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Swan DA, Krantz EM, Byrne C, Okuku F, Nankoma J, Mutyaba I, Phipps W, Schiffer JT. Human Herpes Virus-8 Oral Shedding Heterogeneity is Due to Varying Rates of Reactivation from Latency and Immune Containment. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.11.26.625350. [PMID: 39651144 PMCID: PMC11623612 DOI: 10.1101/2024.11.26.625350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2024]
Abstract
Human herpesvirus-8 (HHV-8) is a gamma herpesvirus linked to the development of Kaposi sarcoma (KS). KS is more common in persons living with HIV (PLWH), but endemic KS in HIV-negative individuals is also common in sub-Saharan Africa. HHV-8 shedding occurs in the oral mucosa and is likely responsible for transmission. The mechanistic drivers of different HHV-8 shedding patterns in infected individuals are unknown. We applied stochastic mathematical models to a longitudinal study of HHV-8 oral shedding in 295 individuals in Uganda who were monitored daily with oral swabs. Participants were divided into four groups based on whether they were HIV-negative or positive as well as KS-negative or positive. In all groups, we observed a wide variance of shedding patterns, including no shedding, episodic low viral load shedding, and persistent high viral load shedding. Our model closely replicates patterns in individual data and attributes higher shedding rates to increased rates of viral reactivation, and lower median viral load values to more rapid and effective engagement of cytolytic immune responses. Our model provides a framework for understanding different shedding patterns observed in individuals with HHV-8 infection. Keypoints HHV8 shedding rate is mosty determined by rate of reactivation from latency while viral loads is mostly dteremined by peripheral immune responses.DAS performed all mathematical modeling and editied the paper; EMK performed statistical analysis and edited the paper; CB assisted with modeling; FO, JN and IM designed and implemented the clinical protocols; WP designed and implemented the clinical protocols and edited the paper; JTS conceived the study and write the paper.
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Mukasine MC, Mulundu G, Kawimbe M, Mutale K, Mumba C, Lidenge SJ, Ngalamika O. Association between KSHV-Specific Humoral and T Cell Responses with Recurrence of HIV-Associated Kaposi Sarcoma. Trop Med Infect Dis 2024; 9:134. [PMID: 38922046 PMCID: PMC11209129 DOI: 10.3390/tropicalmed9060134] [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] [Received: 04/29/2024] [Revised: 05/28/2024] [Accepted: 06/11/2024] [Indexed: 06/27/2024] Open
Abstract
Kaposi sarcoma (KS) is an AIDS-defining angio-proliferative malignancy, with the Kaposi sarcoma-associated herpes virus (KSHV) as its etiologic agent. Upon treatment with chemotherapy, a proportion of HIV-associated KS patients experience disease recurrence within a few months of completing treatment. We aimed at determining whether KSHV-specific adaptive immune responses were associated with KS recurrence upon complete remission. We conducted a prospective cohort study. The primary outcome was the recurrence of HIV-associated KS. An immunofluorescence assay was used to determine anti-KSHV antibodies, an enzyme-linked immunospot was conducted for T cell responses, PCR was carried out to determine KSHV status, and flow cytometry was used for CD4 counting and immunophenotyping. KSHV detection in PBMCs was high and not associated with KS recurrence-free survival (p = 0.29). Anti-KSHV antibody titers were high and not associated with recurrence-free survival (p = 0.63). KSHV-specific T cell responses dropped from baseline levels among individuals with recurrence, but the drop was not statistically significant. Individuals experiencing KS recurrence had a significantly higher proportion of T cell subsets expressing PD1, while those with sustained remission had a significant increase in CD4 T cell counts from baseline levels during the follow-up period (p = 0.02). Anti-KSHV antibodies are not a good correlate of protection from KS recurrence. T cells in individuals experiencing KS recurrence hadhigh PD1 expression, while an increase in CD4 counts was associated with sustained KS remission.
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Affiliation(s)
- Marie-Claire Mukasine
- Department of Pathology and Microbiology, University of Zambia School of Medicine, Lusaka P.O. Box 50110, Zambia; (M.-C.M.); (G.M.); (C.M.)
- HHV8 Research Molecular Virology Laboratory, University Teaching Hospital, Lusaka P.O. Box 50110, Zambia; (M.K.); (K.M.)
| | - Gina Mulundu
- Department of Pathology and Microbiology, University of Zambia School of Medicine, Lusaka P.O. Box 50110, Zambia; (M.-C.M.); (G.M.); (C.M.)
| | - Musonda Kawimbe
- HHV8 Research Molecular Virology Laboratory, University Teaching Hospital, Lusaka P.O. Box 50110, Zambia; (M.K.); (K.M.)
| | - Keagan Mutale
- HHV8 Research Molecular Virology Laboratory, University Teaching Hospital, Lusaka P.O. Box 50110, Zambia; (M.K.); (K.M.)
| | - Chibamba Mumba
- Department of Pathology and Microbiology, University of Zambia School of Medicine, Lusaka P.O. Box 50110, Zambia; (M.-C.M.); (G.M.); (C.M.)
| | - Salum J. Lidenge
- Ocean Road Cancer Institute, Dar es Salaam P.O. Box 3592, Tanzania;
- Department of Clinical Oncology, Muhimbili University of Health and Allied Sciences, Dar es Salaam P.O. Box 65001, Tanzania
| | - Owen Ngalamika
- HHV8 Research Molecular Virology Laboratory, University Teaching Hospital, Lusaka P.O. Box 50110, Zambia; (M.K.); (K.M.)
- Dermatology and Venereology Division, University Teaching Hospital, University of Zambia School of Medicine, Lusaka P.O. Box 50110, Zambia
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Chinna P, Bratl K, Lambarey H, Blumenthal MJ, Schäfer G. The Impact of Co-Infections for Human Gammaherpesvirus Infection and Associated Pathologies. Int J Mol Sci 2023; 24:13066. [PMID: 37685871 PMCID: PMC10487760 DOI: 10.3390/ijms241713066] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 08/18/2023] [Accepted: 08/18/2023] [Indexed: 09/10/2023] Open
Abstract
The two oncogenic human gammaherpesviruses Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) cause significant disease burden, particularly in immunosuppressed individuals. Both viruses display latent and lytic phases of their life cycle with different outcomes for their associated pathologies. The high prevalence of infectious diseases in Sub-Saharan Africa (SSA), particularly HIV/AIDS, tuberculosis, malaria, and more recently, COVID-19, as well as their associated inflammatory responses, could potentially impact either virus' infectious course. However, acute or lytically active EBV and/or KSHV infections often present with symptoms mimicking these predominant diseases leading to misdiagnosis or underdiagnosis of oncogenic herpesvirus-associated pathologies. EBV and/or KSHV infections are generally acquired early in life and remain latent until lytic reactivation is triggered by various stimuli. This review summarizes known associations between infectious agents prevalent in SSA and underlying EBV and/or KSHV infection. While presenting an overview of both viruses' biphasic life cycles, this review aims to highlight the importance of co-infections in the correct identification of risk factors for and diagnoses of EBV- and/or KSHV-associated pathologies, particularly in SSA, where both oncogenic herpesviruses as well as other infectious agents are highly pervasive and can lead to substantial morbidity and mortality.
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Affiliation(s)
- Prishanta Chinna
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town 7925, South Africa; (P.C.); (K.B.); (H.L.); (M.J.B.)
- Institute of Infectious Disease and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa
- Division of Medical Biochemistry and Structural Biology, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa
| | - Katrin Bratl
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town 7925, South Africa; (P.C.); (K.B.); (H.L.); (M.J.B.)
- Institute of Infectious Disease and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa
- Division of Medical Biochemistry and Structural Biology, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa
| | - Humaira Lambarey
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town 7925, South Africa; (P.C.); (K.B.); (H.L.); (M.J.B.)
- Institute of Infectious Disease and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa
- Division of Medical Biochemistry and Structural Biology, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa
| | - Melissa J. Blumenthal
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town 7925, South Africa; (P.C.); (K.B.); (H.L.); (M.J.B.)
- Institute of Infectious Disease and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa
- Division of Medical Biochemistry and Structural Biology, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa
| | - Georgia Schäfer
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town 7925, South Africa; (P.C.); (K.B.); (H.L.); (M.J.B.)
- Institute of Infectious Disease and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa
- Division of Medical Biochemistry and Structural Biology, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa
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Abstract
OBJECTIVE Improved understanding of the effect of HIV infection on Kaposi sarcoma (KS) presentation and outcomes will guide development of more effective KS staging and therapeutic approaches. We enrolled a prospective cohort of epidemic (HIV-positive; HIV + KS) and endemic (HIV-negative; HIV - KS) KS patients in Uganda to identify factors associated with survival and response. METHODS Adults with newly diagnosed KS presenting for care at the Uganda Cancer Institute (UCI) in Kampala, Uganda, between October 2012 and December 2019 were evaluated. Participants received chemotherapy per standard guidelines and were followed over 1 year to assess overall survival (OS) and treatment response. RESULTS Two hundred participants were enrolled; 166 (83%) had HIV + KS, and 176 (88%) were poor-risk tumor (T1) stage. One-year OS was 64% (95% confidence interval [CI] 57-71%), with the hazard of death nearly threefold higher for HIV + KS (hazard ratio [HR] = 2.93; P = 0.023). Among HIV + KS, abnormal chest X-ray (HR = 2.81; P = 0.007), lower CD4 + T-cell count (HR = 0.68 per 100 cells/μl; P = 0.027), higher HIV viral load (HR = 2.22 per log 10 copies/ml; P = 0.026), and higher plasma Kaposi sarcoma-associated herpesvirus (KSHV) copy number (HR = 1.79 per log 10 copies/ml; P = 0.028) were associated with increased mortality. Among HIV - KS, factors associated with mortality included Karnofsky score <70 (HR = 9.17; P = 0.045), abnormal chest X-ray (HR = 8.41; P = 0.025), and higher plasma KSHV copy number (HR = 6.21 per log 10 copies/ml; P < 0.001). CONCLUSIONS Although survival rates were better for HIV - KS than HIV + KS, the high mortality rate seen in both groups underscores the urgent need to identify new staging and therapeutic approaches. Factors associated with mortality, including high plasma KSHV, may serve as important targets of therapy.
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Alomari N, Totonchy J. Host-Level Susceptibility and IRF1 Expression Influence the Ability of IFN-γ to Inhibit KSHV Infection in B Lymphocytes. Viruses 2022; 14:2295. [PMID: 36298850 PMCID: PMC9607942 DOI: 10.3390/v14102295] [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: 09/15/2022] [Revised: 10/08/2022] [Accepted: 10/12/2022] [Indexed: 01/25/2023] Open
Abstract
Kaposi's sarcoma-associated herpesvirus (KSHV) is associated with vascular endothelial cell tumor, Kaposi's sarcoma (KS) and lymphoproliferative disorder, multicentric Castleman's disease (MCD), primary effusion lymphoma (PEL) and KSHV inflammatory cytokine syndrome (KICS). Dysregulation of proinflammatory cytokines is found in most KSHV associated diseases. However, little is known about the role of host microenvironment in the regulation of KSHV establishment in B cells. In the present study, we demonstrated that IFN-γ has a strong inhibitory effect on KSHV infection but only in a subset of tonsil-derived lymphocyte samples that are intrinsically more susceptible to infection, contain higher proportions of naïve B cells, and display increased levels of IRF1 and STAT1-pY701. The effect of IFN-γ in responsive samples was associated with increased frequencies of germinal center B cells (GCB) and decreased infection of plasma cells, suggesting that IFN-γ-mediated modulation of viral dynamics in GC can inhibit the establishment of KSHV infection.
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Affiliation(s)
| | - Jennifer Totonchy
- Biomedical and Pharmaceutical Sciences, Chapman University, Irvine, CA 92618, USA
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Alsaegh MA, Mahmoud O, Varma SR, Zhu S. The Prevalence of EBV and KSHV in Odontogenic Lesions. Int Dent J 2022; 73:42-47. [PMID: 35907672 PMCID: PMC9875224 DOI: 10.1016/j.identj.2022.06.028] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 06/29/2022] [Accepted: 06/30/2022] [Indexed: 01/29/2023] Open
Abstract
OBJECTIVES Odontogenic lesions evolve as a result of altered dental development. This study aimed to evaluate the prevalence and the coinfection of Epstein-Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV) in radicular cysts, dentigerous cysts, odontogenic keratocysts, and ameloblastomas. METHODS Polymerase chain reaction (PCR) was used to analyse 66 cases of odontogenic lesions for the presence of EBV-DNA and KSHV-DNA. These lesions were 15 radicular cysts, 16 dentigerous cysts, 18 odontogenic keratocysts, and 17 ameloblastomas. RESULTS EBV-DNA was detected in 24 (36.4%) of the studied samples as follows: 6 samples (40.0%) of radicular cysts, 4 (25.0%) of dentigerous cysts, 10 (55.6 %) of odontogenic keratocysts, and 4 (23.5%) of ameloblastomas (P = .168). KSHV-DNA was found in 16 (24.2%) of the studied samples as follows: 1 sample (6.7%) of radicular cysts, 6 (37.5%) of dentigerous cysts, 8 (44.4 %) of odontogenic keratocysts, and 1 (5.9%) of ameloblastomas (P = .001). Additionally, EBV and KSHV were positively correlated in all studied samples (P = .002). CONCLUSIONS Both EBV and KSHV are found in odontogenic cysts and ameloblastomas. KSHV and EBV are more prevalent in odontogenic keratocysts than in other studied odontogenic lesions. Further, there is a high prevalence of EBV and KSHV coinfection in odontogenic cysts and ameloblastomas.
