Abstract
BACKGROUND Although the anti-HIV-1 effects of vitamin D (VitD) have been reported, mechanisms behind such protection remain largely unexplored. METHODS The effects of two precursor forms (cholecalciferol/calciol at 0.01, 1 and 100 nM and calcidiol at 100 and 250 nM) on HIV-1 infection, immune activation, and gene expression were analyzed in vitro in cells of Colombian and Italian healthy donors. We quantified levels of released p24 by enzyme-linked immunosorbent assay, of intracellular p24 and cell-surface expression of CD38 and HLA-DR by flow cytometry, and mRNA expression of antiviral and immunoregulatory genes by real-time reverse transcription-polymerase chain reaction. RESULTS Cholecalciferol decreased the frequency of HIV-1-infected p24CD4 T cells and levels of p24 in supernatants in a dose-dependent manner. Moreover, the CD4CD38HLA-DR and CD4CD38HLA-DR subpopulations were more susceptible to infection but displayed the greatest cholecalciferol-induced decreases in infection rate by an X4-tropic strain. Likewise, cholecalciferol at its highest concentration decreased the frequency of CD38HLA-DR but not of CD38HLA-DR T-cell subsets. Analyzing the effects of calcidiol, the main VitD source for immune cells and an R5-tropic strain as the most frequently transmitted virus, a reduction in HIV-1 productive infection was also observed. In addition, an increase in mRNA expression of APOBEC3G and PI3 and a reduction of TRIM22 and CCR5 expression, this latter positively correlated with p24 levels, was noted. CONCLUSIONS VitD reduces HIV-1 infection in T cells possibly by inducing antiviral gene expression, reducing the viral co-receptor CCR5 and, at least at the highest cholecalciferol concentration, by promoting an HIV-1-restrictive CD38HLA-DR immunophenotype.
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Ensoli B, Bellino S, Tripiciano A, Longo O, Francavilla V, Marcotullio S, Cafaro A, Picconi O, Paniccia G, Scoglio A, Arancio A, Ariola C, Ruiz Alvarez MJ, Campagna M, Scaramuzzi D, Iori C, Esposito R, Mussini C, Ghinelli F, Sighinolfi L, Palamara G, Latini A, Angarano G, Ladisa N, Soscia F, Mercurio VS, Lazzarin A, Tambussi G, Visintini R, Mazzotta F, Di Pietro M, Galli M, Rusconi S, Carosi G, Torti C, Di Perri G, Bonora S, Ensoli F, Garaci E. Therapeutic immunization with HIV-1 Tat reduces immune activation and loss of regulatory T-cells and improves immune function in subjects on HAART. PLoS One 2010; 5:e13540. [PMID: 21085635 PMCID: PMC2978690 DOI: 10.1371/journal.pone.0013540] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2010] [Accepted: 09/28/2010] [Indexed: 11/18/2022] Open
Abstract
Although HAART suppresses HIV replication, it is often unable to restore immune homeostasis. Consequently, non-AIDS-defining diseases are increasingly seen in treated individuals. This is attributed to persistent virus expression in reservoirs and to cell activation. Of note, in CD4+ T cells and monocyte-macrophages of virologically-suppressed individuals, there is continued expression of multi-spliced transcripts encoding HIV regulatory proteins. Among them, Tat is essential for virus gene expression and replication, either in primary infection or for virus reactivation during HAART, when Tat is expressed, released extracellularly and exerts, on both the virus and the immune system, effects that contribute to disease maintenance. Here we report results of an ad hoc exploratory interim analysis (up to 48 weeks) on 87 virologically-suppressed HAART-treated individuals enrolled in a phase II randomized open-label multicentric clinical trial of therapeutic immunization with Tat (ISS T-002). Eighty-eight virologically-suppressed HAART-treated individuals, enrolled in a parallel prospective observational study at the same sites (ISS OBS T-002), served for intergroup comparison. Immunization with Tat was safe, induced durable immune responses, and modified the pattern of CD4+ and CD8+ cellular activation (CD38 and HLA-DR) together with reduction of biochemical activation markers and persistent increases of regulatory T cells. This was accompanied by a progressive increment of CD4+ T cells and B cells with reduction of CD8+ T cells and NK cells, which were independent from the type of antiretroviral regimen. Increase in central and effector memory and reduction in terminally-differentiated effector memory CD4+ and CD8+ T cells were accompanied by increases of CD4+ and CD8+ T cell responses against Env and recall antigens. Of note, more immune-compromised individuals experienced greater therapeutic effects. In contrast, these changes were opposite, absent or partial in the OBS population. These findings support the use of Tat immunization to intensify HAART efficacy and to restore immune homeostasis.