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Affiliation(s)
- Mohammed Amjed Alsaegh
- Department of Oral and Craniofacial Health Sciences, College of Dental Medicine, University of Sharjah, Sharjah, UAE,Department of Oral and Maxillofacial Surgery, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China,Corresponding author. Department of Oral and Craniofacial Health Sciences, College of Dental Medicine, University of Sharjah, Building M28, Office No. 125, Sharjah, UAE.
| | - Okba Mahmoud
- Department of Clinical Science, College of Dentistry, Center of Medical and Bio-allied Health Sciences Research, Ajman University, Ajman, UAE
| | - Sudhir Rama Varma
- Department of Clinical Science, College of Dentistry, Center of Medical and Bio-allied Health Sciences Research, Ajman University, Ajman, UAE
| | - Shengrong Zhu
- Department of Oral and Maxillofacial Surgery, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China
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Epidemiology of Kaposi's Sarcoma. Cancers (Basel) 2021; 13:cancers13225692. [PMID: 34830846 PMCID: PMC8616388 DOI: 10.3390/cancers13225692] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 11/09/2021] [Accepted: 11/11/2021] [Indexed: 12/24/2022] Open
Abstract
Kaposi's sarcoma is an angioproliferative tumor caused by human herpesvirus 8 in the context of immunodeficiency, such as that induced by HIV infection or immunosuppressive therapy. Its incidence has dramatically fallen in patients living with HIV (PLHIV) since the introduction of potent antiretroviral combinations 25 years ago due to the restoration of immunity and better control of HIV replication. However, KS is still one of the most frequently occurring cancers in PLHIV, in particular in men who have sex with men and in sub-Saharan Africa, where it is still endemic. Even in the context of restored immunity, the risk of KS is still more than 30 times higher in PLHIV than in the general population. Recent evidence indicates that early initiation of antiretroviral treatment, which is recommended by current guidelines, may reduce the risk of KS but it needs to be accompanied by early access to care. This review mainly focuses on the recent epidemiological features of KS in the context of HIV infection.
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Disseminated AIDS-Related Kaposi Sarcoma Immune Reconstitution Inflammatory Syndrome With Infiltrative Liver Disease. ACG Case Rep J 2021; 8:e00660. [PMID: 34646902 PMCID: PMC8500654 DOI: 10.14309/crj.0000000000000660] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 06/03/2021] [Indexed: 11/17/2022] Open
Abstract
Clinically significant hepatic acquired immunodeficiency syndrome-related Kaposi sarcoma is rarely described in the literature. Kaposi sarcoma immune reconstitution inflammatory syndrome may play a role in the rapid progression of clinically insignificant to significant liver disease. We present an acquired immunodeficiency syndrome patient with disseminated Kaposi sarcoma that developed 3-6 weeks after initiation of highly active antiretroviral therapy.
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Silva DMD, Gonçales JP, Silva Júnior JVJ, Lopes TRR, Bezerra LA, Barros de Lorena VM, Duarte Coêlho MRC. Evaluation of IL-2, IL-4, IL-6, IL-10, TNF-α, and IFN-γ cytokines in HIV/HHV-8 coinfection. J Med Virol 2021; 93:4033-4037. [PMID: 32926412 DOI: 10.1002/jmv.26516] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Revised: 09/02/2020] [Accepted: 09/08/2020] [Indexed: 11/11/2022]
Abstract
Imbalance in the immune response is one of the main pathogenic mechanisms of diseases related with human immunodeficiency virus (HIV)/human gammaherpesvirus 8 (HHV-8) coinfection, such as Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), multicentric Castleman disease (MCD) and the Kaposi's sarcoma-associated herpesvirus inflammatory cytokine syndrome (KICS). However, significant changes in pro- and anti-inflammatory cytokine levels may be observed in HIV/HHV-8 individuals who are negative for KS, PEL, MCD, and/or KICS. In this study, serum levels of interleukin-2 (IL-2), IL-4, IL-6, IL-10, tumor nucrosis factor α (TNF-α) and interferon γ (IFN-γ) were assessed in 69 HIV and 48 HIV/HHV-8 individuals, all negatives for HHV-8-related diseases. The cytokines were measured by flow cytometry and analyzed by the Mann-Whitney test. The p < .05 and 95% confidence interval were considered in all analyzes. IL-4 (p = .0155), IL-6 (p = .0036), and IL-10 (p = .0036) levels were significantly higher in HIV/HHV-8 patients than in the HIV group. On the other hand, IL-2 (p = .2295), TNF-α (p = .1216) and IFN-γ (p = .1178) did not differ between the groups analyzed. To our knowledge, to date, this is the first report on significant differences in the levels of IL-4 and IL-6 in HIV versus HIV/HHV-8 individuals. Finally, these early findings are important as a prognostic tool and contribute to clarifying the HHV-8-host interaction.
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Affiliation(s)
- Dayvson Maurício da Silva
- Virology Sector, Laboratory of Immunopathology Keizo Asami, Federal University of Pernambuco, Recife, Pernambuco, Brazil
| | - Juliana Prado Gonçales
- Virology Sector, Laboratory of Immunopathology Keizo Asami, Federal University of Pernambuco, Recife, Pernambuco, Brazil
| | - José Valter Joaquim Silva Júnior
- Virology Sector, Laboratory of Immunopathology Keizo Asami, Federal University of Pernambuco, Recife, Pernambuco, Brazil
- Virology Sector, Department of Preventive Veterinary Medicine, Federal University of Santa Maria, Santa Maria, Rio Grande do Sul, Brazil
- Department of Microbiology and Parasitology, Federal University of Santa Maria, Santa Maria, Rio Grande do Sul, Brazil
| | - Thaísa Regina Rocha Lopes
- Virology Sector, Laboratory of Immunopathology Keizo Asami, Federal University of Pernambuco, Recife, Pernambuco, Brazil
- Virology Sector, Department of Preventive Veterinary Medicine, Federal University of Santa Maria, Santa Maria, Rio Grande do Sul, Brazil
| | - Luan Araújo Bezerra
- Virology Sector, Laboratory of Immunopathology Keizo Asami, Federal University of Pernambuco, Recife, Pernambuco, Brazil
| | | | - Maria Rosângela Cunha Duarte Coêlho
- Virology Sector, Laboratory of Immunopathology Keizo Asami, Federal University of Pernambuco, Recife, Pernambuco, Brazil
- Department of Physiology and Pharmacology, Federal University of Pernambuco, Recife, Pernambuco, Brazil
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Update on Kaposi sarcoma-associated herpesvirus (KSHV or HHV8) - review. ACTA ACUST UNITED AC 2020; 58:199-208. [PMID: 32681788 DOI: 10.2478/rjim-2020-0017] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Indexed: 12/30/2022]
Abstract
Human herpesvirus 8 (HHV8), also known as Kaposi sarcoma-associated herpesvirus (KSHV), is one of the few pathogens recognized as direct carcinogen, being involved in the pathogenesis of Kaposi sarcoma, primary effusion lymphoma and multicentric Castleman disease. KSHV is a relatively recently discovered virus, with still limited possibilities for diagnosis and treatment. Therefore, ongoing studies are trying to answer the main issues related to the management of KSHV infection and its associated diseases. This review updates the current knowledge of the KSHV infection, discussing aspects related to epidemiology, virological features, clinical manifestations, diagnosis and treatment.
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Alomari N, Totonchy J. Cytokine-Targeted Therapeutics for KSHV-Associated Disease. Viruses 2020; 12:E1097. [PMID: 32998419 PMCID: PMC7600567 DOI: 10.3390/v12101097] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 09/23/2020] [Accepted: 09/25/2020] [Indexed: 12/15/2022] Open
Abstract
Kaposi's sarcoma-associated herpesvirus (KSHV) also known as human herpesvirus 8 (HHV-8), is linked to several human malignancies including Kaposi sarcoma (KS), primary effusion lymphoma (PEL), multicentric Castleman's disease (MCD) and recently KSHV inflammatory cytokine syndrome (KICS). As with other diseases that have a significant inflammatory component, current therapy for KSHV-associated disease is associated with significant off-target effects. However, recent advances in our understanding of the pathogenesis of KSHV have produced new insight into the use of cytokines as potential therapeutic targets. Better understanding of the role of cytokines during KSHV infection and tumorigenesis may lead to new preventive or therapeutic strategies to limit KSHV spread and improve clinical outcomes. The cytokines that appear to be promising candidates as KSHV antiviral therapies include interleukins 6, 10, and 12 as well as interferons and tumor necrosis factor-family cytokines. This review explores our current understanding of the roles that cytokines play in promoting KSHV infection and tumorigenesis, and summarizes the current use of cytokines as therapeutic targets in KSHV-associated diseases.
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Affiliation(s)
| | - Jennifer Totonchy
- Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Irvine, CA 92618, USA;
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Weidner-Glunde M, Kruminis-Kaszkiel E, Savanagouder M. Herpesviral Latency-Common Themes. Pathogens 2020; 9:E125. [PMID: 32075270 PMCID: PMC7167855 DOI: 10.3390/pathogens9020125] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 02/09/2020] [Accepted: 02/14/2020] [Indexed: 12/14/2022] Open
Abstract
Latency establishment is the hallmark feature of herpesviruses, a group of viruses, of which nine are known to infect humans. They have co-evolved alongside their hosts, and mastered manipulation of cellular pathways and tweaking various processes to their advantage. As a result, they are very well adapted to persistence. The members of the three subfamilies belonging to the family Herpesviridae differ with regard to cell tropism, target cells for the latent reservoir, and characteristics of the infection. The mechanisms governing the latent state also seem quite different. Our knowledge about latency is most complete for the gammaherpesviruses due to previously missing adequate latency models for the alpha and beta-herpesviruses. Nevertheless, with advances in cell biology and the availability of appropriate cell-culture and animal models, the common features of the latency in the different subfamilies began to emerge. Three criteria have been set forth to define latency and differentiate it from persistent or abortive infection: 1) persistence of the viral genome, 2) limited viral gene expression with no viral particle production, and 3) the ability to reactivate to a lytic cycle. This review discusses these criteria for each of the subfamilies and highlights the common strategies adopted by herpesviruses to establish latency.
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Affiliation(s)
- Magdalena Weidner-Glunde
- Department of Reproductive Immunology and Pathology, Institute of Animal Reproduction and Food Research of Polish Academy of Sciences, Tuwima Str. 10, 10-748 Olsztyn, Poland; (E.K.-K.); (M.S.)
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Association of NFκB and related-cytokines with the viral load and development of antibodies against HHV-8 in people living with HIV/AIDS. Med Microbiol Immunol 2019; 209:41-49. [PMID: 31586222 DOI: 10.1007/s00430-019-00637-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2019] [Accepted: 09/23/2019] [Indexed: 02/08/2023]
Abstract
Human gammaherpesvirus 8 (HHV-8) replication is influenced by a complex interaction between viral and host elements. Here, we evaluated the expression of NFκB and TNF-α in B (CD19 +) and T (CD3 +) lymphocytes, and the serum concentration of IL-1β and IL-12 cytokines in people living with HIV/AIDS (PLHA), negative for HHV-8-related diseases, and who presented antibodies to latent or lytic antigens from HHV-8. In addition, we also evaluated the correlation of HHV-8 viral load with NFκB, TNF-α, IL-1β and IL-12 levels. The expression of NFκB (p < 0.0001) or TNF-α (p < 0.0001) in B lymphocytes (CD19 +) and the IL-1β (p < 0.0266) and IL-12 (p < 0.0001) concentrations were associated with the presence of antibodies to HHV-8 lytic antigens. The CD19 + NFκB + TNF-α + and CD3 + NFκB + TNF-α + cells were also associated with the presence of antibodies to lytic infection (p < 0.0001). Among all PLHA evaluated, only individuals with the highest titers of lytic antibodies, i.e., 1:320, had detectable HHV-8 viral load. In these, HHV-8 viral load was correlated to NFκB (r = 0.6, p = 0.003) and TNF-α (r = 0.5, p = 0.01) (both in CD19 + lymphocytes) and with IL-1β (r = 0.5, p = 0.01) and IL-12 (r = 0.6, p = 0.006) levels. We believe that viral replication and/or reactivation, in addition to being associated with the development of lytic antibodies against HHV-8, may be associated with inflammatory response via NFκB. Finally, although immune response imbalance has been previously related to HHV-8-associated diseases, our results indicate that important changes in immunity, mainly in the inflammatory response, may be clearly observed in individuals with HHV-8, but who have not yet presented clinical manifestations.
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Koch S, Damas M, Freise A, Hage E, Dhingra A, Rückert J, Gallo A, Kremmer E, Tegge W, Brönstrup M, Brune W, Schulz TF. Kaposi's sarcoma-associated herpesvirus vIRF2 protein utilizes an IFN-dependent pathway to regulate viral early gene expression. PLoS Pathog 2019; 15:e1007743. [PMID: 31059555 PMCID: PMC6522069 DOI: 10.1371/journal.ppat.1007743] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2018] [Revised: 05/16/2019] [Accepted: 03/31/2019] [Indexed: 12/14/2022] Open
Abstract
Kaposi’s sarcoma-associated herpesvirus (KSHV; human herpesvirus 8) belongs to the subfamily of Gammaherpesvirinae and is the etiological agent of Kaposi’s sarcoma as well as of two lymphoproliferative diseases: primary effusion lymphoma and multicentric Castleman disease. The KSHV life cycle is divided into a latent and a lytic phase and is highly regulated by viral immunomodulatory proteins which control the host antiviral immune response. Among them is a group of proteins with homology to cellular interferon regulatory factors, the viral interferon regulatory factors 1–4. The KSHV vIRFs are known as inhibitors of cellular interferon signaling and are involved in different oncogenic pathways. Here we characterized the role of the second vIRF protein, vIRF2, during the KSHV life cycle. We found the vIRF2 protein to be expressed in different KSHV positive cells with early lytic kinetics. Importantly, we observed that vIRF2 suppresses the expression of viral early lytic genes in both newly infected and reactivated persistently infected endothelial cells. This vIRF2-dependent regulation of the KSHV life cycle might involve the increased expression of cellular interferon-induced genes such as the IFIT proteins 1, 2 and 3, which antagonize the expression of early KSHV lytic proteins. Our findings suggest a model in which the viral protein vIRF2 allows KSHV to harness an IFN-dependent pathway to regulate KSHV early gene expression. The life cycle of Kaposi Sarcoma herpesvirus involves both persistence in a latent form and productive replication to generate new viral particles. How the virus switches between latency and productive (‘lytic’) replication is only partially understood. Here we show that a viral homologue of interferon regulatory factors, vIRF2, antagonizes lytic protein expression in endothelial cells. It does this by inducing the expression of cellular interferon-regulated genes such as IFIT 1–3, which in turn dampens early viral gene expression. This observation suggests that vIRF2 allows KSHV to harness the interferon pathway to regulate early viral gene expression in endothelial cells.
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Affiliation(s)
- Sandra Koch
- Hannover Medical School, Institute of Virology, Hannover, Germany
- German Centre for Infection Research, Hannover-Braunschweig Site, Germany
| | - Modester Damas
- Hannover Medical School, Institute of Virology, Hannover, Germany
- German Centre for Infection Research, Hannover-Braunschweig Site, Germany
| | - Anika Freise
- Hannover Medical School, Institute of Virology, Hannover, Germany
- German Centre for Infection Research, Hannover-Braunschweig Site, Germany
| | - Elias Hage
- Hannover Medical School, Institute of Virology, Hannover, Germany
- German Centre for Infection Research, Hannover-Braunschweig Site, Germany
| | - Akshay Dhingra
- Hannover Medical School, Institute of Virology, Hannover, Germany
- German Centre for Infection Research, Hannover-Braunschweig Site, Germany
| | - Jessica Rückert
- Hannover Medical School, Institute of Virology, Hannover, Germany
- German Centre for Infection Research, Hannover-Braunschweig Site, Germany
| | - Antonio Gallo
- Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
- German Centre for Infection Research, Hamburg Site, Germany
| | - Elisabeth Kremmer
- Institute of Molecular Immunology, Helmholtz Centre Munich, German Research Center for Environmental Health, Munich, Germany
| | - Werner Tegge
- Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Mark Brönstrup
- German Centre for Infection Research, Hannover-Braunschweig Site, Germany
- Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Wolfram Brune
- Heinrich-Pette-Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
- German Centre for Infection Research, Hamburg Site, Germany
| | - Thomas F. Schulz
- Hannover Medical School, Institute of Virology, Hannover, Germany
- German Centre for Infection Research, Hannover-Braunschweig Site, Germany
- * E-mail:
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15
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Pellett Madan R, Hand J. Human herpesvirus 6, 7, and 8 in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant 2019; 33:e13518. [PMID: 30844089 DOI: 10.1111/ctr.13518] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2019] [Accepted: 02/26/2019] [Indexed: 12/17/2022]
Abstract
These updated guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation review the diagnosis, prevention, and management of HHV-6A, HHV-6B, HHV-7, and HHV-8 in the pre- and post-transplant period. The majority of HHV-6 (A and B) and HHV-7 infections in transplant recipients are asymptomatic; symptomatic disease is reported infrequently across organs. Routine screening for HHV-6 and 7 DNAemia is not recommended in asymptomatic patients, nor is prophylaxis or preemptive therapy. Detection of viral nucleic acid by quantitative PCR in blood or CSF is the preferred method for diagnosis of HHV-6 and HHV-7 infection. The possibility of chromosomally integrated HHV-6 DNA should be considered in individuals with persistently high viral loads. Antiviral therapy should be initiated for HHV-6 encephalitis and should be considered for other manifestations of disease. HHV-8 causes Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman disease and is also associated with hemophagocytic syndrome and bone marrow failure. HHV-8 screening and monitoring may be indicated to prevent disease. Treatment of HHV-8 related disease centers on reduction of immunosuppression and conversion to sirolimus, while chemotherapy may be needed for unresponsive disease. The role of antiviral therapy for HHV-8 infection has not yet been defined.
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Affiliation(s)
- Rebecca Pellett Madan
- Department of Pediatrics, New York University Langone School of Medicine, New York City, New York
| | - Jonathan Hand
- Department of Infectious Diseases, Ochsner Clinical School, Ochsner Medical Center, The University of Queensland School of Medicine, New Orleans, Louisiana
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Lazăr DC, Avram MF, Romoșan I, Văcariu V, Goldiș A, Cornianu M. Malignant hepatic vascular tumors in adults: Characteristics, diagnostic difficulties and current management. World J Clin Oncol 2019; 10:110-135. [PMID: 30949442 PMCID: PMC6441663 DOI: 10.5306/wjco.v10.i3.110] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2019] [Revised: 02/23/2019] [Accepted: 03/12/2019] [Indexed: 02/06/2023] Open
Abstract
Malignant vascular tumors of the liver include rare primary hepatic mesenchymal tumors developed in the background of a normal liver parenchyma. Most of them are detected incidentally by the increased use of performing imaging techniques. Their diagnosis is challenging, involving clinical and imaging criteria, with final confirmation by histology and immunohistochemistry. Surgery represents the mainstay of treatment. Liver transplantation (LT) has improved substantially the prognosis of hepatic epithelioid hemangioendothelioma (HEHE), with 5-year patient survival rates of up to 81%, based on the European Liver Intestine Transplantation Association-European Liver Transplant Registry study. Unfortunately, the results of surgery and LT are dismal in cases of hepatic angiosarcoma (HAS). Due to the disappointing results of very short survival periods of approximately 6-7 mo after LT, because of tumor recurrence and rapid progression of the disease, HAS is considered an absolute contraindication to LT. Recurrences after surgical resection are high in cases of HEHE and invariably present in cases of HAS. The discovery of reliable prognostic markers and the elaboration of prognostic scores following LT are needed to provide the best therapeutic choice for each patient. Studies on a few patients have demonstrated the stabilization of the disease in a proportion of patients with hepatic vascular tumors using novel targeted antiangiogenic agents, cytokines or immunotherapy. These new approaches, alone or in combination with other therapeutic modalities, such as surgery and classical chemotherapy, need further investigation to assess their role in prolonging patient survival. Personalized therapeutic algorithms according to the histopathological features, behavior, molecular biology and genetics of the tumors should be elaborated in the near future for the management of patients diagnosed with primary malignant vascular tumors of the liver.
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Affiliation(s)
- Daniela Cornelia Lazăr
- Department of Internal Medicine I, University Medical Clinic, University of Medicine and Pharmacy “Victor Babeş”, Timişoara 300041, Romania
| | - Mihaela Flavia Avram
- Department of Surgery X, 1st Surgery Clinic, University of Medicine and Pharmacy “Victor Babeş”, Timişoara 300041, Romania
| | - Ioan Romoșan
- Department of Internal Medicine I, University Medical Clinic, University of Medicine and Pharmacy “Victor Babeş”, Timişoara 300041, Romania
| | - Violetta Văcariu
- Department of Internal Medicine I, University Medical Clinic, University of Medicine and Pharmacy “Victor Babeş”, Timişoara 300041, Romania
| | - Adrian Goldiș
- Department of Gastroenterology and Hepatology, University of Medicine and Pharmacy “Victor Babeş”, Timişoara 300041, Romania
| | - Mărioara Cornianu
- Department of Pathology, University of Medicine and Pharmacy “Victor Babeş”, Timişoara 300041, Romania
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17
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Park MK, Cho H, Roh SW, Kim SJ, Myoung J. Cell Type-Specific Interferon-γ-mediated Antagonism of KSHV Lytic Replication. Sci Rep 2019; 9:2372. [PMID: 30787356 PMCID: PMC6382833 DOI: 10.1038/s41598-019-38870-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Accepted: 01/04/2019] [Indexed: 02/07/2023] Open
Abstract
Kaposi’s sarcoma-associated herpesvirus (KSHV) is causally associated with several malignant tumors: Kaposi’s sarcoma (KS), multicentric Castleman’s disease (MCD), and primary effusion lymphoma (PEL). KS remains the most common AIDS-related malignancy since the AIDS epidemic and thus has been extensively studied. KS is characterized as an angioproliferative disease with massive immune cell infiltration at the early stage. High levels of proinflammatory cytokines and growth factors are found in KS lesions, and their involvement in the survival and growth of tumor cells has been well characterized. However, little is known about the role of the inflammatory microenvironment in the regulation of KSHV gene expression and/or viral replication. In the present study, we demonstrated that IFN-γ and TNF-α profoundly inhibited KSHV progeny production in primary human lymphatic endothelial cells (LECs) as well as induced KSHV-producer cells (iSLK.219) with doxycycline. Of note, IFN-γ inhibited overall KSHV gene expression, while the effects of TNF-α were confined to a selected set of genes, which were also downregulated by IFN-γ. The addition of IFN-γ up to 36 hr after induction of viral lytic replication was effective in terms of the inhibition of infectious virion production, suggesting that its inhibitory effect is exerted at the early stages of KSHV life cycle. We believe these data have potentially important implications for rationalizing a therapeutic agent to treat KSHV-induced tumors in which lytic replication plays a critical role in their pathogenesis: KS and MCD.
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Affiliation(s)
- Mi-Kyung Park
- School of Food Science and Food and Bio-industry Research Institute, Kyungpook National University, Daegu, 41566, Republic of Korea
| | - Hyejeong Cho
- Korea Zoonosis Research Institute, Chonbuk National University, Iksan-Si, Chollabuk-do, 54531, Republic of Korea
| | - Seong Woon Roh
- World Institute of Kimchi, Gwangju, 61755, Republic of Korea
| | - Seong-Jun Kim
- Center for Convergent Research of Emerging Virus Infection, Korea Research Institute of Chemical Technology, Yuseong, Daejeon, 34114, Republic of Korea
| | - Jinjong Myoung
- Korea Zoonosis Research Institute, Chonbuk National University, Iksan-Si, Chollabuk-do, 54531, Republic of Korea.
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Manners O, Murphy JC, Coleman A, Hughes DJ, Whitehouse A. Contribution of the KSHV and EBV lytic cycles to tumourigenesis. Curr Opin Virol 2018; 32:60-70. [PMID: 30268927 PMCID: PMC6259586 DOI: 10.1016/j.coviro.2018.08.014] [Citation(s) in RCA: 81] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Accepted: 08/24/2018] [Indexed: 12/21/2022]
Abstract
Kaposi's Sarcoma-associated herpesvirus (KSHV) and Epstein Barr virus (EBV) are the causative agents of several malignancies. Like all herpesviruses, KSHV and EBV undergo distinct latent and lytic replication programmes. The transition between these states allows the establishment of a lifelong persistent infection, dissemination to sites of disease and the spread to new hosts. Latency-associated viral proteins have been well characterised in transformation and tumourigenesis pathways; however, a number of studies have shown that abrogation of KSHV and EBV lytic gene expression impairs the oncogenesis of several cancers. Furthermore, several lytically expressed proteins have been functionally tethered to the angioproliferative and anti-apoptotic phenotypes of virus-infected cells. As a result, the investigation and therapeutic targeting of KSHV and EBV lytic cycles may be essential for the treatment of their associated malignancies.