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Affiliation(s)
- Barbara Ensoli
- National AIDS Center, Istituto Superiore di Sanità, Rome, Italy.
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Bensi T, Mele F, Ferretti M, Norelli S, El Daker S, Chiocchetti A, Maria Rojo J, Cauda R, Dianzani U, Savarino A. Evaluation of the antiretroviral effects of a PEG-conjugated peptide derived from human CD38. Expert Opin Ther Targets 2009; 13:141-52. [PMID: 19236233 DOI: 10.1517/14728220802637147] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVE Cell infection by HIV-1 is inhibited by both the expression of CD38 and a soluble peptide (sCD38p) corresponding to its extracellular membrane-proximal amino acid sequence (amino acids 51 - 74). We show here the effects of PEG conjugation to sCD38p and provide new insights into the mechanisms behind the anti-HIV-1 effects of CD38 and derived peptides. RESEARCH DESIGN/METHODS In-vitro and in-silico study. RESULTS PEGylation of sCD38p increased its ability to inhibit replication of HIV-1 in MT-4 cells and syncytia formation in cocultures of MT-2 and persistently HIV-1(IIIB)-infected H9(IIIB) cells. In silico modeling suggests that sCD38p and CD4 form stable heterodimers involving, among others, an interaction between lysine 57 (K57) of CD38 and a groove in the CD4 receptor, which, in CD4/gp120 complexes, is partially occupied by a lysine residue of the HIV-1 envelope glycoprotein. K57 substitution with a glycine in sCD38p impaired its ability to inhibit syncytia formation in MT-2/H9(IIIB) cell cocultures and gp120 binding to CD4 in a mouse T cell line expressing human but not mouse CD4. CONCLUSIONS PEGylation significantly improves the anti-HIV-1 activity of sCD38p, whose effect is probably due to competition with gp120 for a common binding site on CD4 although other mechanisms cannot be excluded so far. The inhibitory concentrations of the sCD38p-PEG as well as its poor toxicity, merit further consideration in anti-HIV-1 strategies.
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Affiliation(s)
- Thea Bensi
- 1'A Avogadro' University of Eastern Piedmont, Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), Department of Medical Science, Novara, Italy
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Malavasi F, Deaglio S, Funaro A, Ferrero E, Horenstein AL, Ortolan E, Vaisitti T, Aydin S. Evolution and function of the ADP ribosyl cyclase/CD38 gene family in physiology and pathology. Physiol Rev 2008; 88:841-86. [PMID: 18626062 DOI: 10.1152/physrev.00035.2007] [Citation(s) in RCA: 646] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The membrane proteins CD38 and CD157 belong to an evolutionarily conserved family of enzymes that play crucial roles in human physiology. Expressed in distinct patterns in most tissues, CD38 (and CD157) cleaves NAD(+) and NADP(+), generating cyclic ADP ribose (cADPR), NAADP, and ADPR. These reaction products are essential for the regulation of intracellular Ca(2+), the most ancient and universal cell signaling system. The entire family of enzymes controls complex processes, including egg fertilization, cell activation and proliferation, muscle contraction, hormone secretion, and immune responses. Over the course of evolution, the molecules have developed the ability to interact laterally and frontally with other surface proteins and have acquired receptor-like features. As detailed in this review, the loss of CD38 function is associated with impaired immune responses, metabolic disturbances, and behavioral modifications in mice. CD38 is a powerful disease marker for human leukemias and myelomas, is directly involved in the pathogenesis and outcome of human immunodeficiency virus infection and chronic lymphocytic leukemia, and controls insulin release and the development of diabetes. Here, the data concerning diseases are examined in view of potential clinical applications in diagnosis, prognosis, and therapy. The concluding remarks try to frame all of the currently available information within a unified working model that takes into account both the enzymatic and receptorial functions of the molecules.