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Affiliation(s)
- Oliver Manners
- School of Molecular and Cellular Biology, University of Leeds, Leeds, LS2 9JT, United Kingdom; Astbury Centre for Structural Molecular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, United Kingdom
| | - James C Murphy
- School of Molecular and Cellular Biology, University of Leeds, Leeds, LS2 9JT, United Kingdom; Astbury Centre for Structural Molecular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, United Kingdom
| | - Alex Coleman
- School of Molecular and Cellular Biology, University of Leeds, Leeds, LS2 9JT, United Kingdom; Astbury Centre for Structural Molecular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, United Kingdom
| | - David J Hughes
- School of Biology, Biomolecular Sciences Building, University of St Andrews, Fife, KY16 9AJ, United Kingdom
| | - Adrian Whitehouse
- School of Molecular and Cellular Biology, University of Leeds, Leeds, LS2 9JT, United Kingdom; Astbury Centre for Structural Molecular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, United Kingdom; Department of Biochemistry & Microbiology, Rhodes University, Grahamstown, 6140, South Africa.
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Zhou J, Zhao GL, Wang XM, Du XS, Su S, Li CG, Nair V, Yao YX, Cheng ZQ. Synergistic Viral Replication of Marek's Disease Virus and Avian Leukosis Virus Subgroup J is Responsible for the Enhanced Pathogenicity in the Superinfection of Chickens. Viruses 2018; 10:E271. [PMID: 29783672 PMCID: PMC5977264 DOI: 10.3390/v10050271] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2018] [Revised: 05/09/2018] [Accepted: 05/15/2018] [Indexed: 12/13/2022] Open
Abstract
Superinfection of Marek's disease virus (MDV) and avian leukosis virus subgroup J (ALV-J) causes lethal neoplasia and death in chickens. However, whether there is synergism between the two viruses in viral replication and pathogenicity has remained elusive. In this study, we found that the superinfection of MDV and ALV-J increased the viral replication of the two viruses in RNA and protein level, and synergistically promoted the expression of IL-10, IL-6, and TGF-β in chicken embryo fibroblasts (CEF). Moreover, MDV and ALV-J protein expression in dual-infected cells detected by confocal laser scanning microscope appeared earlier in the cytoplasm and the nucleus, and caused more severe cytopathy than single infection, suggesting that synergistically increased MDV and ALV-J viral-protein biosynthesis is responsible for the severe cytopathy. In vivo, compared to the single virus infected chickens, the mortality and tumor formation rates increased significantly in MDV and ALV-J dual-infected chickens. Viral loads of MDV and ALV-J in tissues of dual-infected chickens were significantly higher than those of single-infected chickens. Histopathology observation showed that more severe inflammation and tumor cells metastases were present in dual-infected chickens. In the present study, we concluded that synergistic viral replication of MDV and ALV-J is responsible for the enhanced pathogenicity in superinfection of chickens.
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Affiliation(s)
- Jing Zhou
- College of Veterinary Medicine, Shandong Agricultural University, Tai'an 271018, China.
| | - Guo-Liang Zhao
- College of Veterinary Medicine, Shandong Agricultural University, Tai'an 271018, China.
| | - Xiao-Man Wang
- College of Veterinary Medicine, Shandong Agricultural University, Tai'an 271018, China.
| | - Xu-Sheng Du
- College of Veterinary Medicine, Shandong Agricultural University, Tai'an 271018, China.
| | - Shuai Su
- College of Veterinary Medicine, Shandong Agricultural University, Tai'an 271018, China.
| | - Chen-Gui Li
- College of Veterinary Medicine, Shandong Agricultural University, Tai'an 271018, China.
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Tai'an 271018, China.
| | - Venugopal Nair
- The Pirbright Institute & UK-China Centre of Excellence on Avian Disease Research, Pirbright, Ash Road, Guildford, Surrey GU24 0NF, UK.
| | - Yong-Xiu Yao
- The Pirbright Institute & UK-China Centre of Excellence on Avian Disease Research, Pirbright, Ash Road, Guildford, Surrey GU24 0NF, UK.
| | - Zi-Qiang Cheng
- College of Veterinary Medicine, Shandong Agricultural University, Tai'an 271018, China.
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Tai'an 271018, China.
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20
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Abere B, Mamo TM, Hartmann S, Samarina N, Hage E, Rückert J, Hotop SK, Büsche G, Schulz TF. The Kaposi's sarcoma-associated herpesvirus (KSHV) non-structural membrane protein K15 is required for viral lytic replication and may represent a therapeutic target. PLoS Pathog 2017; 13:e1006639. [PMID: 28938025 PMCID: PMC5627962 DOI: 10.1371/journal.ppat.1006639] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Revised: 10/04/2017] [Accepted: 09/09/2017] [Indexed: 12/18/2022] Open
Abstract
Kaposi’s sarcoma-associated herpesvirus (KSHV) is the infectious cause of the highly vascularized tumor Kaposi’s sarcoma (KS), which is characterized by proliferating spindle cells of endothelial origin, extensive neo-angiogenesis and inflammatory infiltrates. The KSHV K15 protein contributes to the angiogenic and invasive properties of KSHV-infected endothelial cells. Here, we asked whether K15 could also play a role in KSHV lytic replication. Deletion of the K15 gene from the viral genome or its depletion by siRNA lead to reduced virus reactivation, as evidenced by the decreased expression levels of KSHV lytic proteins RTA, K-bZIP, ORF 45 and K8.1 as well as reduced release of infectious virus. Similar results were found for a K1 deletion virus. Deleting either K15 or K1 from the viral genome also compromised the ability of KSHV to activate PLCγ1, Erk1/2 and Akt1. In infected primary lymphatic endothelial (LEC-rKSHV) cells, which have previously been shown to spontaneously display a viral lytic transcription pattern, transfection of siRNA against K15, but not K1, abolished viral lytic replication as well as KSHV-induced spindle cell formation. Using a newly generated monoclonal antibody to K15, we found an abundant K15 protein expression in KS tumor biopsies obtained from HIV positive patients, emphasizing the physiological relevance of our findings. Finally, we used a dominant negative inhibitor of the K15-PLCγ1 interaction to establish proof of principle that pharmacological intervention with K15-dependent pathways may represent a novel approach to block KSHV reactivation and thereby its pathogenesis. Both the latent and lytic replication phases of the KSHV life cycle are thought to contribute to its persistence and pathogenesis. The non-structural signaling membrane protein K15 is involved in the angiogenic and invasive properties of KSHV-infected endothelial cells. Here we show that the K15 protein is required for virus replication, early viral gene expression and virus production through its activation of the cellular signaling pathways PLCγ1 and Erk 1/2. K15 is abundantly expressed in KSHV-infected lymphatic endothelial cells (LECs) and contributes to KSHV-induced endothelial spindle cell formation. The abundant K15 protein expression observed in LECs is also observed in KS tumors. We also show that it may be possible to target K15 in order to intervene therapeutically with KSHV lytic replication and pathogenesis.
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Affiliation(s)
- Bizunesh Abere
- Institute of Virology, Hannover Medical School, Hannover, Germany
- German Centre for Infection Research, Hannover–Braunschweig Site, Germany
| | - Tamrat M. Mamo
- Institute of Molecular Biology, Hannover Medical School, Hannover, Germany
| | - Silke Hartmann
- Institute of Virology, Hannover Medical School, Hannover, Germany
- German Centre for Infection Research, Hannover–Braunschweig Site, Germany
| | - Naira Samarina
- Institute of Virology, Hannover Medical School, Hannover, Germany
- German Centre for Infection Research, Hannover–Braunschweig Site, Germany
| | - Elias Hage
- Institute of Virology, Hannover Medical School, Hannover, Germany
- German Centre for Infection Research, Hannover–Braunschweig Site, Germany
| | - Jessica Rückert
- Institute of Virology, Hannover Medical School, Hannover, Germany
- German Centre for Infection Research, Hannover–Braunschweig Site, Germany
| | - Sven-Kevin Hotop
- German Centre for Infection Research, Hannover–Braunschweig Site, Germany
- Department of Chemical Biology, Helmholtz Center for Infection Research, Braunschweig, Germany
| | - Guntram Büsche
- Institute of Pathology, Hannover Medical School, Hannover, Germany
| | - Thomas F. Schulz
- Institute of Virology, Hannover Medical School, Hannover, Germany
- German Centre for Infection Research, Hannover–Braunschweig Site, Germany
- * E-mail:
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21
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Aneja KK, Yuan Y. Reactivation and Lytic Replication of Kaposi's Sarcoma-Associated Herpesvirus: An Update. Front Microbiol 2017; 8:613. [PMID: 28473805 PMCID: PMC5397509 DOI: 10.3389/fmicb.2017.00613] [Citation(s) in RCA: 135] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Accepted: 03/27/2017] [Indexed: 12/30/2022] Open
Abstract
The life cycle of Kaposi’s sarcoma-associated herpesvirus (KSHV) consists of two phases, latent and lytic. The virus establishes latency as a strategy for avoiding host immune surveillance and fusing symbiotically with the host for lifetime persistent infection. However, latency can be disrupted and KSHV is reactivated for entry into the lytic replication. Viral lytic replication is crucial for efficient dissemination from its long-term reservoir to the sites of disease and for the spread of the virus to new hosts. The balance of these two phases in the KSHV life cycle is important for both the virus and the host and control of the switch between these two phases is extremely complex. Various environmental factors such as oxidative stress, hypoxia, and certain chemicals have been shown to switch KSHV from latency to lytic reactivation. Immunosuppression, unbalanced inflammatory cytokines, and other viral co-infections also lead to the reactivation of KSHV. This review article summarizes the current understanding of the initiation and regulation of KSHV reactivation and the mechanisms underlying the process of viral lytic replication. In particular, the central role of an immediate-early gene product RTA in KSHV reactivation has been extensively investigated. These studies revealed multiple layers of regulation in activation of RTA as well as the multifunctional roles of RTA in the lytic replication cascade. Epigenetic regulation is known as a critical layer of control for the switch of KSHV between latency and lytic replication. The viral non-coding RNA, PAN, was demonstrated to play a central role in the epigenetic regulation by serving as a guide RNA that brought chromatin remodeling enzymes to the promoters of RTA and other lytic genes. In addition, a novel dimension of regulation by microPeptides emerged and has been shown to regulate RTA expression at the protein level. Overall, extensive investigation of KSHV reactivation and lytic replication has revealed a sophisticated regulation network that controls the important events in KSHV life cycle.
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Affiliation(s)
- Kawalpreet K Aneja
- Department of Microbiology, University of Pennsylvania School of Dental Medicine, PhiladelphiaPA, USA
| | - Yan Yuan
- Department of Microbiology, University of Pennsylvania School of Dental Medicine, PhiladelphiaPA, USA
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22
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Van Leer-Greenberg B, Kole A, Chawla S. Hepatic Kaposi sarcoma: A case report and review of the literature. World J Hepatol 2017; 9:171-179. [PMID: 28217255 PMCID: PMC5295157 DOI: 10.4254/wjh.v9.i4.171] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2016] [Revised: 11/28/2016] [Accepted: 12/13/2016] [Indexed: 02/06/2023] Open
Abstract
Kaposi sarcoma (KS) is an aggressive cancer caused by human herpesvirus-8, primarily seen in immunocompromised patients. As opposed to the well-described cutaneous manifestations and pulmonary complications of KS, hepatic KS is rarely reported before death as most patients with hepatic KS do not manifest symptoms or evidence of liver injury. In patients with acquired immune deficiency syndrome, hepatic involvement of KS is present in 12%-24% of the population on incidental imaging and in approximately 35% of patients with cutaneous KS if an autopsy was completed after their death. Patients with clinically significant hepatic injury due to hepatic KS usually have an aggressive course of disease with hepatic failure often progressing to multi-organ failure and death. Here we report an unusual presentation of acute liver injury due to hepatic KS and briefly review the published literature on hepatic KS.
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Affiliation(s)
- Brett Van Leer-Greenberg
- Brett Van Leer-Greenberg, Abhisake Kole, Saurabh Chawla, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, United States
| | - Abhisake Kole
- Brett Van Leer-Greenberg, Abhisake Kole, Saurabh Chawla, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, United States
| | - Saurabh Chawla
- Brett Van Leer-Greenberg, Abhisake Kole, Saurabh Chawla, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, United States
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Qin J, Lu C. Infection of KSHV and Interaction with HIV: The Bad Romance. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 1018:237-251. [PMID: 29052142 DOI: 10.1007/978-981-10-5765-6_15] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Kaposi's sarcoma-associated herpesvirus (KSHV), namely, human herpesvirus 8 (HHV-8), is considered as the pathogen of Kaposi's sarcoma (KS), the most frequent cancer in untreated HIV-infected individuals. Patients infected with HIV have a much higher possibility developing KS than average individual. Researchers have found that HIV, which functions as a cofactor of KS, contributes a lot to the development of KS. In this article, we will give a brief introduction of KS and KSHV and how the interaction between KSHV and HIV contributes to the development of KS. Also we will take a glance at the development of treatment in KS, especially AIDS-KS.
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Affiliation(s)
- Jie Qin
- Key Laboratory of Pathogen Biology (Jiangsu Province), Nanjing Medical University, Nanjing, People's Republic of China.,Department of Microbiology, Nanjing Medical University, Nanjing, 210029, People's Republic of China
| | - Chun Lu
- Key Laboratory of Pathogen Biology (Jiangsu Province), Nanjing Medical University, Nanjing, People's Republic of China. .,Department of Microbiology, Nanjing Medical University, Nanjing, 210029, People's Republic of China.
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24
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Gandhi M, Koelle DM, Ameli N, Bacchetti P, Greenspan JS, Navazesh M, Anastos K, Greenblatt RM. Prevalence of Human Herpesvirus-8 Salivary Shedding in HIV Increases with CD4 Count. J Dent Res 2016; 83:639-43. [PMID: 15271974 DOI: 10.1177/154405910408300811] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Human herpesvirus-8 (HHV-8) is the etiologic agent of Kaposi’s sarcoma (KS), which occurs in epidemic form in human immunodeficiency virus(HIV)-infected individuals. Saliva is the only mucosal fluid in which infectious HHV-8 has been identified, although factors associated with HHV-8 salivary shedding remain unclear. Our study performed PCR analysis for HHV-8 DNA in saliva (and other body fluids) in 66 HIV- and HHV-8-co-infected women without KS so that we could examine predictors for HHV-8 DNA detection. CD4 count was the most significant predictor of HHV-8 salivary shedding, with increased prevalence of HHV-8 salivary DNA at higher CD4 counts. The odds of salivary HHV8 shedding at CD4 counts > = 350 cells/μL was 63 times the odds of shedding at CD4 < 350 (95%CI, 1.3–3078), with an increase in effect size when the analysis was restricted to those with a CD4 nadir > 200. Analysis of these data suggests an increased potential for HHV-8 transmission early in HIV infection, with implications for HHV-8 prevention.
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Affiliation(s)
- M Gandhi
- University of California, San Francisco (UCSF), 405 Irving Street, 2nd floor, San Francisco, CA 94122, USA.
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25
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Abere B, Schulz TF. KSHV non-structural membrane proteins involved in the activation of intracellular signaling pathways and the pathogenesis of Kaposi's sarcoma. Curr Opin Virol 2016; 20:11-19. [DOI: 10.1016/j.coviro.2016.07.008] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2016] [Revised: 07/15/2016] [Accepted: 07/19/2016] [Indexed: 11/30/2022]
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HIV-1 Vpr Inhibits Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication by Inducing MicroRNA miR-942-5p and Activating NF-κB Signaling. J Virol 2016; 90:8739-53. [PMID: 27440900 DOI: 10.1128/jvi.00797-16] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Accepted: 07/15/2016] [Indexed: 12/18/2022] Open
Abstract
UNLABELLED Kaposi's sarcoma-associated herpesvirus (KSHV) infection is required for the development of several AIDS-related malignancies, including Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). The high incidence of AIDS-KS has been ascribed to the interaction of KSHV and HIV-1. We have previously shown that HIV-1-secreted proteins Tat and Nef regulate the KSHV life cycle and synergize with KSHV oncogenes to promote angiogenesis and tumorigenesis. Here, we examined the regulation of KSHV latency by HIV-1 viral protein R (Vpr). We found that soluble Vpr inhibits the expression of KSHV lytic transcripts and proteins, as well as viral particle production by activating NF-κB signaling following internalization into PEL cells. By analyzing the expression profiles of microRNAs combined with target search by bioinformatics and luciferase reporter analyses, we identified a Vpr-upregulated cellular microRNA (miRNA), miR-942-5p, that directly targeted IκBα. Suppression of miR-942-5p relieved the expression of IκBα and reduced Vpr inhibition of KSHV lytic replication, while overexpression of miR-942-5p enhanced Vpr inhibition of KSHV lytic replication. Our findings collectively illustrate that, by activating NF-κB signaling through upregulating a cellular miRNA to target IκBα, internalized HIV-1 Vpr inhibits KSHV lytic replication. These results have demonstrated an essential role of Vpr in the life cycle of KSHV. IMPORTANCE Coinfection by HIV-1 promotes the aggressive growth of Kaposi's sarcoma-associated herpesvirus (KSHV)-related malignancies, including Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). In this study, we have shown that soluble HIV-1 Vpr inhibits KSHV lytic replication by activating NF-κB signaling following internalization into PEL cells. Mechanistic studies revealed that a cellular microRNA upregulated by Vpr, miR-942-5p, directly targeted IκBα. Suppression of miR-942-5p relieved IκBα expression and reduced Vpr inhibition of KSHV replication, while overexpression of miR-942-5p enhanced Vpr inhibition of KSHV replication. These results indicate that by activating NF-κB signaling through upregulating a cellular miRNA to target IκBα, internalized Vpr inhibits KSHV lytic replication. This work illustrates a molecular mechanism by which HIV-1-secreted regulatory protein Vpr regulates KSHV latency and the pathogenesis of AIDS-related malignancies.
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Chuerduangphui J, Pientong C, Chaiyarit P, Patarapadungkit N, Chotiyano A, Kongyingyoes B, Promthet S, Swangphon P, Wongjampa W, Ekalaksananan T. Effect of human papillomavirus 16 oncoproteins on oncostatin M upregulation in oral squamous cell carcinoma. Med Oncol 2016; 33:83. [PMID: 27349249 DOI: 10.1007/s12032-016-0800-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2016] [Accepted: 06/21/2016] [Indexed: 01/17/2023]
Abstract
Human papillomavirus (HPV) infection modulates several host cytokines contributing to cancer development. Oncostatin M (OSM), an IL-6 family cytokine, acts to promote cell senescence and inhibit growth. Its dysregulation promotes cell survival, cell proliferation and metastasis in various malignancies. The effect of HPV on OSM dysregulation has not been investigated. To elucidate this, immunohistochemistry was used on formalin-fixed, paraffin-embedded oral squamous cell carcinoma (OSCC) tissues: HPV-positive (50) and HPV-negative (50) cases. Immortalized human cervical keratinocytes expressing HPV16E6 (HCK1T, Tet-On system) were used to demonstrate the role of HPV16E6 in OSM expression. In addition, a vector containing HPV16E6/E7 was transiently transfected into oral cancer cell lines. Cell viability, cell-cycle progression and cell migration were evaluated using flow cytometry and a wound healing assay, respectively. The results showed various intensities of OSM expression in OSCC. Interestingly, the median percentages of strongly stained cells were significantly higher in HPV-positive OSCCs than in HPV-negative OSCCs. To explore the role of HPV oncoproteins on OSM expression, the expression of HPV16E6 in the HCK1T Tet-On condition was induced by doxycycline and HPV16E6 was found to significantly upregulate levels of OSM mRNA and protein, with concomitant upregulation of c-Myc. In addition, the levels of OSM mRNA and protein in E6/E7 transiently transfected oral cancer cells also gradually increased in a time-dependent manner and these transfected cells showed greater viability and higher migration rates and cell-cycle progression than controls. This result demonstrates that HPV16 oncoproteins upregulate OSM and play an important role to promote OSCC development.
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Affiliation(s)
- Jureeporn Chuerduangphui
- Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.,HPV & EBV and Carcinogenesis Research Group, Khon Kaen University, Khon Kaen, Thailand
| | - Chamsai Pientong
- Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.,HPV & EBV and Carcinogenesis Research Group, Khon Kaen University, Khon Kaen, Thailand
| | - Ponlatham Chaiyarit
- Department of Oral Diagnosis, Faculty of Dentistry, Khon Kaen University, Khon Kaen, Thailand.,Research Group of Chronic Inflammatory Oral Diseases and Systemic Diseases Associated with Oral Health, Faculty of Dentistry, Khon Kaen University, Khon Kaen, Thailand
| | - Natcha Patarapadungkit
- Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.,HPV & EBV and Carcinogenesis Research Group, Khon Kaen University, Khon Kaen, Thailand
| | - Apinya Chotiyano
- Anatomical Pathology Unit, Khon Kaen Hospital, Khon Kaen, Thailand.,HPV & EBV and Carcinogenesis Research Group, Khon Kaen University, Khon Kaen, Thailand
| | - Bunkerd Kongyingyoes
- Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Supannee Promthet
- Department of Epidemiology, Faculty of Public Health, Khon Kaen University, Khon Kaen, Thailand.,HPV & EBV and Carcinogenesis Research Group, Khon Kaen University, Khon Kaen, Thailand
| | - Piyawut Swangphon
- Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.,HPV & EBV and Carcinogenesis Research Group, Khon Kaen University, Khon Kaen, Thailand
| | - Weerayut Wongjampa
- Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand.,HPV & EBV and Carcinogenesis Research Group, Khon Kaen University, Khon Kaen, Thailand
| | - Tipaya Ekalaksananan
- Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand. .,HPV & EBV and Carcinogenesis Research Group, Khon Kaen University, Khon Kaen, Thailand.
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Strahan R, Uppal T, Verma SC. Next-Generation Sequencing in the Understanding of Kaposi's Sarcoma-Associated Herpesvirus (KSHV) Biology. Viruses 2016; 8:92. [PMID: 27043613 PMCID: PMC4848587 DOI: 10.3390/v8040092] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Revised: 03/21/2016] [Accepted: 03/23/2016] [Indexed: 12/16/2022] Open
Abstract
Non-Sanger-based novel nucleic acid sequencing techniques, referred to as Next-Generation Sequencing (NGS), provide a rapid, reliable, high-throughput, and massively parallel sequencing methodology that has improved our understanding of human cancers and cancer-related viruses. NGS has become a quintessential research tool for more effective characterization of complex viral and host genomes through its ever-expanding repertoire, which consists of whole-genome sequencing, whole-transcriptome sequencing, and whole-epigenome sequencing. These new NGS platforms provide a comprehensive and systematic genome-wide analysis of genomic sequences and a full transcriptional profile at a single nucleotide resolution. When combined, these techniques help unlock the function of novel genes and the related pathways that contribute to the overall viral pathogenesis. Ongoing research in the field of virology endeavors to identify the role of various underlying mechanisms that control the regulation of the herpesvirus biphasic lifecycle in order to discover potential therapeutic targets and treatment strategies. In this review, we have complied the most recent findings about the application of NGS in Kaposi’s sarcoma-associated herpesvirus (KSHV) biology, including identification of novel genomic features and whole-genome KSHV diversities, global gene regulatory network profiling for intricate transcriptome analyses, and surveying of epigenetic marks (DNA methylation, modified histones, and chromatin remodelers) during de novo, latent, and productive KSHV infections.
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Affiliation(s)
- Roxanne Strahan
- Department of Microbiology and Immunology, School of Medicine, University of Nevada, 1664 N, Virginia Street, MS 320, Reno, NV 89557, USA.
| | - Timsy Uppal
- Department of Microbiology and Immunology, School of Medicine, University of Nevada, 1664 N, Virginia Street, MS 320, Reno, NV 89557, USA.
| | - Subhash C Verma
- Department of Microbiology and Immunology, School of Medicine, University of Nevada, 1664 N, Virginia Street, MS 320, Reno, NV 89557, USA.
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30
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Thakker S, Verma SC. Co-infections and Pathogenesis of KSHV-Associated Malignancies. Front Microbiol 2016; 7:151. [PMID: 26913028 PMCID: PMC4753363 DOI: 10.3389/fmicb.2016.00151] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2015] [Accepted: 01/27/2016] [Indexed: 12/25/2022] Open
Abstract
Kaposi’s sarcoma-associated herpesvirus (KSHV), also known as human herpes virus 8 (HHV-8) is one of the several carcinogenic viruses that infect humans. KSHV infection has been implicated in the development of Kaposi’s sarcoma (KS), primary effusion lymphoma, and multicentric Castleman’s Disease. While KSHV infection is necessary for the development of KSHV associated malignancies, it is not sufficient to induce tumorigenesis. Evidently, other co-factors are essential for the progression of KSHV induced malignancies. One of the most important co-factors, necessary for the progression of KSHV induced tumors, is immune suppression that frequently arises during co-infection with HIV and also by other immune suppressants. In this mini-review, we discuss the roles of co-infection with HIV and other pathogens on KSHV infection and pathogenesis.