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Affiliation(s)
- Fabio Malavasi
- Laboratory of Immunogenetics, Department of Genetics, Biology, and Biochemistry and Centro di Ricerca in Medicina Sperimentale, University of Torino Medical School, Torino, Italy.
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Liu Q, Kriksunov IA, Graeff R, Munshi C, Lee HC, Hao Q. Crystal structure of human CD38 extracellular domain. Structure 2005; 13:1331-9. [PMID: 16154090 DOI: 10.1016/j.str.2005.05.012] [Citation(s) in RCA: 132] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2005] [Revised: 05/26/2005] [Accepted: 05/27/2005] [Indexed: 12/17/2022]
Abstract
Human CD38 is a multifunctional protein involved in diverse functions. As an enzyme, it is responsible for the synthesis of two Ca2+ messengers, cADPR and NAADP; as an antigen, it is involved in regulating cell adhesion, differentiation, and proliferation. Besides, CD38 is a marker of progression of HIV-1 infection and a negative prognostic marker of B-CLL. We have determined the crystal structure of the soluble extracellular domain of human CD38 to 1.9 A resolution. The enzyme's overall topology is similar to the related proteins CD157 and the Aplysia ADP-ribosyl cyclase, except with large structural changes at the two termini. The extended positively charged N terminus has lateral associations with the other CD38 molecule in the crystallographic asymmetric unit. The analysis of the CD38 substrate binding models revealed two key residues that may be critical in controlling CD38's multifunctionality of NAD hydrolysis, ADP-ribosyl cyclase, and cADPR hydrolysis activities.
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Affiliation(s)
- Qun Liu
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA
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Savarino A, Bensi T, Chiocchetti A, Bottarel F, Mesturini R, Ferrero E, Calosso L, Deaglio S, Ortolan E, Buttò S, Cafaro A, Katada T, Ensoli B, Malavasi F, Dianzani U. Human CD38 interferes with HIV-1 fusion through a sequence homologous to the V3 loop of the viral envelope glycoprotein gp120. FASEB J 2003; 17:461-3. [PMID: 12551845 DOI: 10.1096/fj.02-0512fje] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
CD38 is a progression marker in HIV-1 infection, it displays lateral association with CD4, and down-modulates gp120/CD4 binding. The aim of this study was to elucidate the mechanism behind the interplay between CD4, CD38, and HIV-1. We used mouse cell transfectants expressing human CD4 and either CD38 or other CD4-associated molecules to show that CD38 specifically inhibits gp120/CD4 binding. Human cell transfectants expressing truncated forms of CD38 and bioinformatic analysis were used to map the anti-HIV activity and show that it is concentrated in the membrane-proximal region. This region displayed significant sequence-similarity with the V3 loop of the HIV-1 gp120 glycoprotein. In line with this similarity, synthetic soluble peptides derived from this region reproduced the anti-HIV effects of full-length CD38 and inhibited HIV-1 and HIV-2 primary isolates from different subtypes and with different coreceptor use. A multiple-branched peptide construct presenting part of the sequence of the V3-like region potently and selectively inhibited HIV-1 replication in the nanomolar range. Conversely, a deletion in the V3-like region abrogated the anti-HIV-1 activity of CD38 and its lateral association with CD4. These findings may provide new insights into the early events of HIV-1 fusion and strategies to intervene.
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Affiliation(s)
- Andrea Savarino
- Laboratory of Immunology, Interdisciplinary Research Center of Autoimmune Diseases, Department of Medical Science, University of Eastern Piedmont, Novara, Italy.
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Savarino A, Gennero L, Chen HC, Serrano D, Malavasi F, Boelaert JR, Sperber K. Anti-HIV effects of chloroquine: mechanisms of inhibition and spectrum of activity. AIDS 2001; 15:2221-9. [PMID: 11698694 DOI: 10.1097/00002030-200111230-00002] [Citation(s) in RCA: 94] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
OBJECTIVE To investigate the mechanisms and spectrum of the anti-HIV activity of chloroquine. DESIGN AND METHODS MT-4 cells or peripheral blood mononuclear cells were infected with X4, R5 or R5/X4 HIV-1 strains from clades A-E and HIV-2. The cells were then treated with clinically relevant and achievable chloroquine concentrations (i.e. 0-12.5 microM), so as to determine the EC50. The effects of chloroquine on reverse transcription and integration were tested using a replication-defective reporter HIV-1 construct (pRRL.sin.hPGK.GFP). The effects of the drug on the viral envelope were assessed by syncytium assays and immunoprecipitation, using antibodies to different epitopes of gp120. RESULTS In de-novo infected MT-4 cells, chloroquine selectively inhibited HIV-1 IIIB replication but not pRRL.sin.hPGK.GFP. In chronically HIV-1-infected H9 IIIB cells, chloroquine decreased the infectivity of the newly produced virus and the ability of these cells to form syncytia in co-culture with MT-2 cells. These effects were associated with structural changes in the gp120 glycoprotein, such as a reduction of reactivity with antibodies directed against the glycosylated 2G12 epitope. Although affecting a variable target such as gp120, chloroquine was capable of inhibiting X4, R5 and R5/X4 primary HIV-1 isolates from subtypes A, B, C, D, E and HIV-2. CONCLUSION At clinically achievable concentrations chloroquine inhibits HIV-1 post-integrationally by affecting newly produced viral envelope glycoproteins, and the drug has broad-spectrum anti-HIV-1 and HIV-2 activity.
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Affiliation(s)
- A Savarino
- Department of Clinical Immunology, Mount Sinai School of Medicine, New York, NY, USA
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Mañes S, del Real G, Lacalle RA, Lucas P, Gómez-Moutón C, Sánchez-Palomino S, Delgado R, Alcamí J, Mira E, Martínez-A C. Membrane raft microdomains mediate lateral assemblies required for HIV-1 infection. EMBO Rep 2000; 1:190-6. [PMID: 11265761 PMCID: PMC1084257 DOI: 10.1093/embo-reports/kvd025] [Citation(s) in RCA: 290] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2000] [Revised: 06/06/2000] [Accepted: 06/21/2000] [Indexed: 11/12/2022] Open
Abstract
HIV-1 infection triggers lateral membrane diffusion following interaction of the viral envelope with cell surface receptors. We show that these membrane changes are necessary for infection, as initial gp120-CD4 engagement leads to redistribution and clustering of membrane microdomains, enabling subsequent interaction of this complex with HIV-1 co-receptors. Disruption of cell membrane rafts by cholesterol depletion before viral exposure inhibits entry by both X4 and R5 strains of HIV-1, although viral replication in infected cells is unaffected by this treatment. This inhibitory effect is fully reversed by cholesterol replenishment of the cell membrane. These results indicate a general mechanism for HIV-1 envelope glycoprotein-mediated fusion by reorganization of membrane microdomains in the target cell, and offer new strategies for preventing HIV-1 infection.
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Affiliation(s)
- S Mañes
- Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain.
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Savarino A, Bottarel F, Malavasi F, Dianzani U. Role of CD38 in HIV-1 infection: an epiphenomenon of T-cell activation or an active player in virus/host interactions? AIDS 2000; 14:1079-89. [PMID: 10894271 DOI: 10.1097/00002030-200006160-00004] [Citation(s) in RCA: 97] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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