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Yao S, Hu M, Hao T, Li W, Xue X, Xue M, Zhu X, Zhou F, Qin D, Yan Q, Zhu J, Gao SJ, Lu C. MiRNA-891a-5p mediates HIV-1 Tat and KSHV Orf-K1 synergistic induction of angiogenesis by activating NF-κB signaling. Nucleic Acids Res 2015; 43:9362-78. [PMID: 26446987 PMCID: PMC4627096 DOI: 10.1093/nar/gkv988] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2015] [Accepted: 09/19/2015] [Indexed: 12/03/2022] Open
Abstract
Co-infection with HIV-1 and Kaposi's sarcoma-associated herpesvirus (KSHV) is the cause of aggressive AIDS-related Kaposi's sarcoma (AIDS-KS) characterized by abnormal angiogenesis. The impact of HIV-1 and KSHV interaction on the pathogenesis and extensive angiogenesis of AIDS-KS remains unclear. Here, we explored the synergistic effect of HIV-1 Tat and KSHV oncogene Orf-K1 on angiogenesis. Our results showed that soluble Tat or ectopic expression of Tat enhanced K1-induced cell proliferation, microtubule formation and angiogenesis in chorioallantoic membrane and nude mice models. Mechanistic studies revealed that Tat promoted K1-induced angiogenesis by enhancing NF-κB signaling. Mechanistically, we showed that Tat synergized with K1 to induce the expression of miR-891a-5p, which directly targeted IκBα 3′ untranslated region, leading to NF-κB activation. Consequently, inhibition of miR-891a-5p increased IκBα level, prevented nuclear translocation of NF-κB p65 and ultimately suppressed the synergistic effect of Tat- and K1-induced angiogenesis. Our results illustrate that, by targeting IκBα to activate the NF-κB pathway, miR-891a-5p mediates Tat and K1 synergistic induction of angiogenesis. Therefore, the miR-891a-5p/NF-κB pathway is important in the pathogenesis of AIDS-KS, which could be an attractive therapeutic target for AIDS-KS.
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Affiliation(s)
- Shuihong Yao
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, P.R. China Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, P.R. China Department of Microbiology, Nanjing Medical University, Nanjing 210029, P.R. China Medical School, Quzhou College of Technology, Quzhou 324000, P.R. China
| | - Minmin Hu
- Department of Microbiology, Nanjing Medical University, Nanjing 210029, P.R. China
| | - Tingting Hao
- Department of Medical Laboratory, The Affiliated Hospital of Xuzhou Medical College, Xuzhou 221000, P.R. China
| | - Wan Li
- Department of Microbiology, Nanjing Medical University, Nanjing 210029, P.R. China
| | - Xue Xue
- Department of Microbiology, Nanjing Medical University, Nanjing 210029, P.R. China
| | - Min Xue
- Department of Microbiology, Nanjing Medical University, Nanjing 210029, P.R. China
| | - Xiaofei Zhu
- Department of Microbiology, Nanjing Medical University, Nanjing 210029, P.R. China
| | - Feng Zhou
- Department of Microbiology, Nanjing Medical University, Nanjing 210029, P.R. China
| | - Di Qin
- Department of Microbiology, Nanjing Medical University, Nanjing 210029, P.R. China
| | - Qin Yan
- Department of Microbiology, Nanjing Medical University, Nanjing 210029, P.R. China
| | - Jianzhong Zhu
- Cancer Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232, USA
| | - Shou-Jiang Gao
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Chun Lu
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, P.R. China Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, P.R. China Department of Microbiology, Nanjing Medical University, Nanjing 210029, P.R. China
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Rohner E, Wyss N, Heg Z, Faralli Z, Mbulaiteye SM, Novak U, Zwahlen M, Egger M, Bohlius J. HIV and human herpesvirus 8 co-infection across the globe: Systematic review and meta-analysis. Int J Cancer 2015; 138:45-54. [PMID: 26175054 DOI: 10.1002/ijc.29687] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2015] [Revised: 06/22/2015] [Accepted: 06/30/2015] [Indexed: 11/06/2022]
Abstract
HIV-infection is an important risk factor for developing Kaposi sarcoma (KS), but it is unclear whether HIV-positive persons are also at increased risk of co-infection with human herpesvirus 8 (HHV-8), the infectious cause of KS. We systematically searched literature up to December 2012 and included studies reporting HHV-8 seroprevalence for HIV-positive and HIV-negative persons. We used random-effects meta-analysis to combine odds ratios (ORs) of the association between HIV and HHV-8 seropositivity and conducted random-effects meta-regression to identify sources of heterogeneity. We included 93 studies with 58,357 participants from 32 countries in sub-Saharan Africa, North and South America, Europe, Asia, and Australia. Overall, HIV-positive persons were more likely to be HHV-8 seropositive than HIV-negative persons (OR 1.99, 95% confidence interval [CI] 1.70-2.34) with considerable heterogeneity among studies (I(2) 84%). The association was strongest in men who have sex with men (MSM, OR 3.95, 95% CI 2.92-5.35), patients with hemophilia (OR 3.11, 95% CI 1.19-8.11), and children (OR 2.45, 95% CI 1.58-3.81), but weaker in heterosexuals who engage in low-risk (OR 1.42, 95% CI 1.16-1.74) or high-risk sexual behavior (OR 1.66, 95% CI 1.27-2.17), persons who inject drugs (OR 1.66, 95% CI 1.28-2.14), and pregnant women (OR 1.68, 95% CI 1.15-2.47), p value for interaction <0.001. In conclusion, HIV-infection was associated with an increased HHV-8 seroprevalence in all population groups examined. A better understanding of HHV-8 transmission in different age and behavioral groups is needed to develop strategies to prevent HHV-8 transmission.
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Affiliation(s)
- Eliane Rohner
- Institute of Social and Preventive Medicine (ISPM), University of Bern, Bern, Switzerland
| | - Natascha Wyss
- Institute of Social and Preventive Medicine (ISPM), University of Bern, Bern, Switzerland
| | - Zina Heg
- Institute of Social and Preventive Medicine (ISPM), University of Bern, Bern, Switzerland
| | - Zully Faralli
- Institute of Social and Preventive Medicine (ISPM), University of Bern, Bern, Switzerland
| | - Sam M Mbulaiteye
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD
| | - Urban Novak
- Department of Medical Oncology, Inselspital, University Hospital, Bern, Switzerland
| | - Marcel Zwahlen
- Institute of Social and Preventive Medicine (ISPM), University of Bern, Bern, Switzerland
| | - Matthias Egger
- Institute of Social and Preventive Medicine (ISPM), University of Bern, Bern, Switzerland.,Centre for Infectious Disease Epidemiology & Research, School of Public Health & Family Medicine, University of Cape Town, Cape Town, South Africa
| | - Julia Bohlius
- Institute of Social and Preventive Medicine (ISPM), University of Bern, Bern, Switzerland
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Fan W, Tang Q, Shen C, Qin D, Lu C, Yan Q. Preparation and characterization of polyclonal antibody against Kaposi's sarcoma-associated herpesvirus lytic gene encoding RTA. Folia Microbiol (Praha) 2015; 60:473-81. [PMID: 25832009 DOI: 10.1007/s12223-015-0387-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Accepted: 03/15/2015] [Indexed: 12/30/2022]
Abstract
Replication and transcription activator (RTA) is a critical lytic protein encoded by Kaposi's sarcoma-associated herpesvirus (KSHV). To prepare rabbit polyclonal antibody against RTA, three antigenic polypeptides of KSHV RTA were initially synthesized. The fragment of RTA was cloned into p3FlagBsd to construct the recombinant plasmid, pRTA-Flag. 293 T and EA.hy926 cells were transfected with pRTA-Flag to obtain RTA-Flag fusion protein, which was detected using anti-Flag antibody. Next, New Zealand white rabbits were immunized with keyhole limpet hemocyanin-conjugated peptides to generate polyclonal antibodies against RTA. Enzyme-linked immunosorbent assays were performed to characterize the polyclonal antibodies, and the titers of the polyclonal antibodies against RTA were greater than 1:11,000. Western blotting and immunofluorescence assay revealed that the prepared antibody reacted specifically with the RTA-Flag fusion protein as well as the native viral protein in KSHV-infected primary effusion lymphoma cells. Collectively, our work successfully constructed the recombinant expression vector, pRTA-Flag, and prepared the polyclonal antibody against RTA, which was valuable for investigating the biochemical and biological functions of the critical KSHV lytic gene.
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Affiliation(s)
- Weifei Fan
- Department of Oncology, Jiangsu Province Official Hospital, 65 Jiangsu Road, Nanjing, 210024, People's Republic of China
| | - Qiao Tang
- Department of Clinical Laboratory, The Affiliated Nanjing First Hospital of Nanjing Medical University, Nanjing, 210029, People's Republic of China
| | - Chenyou Shen
- Department of Microbiology, Nanjing Medical University, Nanjing, Jiangsu, 210029, People's Republic of China
| | - Di Qin
- Department of Microbiology, Nanjing Medical University, Nanjing, Jiangsu, 210029, People's Republic of China
| | - Chun Lu
- Department of Microbiology, Nanjing Medical University, Nanjing, Jiangsu, 210029, People's Republic of China
| | - Qin Yan
- Department of Microbiology, Nanjing Medical University, Nanjing, Jiangsu, 210029, People's Republic of China.
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Abstract
Kaposi’s sarcoma-associated herpesvirus (KSHV) primarily persists as a latent episome in infected cells. During latent infection, only a limited number of viral genes are expressed that help to maintain the viral episome and prevent lytic reactivation. The latent KSHV genome persists as a highly ordered chromatin structure with bivalent chromatin marks at the promoter-regulatory region of the major immediate-early gene promoter. Various stimuli can induce chromatin modifications to an active euchromatic epigenetic mark, leading to the expression of genes required for the transition from the latent to the lytic phase of KSHV life cycle. Enhanced replication and transcription activator (RTA) gene expression triggers a cascade of events, resulting in the modulation of various cellular pathways to support viral DNA synthesis. RTA also binds to the origin of lytic DNA replication to recruit viral, as well as cellular, proteins for the initiation of the lytic DNA replication of KSHV. In this review we will discuss some of the pivotal genetic and epigenetic factors that control KSHV reactivation from the transcriptionally restricted latent program.
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35
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Deng Z, Uehara T, Maeda H, Hasegawa M, Matayoshi S, Kiyuna A, Agena S, Pan X, Zhang C, Yamashita Y, Xie M, Suzuki M. Epstein-Barr virus and human papillomavirus infections and genotype distribution in head and neck cancers. PLoS One 2014; 9:e113702. [PMID: 25405488 PMCID: PMC4236156 DOI: 10.1371/journal.pone.0113702] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2014] [Accepted: 10/28/2014] [Indexed: 12/17/2022] Open
Abstract
OBJECTIVE To investigate the prevalence, genotypes, and prognostic values of Epstein-Barr virus (EBV) and human papillomavirus (HPV) infections in Japanese patients with different types of head and neck cancer (HNC). METHODS AND MATERIALS HPV and EBV DNA, EBV genotypes and LMP-1 variants, and HPV mRNA expression were detected by PCR from fresh-frozen HNC samples. HPV genotypes were determined by direct sequencing, and EBV encoded RNA (EBER) was examined by in situ hybridization. RESULTS Of the 209 HNC patients, 63 (30.1%) had HPV infection, and HPV-16 was the most common subtype (86.9%). HPV E6/E7 mRNA expression was found in 23 of 60 (38.3%) HPV DNA-positive cases detected. The site of highest prevalence of HPV was the oropharynx (45.9%). Among 146 (69.9%) HNCs in which EBV DNA was identified, 107 (73.3%) and 27 (18.5%) contained types A and B, respectively, and 124 (84.9%) showed the existence of del-LMP-1. However, only 13 (6.2%) HNCs were positive for EBER, 12 (92.3%) of which derived from the nasopharynx. Co-infection of HPV and EBER was found in only 1.0% of HNCs and 10.0% of NPCs. Kaplan-Meier survival analysis showed significantly better disease-specific and overall survival in the HPV DNA+/mRNA+ oropharyngeal squamous cell carcinoma (OPC) patients than in the other OPC patients (P = 0.027 and 0.017, respectively). Multivariate analysis showed that stage T1-3 (P = 0.002) and HPV mRNA-positive status (P = 0.061) independently predicted better disease-specific survival. No significant difference in disease-specific survival was found between the EBER-positive and -negative NPC patients (P = 0.155). CONCLUSIONS Our findings indicate that co-infection with HPV and EBV is rare in HNC. Oropharyngeal SCC with active HPV infection was related to a highly favorable outcome, while EBV status was not prognostic in the NPC cohort.
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Affiliation(s)
- Zeyi Deng
- Department of Otorhinolaryngology, Head and Neck Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
- Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan
- * E-mail: (ZD); (MX)
| | - Takayuki Uehara
- Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan
| | - Hiroyuki Maeda
- Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan
| | - Masahiro Hasegawa
- Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan
| | - Sen Matayoshi
- Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan
| | - Asanori Kiyuna
- Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan
| | - Shinya Agena
- Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan
| | - Xiaoli Pan
- Department of Otorhinolaryngology, Head and Neck Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
- Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan
| | - Chunlin Zhang
- Department of Otorhinolaryngology, Head and Neck Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
- Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan
| | - Yukashi Yamashita
- Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan
| | - Minqiang Xie
- Department of Otorhinolaryngology, Head and Neck Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, China
- * E-mail: (ZD); (MX)
| | - Mikio Suzuki
- Department of Otorhinolaryngology, Head and Neck Surgery, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan
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Interplay between Kaposi's sarcoma-associated herpesvirus and the innate immune system. Cytokine Growth Factor Rev 2014; 25:597-609. [PMID: 25037686 DOI: 10.1016/j.cytogfr.2014.06.001] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2014] [Accepted: 06/16/2014] [Indexed: 02/04/2023]
Abstract
Understanding of the innate immune response to viral infections is rapidly progressing, especially with regards to the detection of DNA viruses. Kaposi's sarcoma-associated herpesvirus (KSHV) is a large dsDNA virus that is responsible for three human diseases: Kaposi's sarcoma, primary effusion lymphoma and multicentric Castleman's disease. The major target cells of KSHV (B cells and endothelial cells) express a wide range of pattern recognition receptors (PRRs) and play a central role in mobilizing inflammatory responses. On the other hand, KSHV encodes an array of immune evasion genes, including several pirated host genes, which interfere with multiple aspects of the immune response. This review summarizes current understanding of innate immune recognition of KSHV and the role of immune evasion genes that shape the antiviral and inflammatory responses.
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Phipps W, Saracino M, Selke S, Huang ML, Jaoko W, Mandaliya K, Wald A, Casper C, McClelland RS. Oral HHV-8 replication among women in Mombasa, Kenya. J Med Virol 2014; 86:1759-65. [PMID: 24692069 DOI: 10.1002/jmv.23941] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/11/2014] [Indexed: 01/08/2023]
Abstract
Human herpesvirus-8 (HHV-8) replication in the oropharynx may play an important role in HHV-8 transmission and contribute to the development of Kaposi sarcoma (KS) in some individuals. Studies in the United States and Europe report high rates of HHV-8 DNA detection in saliva of HHV-8 infected men, but little is known about the natural history of HHV-8 among persons in sub-Saharan Africa, where prevalence of HHV-8 infection and KS is greatest. To address this gap, this study evaluated oral HHV-8 replication in a cohort of 40 HHV-8 seropositive Kenyan women. Study clinicians collected daily oral swabs from participants for up to 30 consecutive days, and swab samples were tested for HHV-8 DNA using quantitative, real-time polymerase chain reaction. HHV-8 was detected at least once in 27 (68%) participants, and the overall shedding rate was 23%. On days with HHV-8 detection, mean HHV-8 quantity was 4.5 log10 copies/ml. Among HIV-infected women, CD4 count ≥500 cells/mm(3) versus <500 cells/mm(3) was associated with higher HHV-8 copy number (4.8 log10 copies/ml vs. 3.4 log10 copies/ml; coef 1.2 [95% CI, 0.5-1.9]; P = 0.001) and a higher HHV-8 shedding rate (49% vs.12%; RR, 4.2 [95% CI, 0.8-21.4]; P = 0.08). No other factors were associated with HHV-8 shedding rate or copy number. The study demonstrates high rates and quantity of HHV-8 in the oropharynx of HHV-8 seropositive African women. These findings support the observation that oral replication is an essential feature of HHV-8 infection, with likely implications for HHV-8 transmission and KS pathogenesis.
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Affiliation(s)
- Warren Phipps
- Department of Medicine, University of Washington, Seattle, Washington; Vaccine and Infectious Diseases Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
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Systematic analysis of a xenograft mice model for KSHV+ primary effusion lymphoma (PEL). PLoS One 2014; 9:e90349. [PMID: 24587336 PMCID: PMC3938717 DOI: 10.1371/journal.pone.0090349] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2013] [Accepted: 01/28/2014] [Indexed: 11/19/2022] Open
Abstract
Kaposi's sarcoma-associated herpesvirus is the causative agent of primary effusion lymphoma (PEL), which arises preferentially in the setting of infection with human immunodeficiency virus (HIV). Even with standard cytotoxic chemotherapy, PEL continues to cause high mortality rates, requiring the development of novel therapeutic strategies. PEL xenograft models employing immunodeficient mice have been used to study the in vivo effects of a variety of therapeutic approaches. However, it remains unclear whether these xenograft models entirely reflect clinical presentations of KSHV(+) PEL, especially given the recent description of extracavitary solid tumor variants arising in patients. In addition, effusion and solid tumor cells propagated in vivo exhibit unique biology, differing from one another or from their parental cell lines propagated through in vitro culture. Therefore, we used a KSHV(+) PEL/BCBL-1 xenograft model involving non-obese diabetic/severe-combined immunodeficient (NOD/SCID) mice, and compared characteristics of effusion and solid tumors with their parent cell culture-derived counterparts. Our results indicate that although this xenograft model can be used for study of effusion and solid lymphoma observed in patients, tumor cells in vivo display unique features to those passed in vitro, including viral lytic gene expression profile, rate of solid tumor development, the host proteins and the complex of tumor microenvironment. These items should be carefully considered when the xenograft model is used for testing novel therapeutic strategies against KSHV-related lymphoma.
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Inhibition of Kaposi's sarcoma-associated herpesvirus lytic replication by HIV-1 Nef and cellular microRNA hsa-miR-1258. J Virol 2014; 88:4987-5000. [PMID: 24554664 DOI: 10.1128/jvi.00025-14] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
UNLABELLED Kaposi's sarcoma-associated herpesvirus (KSHV) is causally linked to several AIDS-related malignancies, including Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman's disease. The interaction of human immunodeficiency virus type 1 (HIV-1) and KSHV has a central role in promoting the aggressive manifestations of AIDS-KS. We have previously shown that negative factor (Nef), a secreted HIV-1 protein, synergizes with KSHV viral interleukin-6 (vIL-6) to promote angiogenesis and tumorigenesis by activating the AKT pathway (X. Zhu, et al., Oncogene, 22 April 2013, http://dx.doi.org/10.1038/onc.2013.136). Here, we further demonstrated the role of soluble and ectopic Nef in the regulation of KSHV latency. We found that both soluble Nef protein and ectopic expression of Nef by transfection suppressed the expression of KSHV viral lytic mRNA transcripts and proteins and the production of infectious viral particles. MicroRNA (miRNA) microarray analysis identified a number of Nef-regulated miRNAs. Bioinformatics and luciferase reporter analyses showed that one of the Nef-upregulated miRNAs, cellular miRNA 1258 (hsa-miR-1258), directly targeted a seed sequence in the 3' untranslated region (UTR) of the mRNA encoding the major lytic switch protein (RTA), which controls KSHV reactivation from latency. Ectopic expression of hsa-miR-1258 impaired RTA synthesis and enhanced Nef-mediated inhibition of KSHV replication, whereas repression of hsa-miR-1258 has the opposite effect. Mutation of the seed sequence in the RTA 3'UTR abolished downregulation of RTA by hsa-miR-1258. Collectively, these novel findings demonstrate that, by regulating cellular miRNA, Nef may inhibit KSHV replication to promote viral latency and contribute to the pathogenesis of AIDS-related malignancies. IMPORTANCE This study found that Nef, a secreted HIV-1 protein, suppressed KSHV lytic replication to promote KSHV latency. Mechanistic studies indicated that a Nef-upregulated cellular miRNA, hsa-miR-1258, inhibits KSHV replication by directly targeting a seed sequence in the KSHV RTA 3'UTR. These results illustrate that, in addition to viral miRNAs, cellular miRNAs also play an important role in regulating the life cycle of KSHV. Overall, this is the first study to report the involvement of Nef in KSHV latency, implying its likely important role in the pathogenesis of AIDS-related malignancies.
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Maskew M, MacPhail AP, Whitby D, Egger M, Fox MP. Kaposi sarcoma-associated herpes virus and response to antiretroviral therapy: a prospective study of HIV-infected adults. J Acquir Immune Defic Syndr 2013; 63:442-8. [PMID: 23614996 PMCID: PMC3712196 DOI: 10.1097/qai.0b013e3182969cc1] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND The possible impact of coinfection with the Kaposi sarcoma-associated herpes virus (KSHV) on the response to antiretroviral therapy (ART) is unknown. Prospective studies are rare, particularly in Africa. METHODS We enrolled a prospective cohort of HIV-infected adults initiating ART in Johannesburg, South Africa. The subjects were defined as seropositive to KSHV if they were reactive to either KSHV lytic K8.1 or latent Orf73 antigen or to both. The subjects were followed from ART initiation until 18 months of treatment. HIV viral load and CD4 counts were tested 6 monthly. Linear generalized estimating and log-binomial regression models were used to estimate the effect of KSHV infection on immunologic recovery and response and HIV viral load suppression within 18 months after ART initiation. RESULTS Three hundred eighty-five subjects initiating ART from November 2008 to March 2009 were considered to be eligible including 184 (48%) KSHV+. The KSHV+ group was similar to the KSHV- in terms of age, gender, initiating CD4 count, body mass index, tuberculosis, and hemoglobin levels. The KSHV+ group gained a similar number of cells at 6 [difference of 10 cells per cubic millimeter, 95% confidence interval (CI): -11 to 31], 12 (3 cells per cubic millimeter, 95% CI: -19 to 25), and 18 months (24 cells per cubic millimeter, 95% CI: -13 to 61) compared with that gained by the KSHV- group. Adjusted relative risk of failure to suppress viral load to <400 copies per milliliter (1.03; 95% CI: 0.90 to 1.17) were similar for KSHV+ and KSHV- by 6 months on treatment. CONCLUSIONS In a population with a high KSHV prevalence, HIV-positive adults coinfected with KSHV achieved similar immunologic and virologic responses to ART early after treatment initiation compared with those with KSHV-.
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Affiliation(s)
- Mhairi Maskew
- Health Economics and Epidemiology Research Office, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South
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Toth Z, Brulois K, Jung JU. The chromatin landscape of Kaposi's sarcoma-associated herpesvirus. Viruses 2013; 5:1346-73. [PMID: 23698402 PMCID: PMC3712311 DOI: 10.3390/v5051346] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2013] [Revised: 05/17/2013] [Accepted: 05/17/2013] [Indexed: 12/15/2022] Open
Abstract
Kaposi's sarcoma-associated herpesvirus is an oncogenic γ-herpesvirus that causes latent infection in humans. In cells, the viral genome adopts a highly organized chromatin structure, which is controlled by a wide variety of cellular and viral chromatin regulatory factors. In the past few years, interrogation of the chromatinized KSHV genome by whole genome-analyzing tools revealed that the complex chromatin landscape spanning the viral genome in infected cells has important regulatory roles during the viral life cycle. This review summarizes the most recent findings regarding the role of histone modifications, histone modifying enzymes, DNA methylation, microRNAs, non-coding RNAs and the nuclear organization of the KSHV epigenome in the regulation of latent and lytic viral gene expression programs as well as their connection to KSHV-associated pathogenesis.
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Affiliation(s)
- Zsolt Toth
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Harlyne J. Norris Cancer Research Tower, 1450 Biggy Street, Los Angeles, CA 90033, USA.
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Zhu X, Guo Y, Yao S, Yan Q, Xue M, Hao T, Zhou F, Zhu J, Qin D, Lu C. Synergy between Kaposi's sarcoma-associated herpesvirus (KSHV) vIL-6 and HIV-1 Nef protein in promotion of angiogenesis and oncogenesis: role of the AKT signaling pathway. Oncogene 2013; 33:1986-96. [PMID: 23604117 DOI: 10.1038/onc.2013.136] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2012] [Revised: 02/04/2013] [Accepted: 02/28/2013] [Indexed: 12/16/2022]
Abstract
Kaposi's sarcoma-associated herpesvirus (KSHV) is the cause of Kaposi's sarcoma (KS), which is the most common AIDS-associated malignancy. KS is characterized by neovascularization and spindle cell proliferation. The interaction between HIV-1 and KSHV has a central role in promoting the aggressive manifestations of KS in AIDS patients; however, the pathogenesis underlying AIDS-related KS (AIDS-KS) remains unknown. Herein, we examined the potential of HIV-1 negative factor (Nef) to impact KSHV viral interleukin-6 (vIL-6)-induced angiogenesis and tumorigenesis. In vitro experiments showed that exogenous Nef penetrated vIL-6-expressing endothelial cells. Both internalized and ectopic expression of Nef in endothelial cells and fibroblasts synergized with vIL-6 to promote vascular tube formation and cell proliferation. Using a chicken chorioallantoic membrane (CAM) model, we demonstrated that Nef synergistically promotes vIL-6-induced angiogenesis and tumorigenesis. Animal experiments further showed that Nef facilitates vIL-6-induced angiogenesis and tumor formation in athymic nu/nu mice. Mechanistic studies indicated that Nef synergizes with vIL-6 to enhance angiogenesis and tumorigenesis by activating the AKT pathway in the CAM model, as well as nude mice. LY294002, a specific inhibitor of phosphatidylinositol-3-kinase (PI3K), significantly impaired the ability of Nef to promote vIL-6-induced tumorigenesis in an allograft model of nude mice. Our data provide first-line evidence that Nef may contribute to the pathogenesis underlying AIDS-KS in synergy with vIL-6. These novel findings also suggest that targeting the PI3K/AKT signal may be a potentially effective therapeutic approach in AIDS-KS patients.
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Affiliation(s)
- X Zhu
- 1] State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, PR China [2] Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, PR China [3] Department of Microbiology and Immunology, Nanjing Medical University, Nanjing, PR China [4] Department of Laboratory Medicine, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, PR China
| | - Y Guo
- Department of Microbiology and Immunology, Nanjing Medical University, Nanjing, PR China
| | - S Yao
- Medical School, Quzhou College of Technology, Quzhou, PR China
| | - Q Yan
- Department of Microbiology and Immunology, Nanjing Medical University, Nanjing, PR China
| | - M Xue
- Department of Microbiology and Immunology, Nanjing Medical University, Nanjing, PR China
| | - T Hao
- Department of Microbiology and Immunology, Nanjing Medical University, Nanjing, PR China
| | - F Zhou
- Department of Microbiology and Immunology, Nanjing Medical University, Nanjing, PR China
| | - J Zhu
- Cancer Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - D Qin
- Department of Microbiology and Immunology, Nanjing Medical University, Nanjing, PR China
| | - C Lu
- 1] State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, PR China [2] Key Laboratory of Pathogen Biology of Jiangsu Province, Nanjing Medical University, Nanjing, PR China [3] Department of Microbiology and Immunology, Nanjing Medical University, Nanjing, PR China
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Knowlton ER, Lepone LM, Li J, Rappocciolo G, Jenkins FJ, Rinaldo CR. Professional antigen presenting cells in human herpesvirus 8 infection. Front Immunol 2013; 3:427. [PMID: 23346088 PMCID: PMC3549500 DOI: 10.3389/fimmu.2012.00427] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2012] [Accepted: 12/24/2012] [Indexed: 12/18/2022] Open
Abstract
Professional antigen presenting cells (APC), i.e., dendritic cells (DC), monocytes/macrophages, and B lymphocytes, are critically important in the recognition of an invading pathogen and presentation of antigens to the T cell-mediated arm of immunity. Human herpesvirus 8 (HHV-8) is one of the few human viruses that primarily targets these APC for infection, altering their cytokine profiles, manipulating their surface expression of MHC molecules, and altering their ability to activate HHV-8-specific T cells. This could be why T cell responses to HHV-8 antigens are not very robust. Of these APC, only B cells support complete, lytic HHV-8 infection. However, both complete and abortive virus replication cycles in APC could directly affect viral pathogenesis and progression to Kaposi's sarcoma (KS) and HHV-8-associated B cell cancers. In this review, we discuss the effects of HHV-8 infection on professional APC and their relationship to the development of KS and B cell lymphomas.
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Affiliation(s)
- Emilee R Knowlton
- Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh Pittsburgh, PA, USA
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44
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Bhatt AP, Damania B. AKTivation of PI3K/AKT/mTOR signaling pathway by KSHV. Front Immunol 2013; 3:401. [PMID: 23316192 PMCID: PMC3539662 DOI: 10.3389/fimmu.2012.00401] [Citation(s) in RCA: 94] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2012] [Accepted: 12/12/2012] [Indexed: 12/21/2022] Open
Abstract
As an obligate intracellular parasite, Kaposi sarcoma-associated herpesvirus (KSHV) relies on the host cell machinery to meet its needs for survival, viral replication, production, and dissemination of progeny virions. KSHV is a gammaherpesvirus that is associated with three different malignancies: Kaposi sarcoma (KS), and two B cell lymphoproliferative disorders, primary effusion lymphoma (PEL) and multicentric Castleman’s disease. KSHV viral proteins modulate the cellular phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway, which is a ubiquitous pathway that also controls B lymphocyte proliferation and development. We review the mechanisms by which KSHV manipulates the PI3K/AKT/mTOR pathway, with a specific focus on B cells.
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Affiliation(s)
- Aadra P Bhatt
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill Chapel Hill, NC, USA ; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill Chapel Hill, NC, USA
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45
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Cappelletti M, Taddeo A, Colombo E, Brambilla L, Bellinvia M, Pregliasco F, Villa ML, Della Bella S. Immunogenicity and safety of seasonal influenza vaccination in patients with classic Kaposi's sarcoma. J Invest Dermatol 2012; 132:2414-2421. [PMID: 22622418 DOI: 10.1038/jid.2012.151] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Classic Kaposi's sarcoma (cKS) is a human herpesvirus-8 (HHV-8)-associated lympho-angioproliferative tumor typically occurring in the elderly. It is associated with HHV-8-driven perturbed balance of peripheral B-cell subsets, which may have an impact on immune responses to antigenic stimulation. We took advantage of the common practice of cKS patients to undergo seasonal influenza vaccination because of advanced age and analyzed the immunogenicity and safety of licensed trivalent influenza vaccine in 46 cKS patients and 44 matched controls. Licensure criteria for immunogenicity were fulfilled in both groups. Four weeks after vaccination, hemagglutination-inhibition antibody titers against each viral strain contained in the vaccine increased in patients and controls (all P<0.001). Protection against at least one strain was achieved by 96% of cKS and 91% of control subjects. Protection against all strains persisted after 12 weeks, demonstrating a long-lasting response to vaccination. The vaccine was equally well tolerated by patients and controls, as assessed by evaluating solicited local and systemic reactions to the vaccine, and appearance or increase of antinuclear autoantibodies. HHV-8 virological rebound was observed in four cKS patients, but was not accompanied by progression of KS lesions. We conclude that seasonal influenza vaccine given to cKS patients is immunogenic and safe.
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Affiliation(s)
- Monica Cappelletti
- Department of Biomedical Sciences and Technologies, University of Milan, Milano, Italy
| | - Adriano Taddeo
- Department of Biomedical Sciences and Technologies, University of Milan, Milano, Italy
| | - Elena Colombo
- Department of Biomedical Sciences and Technologies, University of Milan, Milano, Italy
| | - Lucia Brambilla
- Institute of Dermatological Sciences, Fondazione IRCCS Ospedale Maggiore Policlinico Mangiagalli e Regina Elena, Milano, Italy
| | - Monica Bellinvia
- Institute of Dermatological Sciences, Fondazione IRCCS Ospedale Maggiore Policlinico Mangiagalli e Regina Elena, Milano, Italy
| | - Fabrizio Pregliasco
- Department of Public Health, Microbiology and Virology, University of Milan, Milano, Italy
| | - Maria L Villa
- Department of Biomedical Sciences and Technologies, University of Milan, Milano, Italy
| | - Silvia Della Bella
- Department of Translational Medicine, University of Milan, Laboratory of Clinical and Experimental Immunology, IRCCS Istituto Clinico Humanitas, Rozzano (Milano), Italy.
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Morrison WB. Inflammation and cancer: a comparative view. J Vet Intern Med 2011; 26:18-31. [PMID: 22151229 DOI: 10.1111/j.1939-1676.2011.00836.x] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2010] [Revised: 09/22/2011] [Accepted: 10/05/2011] [Indexed: 12/11/2022] Open
Abstract
Rudolph Virchow first speculated on a relationship between inflammation and cancer more than 150 years ago. Subsequently, chronic inflammation and associated reactive free radical overload and some types of bacterial, viral, and parasite infections that cause inflammation were recognized as important risk factors for cancer development and account for one in four of all human cancers worldwide. Even viruses that do not directly cause inflammation can cause cancer when they act in conjunction with proinflammatory cofactors or when they initiate or promote cancer via the same signaling pathways utilized in inflammation. Whatever its origin, inflammation in the tumor microenvironment has many cancer-promoting effects and aids in the proliferation and survival of malignant cells and promotes angiogenesis and metastasis. Mediators of inflammation such as cytokines, free radicals, prostaglandins, and growth factors can induce DNA damage in tumor suppressor genes and post-translational modifications of proteins involved in essential cellular processes including apoptosis, DNA repair, and cell cycle checkpoints that can lead to initiation and progression of cancer.
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Affiliation(s)
- Wallace B Morrison
- Department of Veterinary Clinical Sciences, Purdue University, West Lafayette, IN, USA.
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47
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Emerging topics in human tumor virology. Int J Cancer 2011; 129:1289-99. [DOI: 10.1002/ijc.26087] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2011] [Accepted: 03/11/2011] [Indexed: 12/17/2022]
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48
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Rama I, Grinyó JM. Malignancy after renal transplantation: the role of immunosuppression. Nat Rev Nephrol 2011; 6:511-9. [PMID: 20736984 DOI: 10.1038/nrneph.2010.102] [Citation(s) in RCA: 138] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Outcomes of kidney transplantation, in terms of graft and patient survival, have improved over the past few decades, partly as a result of the introduction of new immunosuppressive drugs. Many immunosuppressive agents are associated with an increased risk of cardiovascular events and an increased risk of cancer, however, which can compromise patient survival. Cancer is more common among solid-organ transplant recipients than it is in the general population or in patients on dialysis. In fact, malignancy is the third most common cause of death in renal transplant recipients. Immunosuppressive treatments used in renal transplant recipients can cause malignancy by supporting oncogenesis caused by certain viruses or by impairing immune surveillance thereby enabling faster tumor growth. In this Review, we describe the epidemiological and clinical characteristics of common tumor types occurring after kidney transplantation, and the etiopathogenetic factors that lead to their appearance, with a particular focus on the relationship between immunosuppressive treatment and malignancy. Immunosuppressive drugs associated with an increased risk of malignancy after transplantation are also discussed, as are immunosuppressive drugs that seem to have antioncogenic properties.
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Affiliation(s)
- Inés Rama
- Hospital Universitari de Bellvitge, Feixa Llarga s/n 08907, L'Hospitalet de Llobregat, Barcelona, Spain
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49
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Ye F, Lei X, Gao SJ. Mechanisms of Kaposi's Sarcoma-Associated Herpesvirus Latency and Reactivation. Adv Virol 2011; 2011:193860. [PMID: 21625290 PMCID: PMC3103228 DOI: 10.1155/2011/193860] [Citation(s) in RCA: 126] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2010] [Revised: 03/06/2011] [Accepted: 03/07/2011] [Indexed: 01/09/2023] Open
Abstract
The life cycle of Kaposi's sarcoma-associated herpesvirus (KSHV) consists of latent and lytic replication phases. During latent infection, only a limited number of KSHV genes are expressed. However, this phase of replication is essential for persistent infection, evasion of host immune response, and induction of KSHV-related malignancies. KSHV reactivation from latency produces a wide range of viral products and infectious virions. The resulting de novo infection and viral lytic products modulate diverse cellular pathways and stromal microenvironment, which promote the development of Kaposi's sarcoma (KS). The mechanisms controlling KSHV latency and reactivation are complex, involving both viral and host factors, and are modulated by diverse environmental factors. Here, we review the cellular and molecular basis of KSHV latency and reactivation with a focus on the most recent advancements in the field.
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Affiliation(s)
- Fengchun Ye
- Tumor Virology Program, Greehey Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
- Department of Pediatrics, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
- Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| | - Xiufen Lei
- Tumor Virology Program, Greehey Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
- Department of Pediatrics, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
- Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| | - Shou-Jiang Gao
- Tumor Virology Program, Greehey Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
- Department of Pediatrics, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
- Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
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50
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Uldrick TS, Wang V, O’Mahony D, Aleman K, Wyvill KM, Marshall V, Steinberg SM, Pittaluga S, Maric I, Whitby D, Tosato G, Little RF, Yarchoan R. An interleukin-6-related systemic inflammatory syndrome in patients co-infected with Kaposi sarcoma-associated herpesvirus and HIV but without Multicentric Castleman disease. Clin Infect Dis 2010; 51:350-8. [PMID: 20583924 PMCID: PMC2946207 DOI: 10.1086/654798] [Citation(s) in RCA: 229] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND Kaposi sarcoma-associated herpesvirus (KSHV) is the causal agent for Kaposi sarcoma (KS) and multicentric Castleman disease (MCD) in human immunodeficiency virus (HIV)-infected patients. Patients with KSHV-MCD develop fevers, wasting, hypoalbuminemia, cytopenias, and hyponatremia that are related to overproduction of KSHV-encoded viral interleukin (IL)-6 (vIL-6) and human IL-6 (hIL-6). METHODS We identified 6 HIV-infected patients with KS or serological evidence of KSHV infection who had severe inflammatory MCD-like symptoms but in whom we could not diagnose MCD, and we hypothesized that these symptoms resulted from vIL-6 overproduction. Serum vIL-6 levels were assessed in these 6 patients and compared with levels in 8 control patients with symptomatic KSHV-MCD and 32 control patients with KS. KSHV viral load, serum hIL-6 level, and human IL-10 level were also evaluated. RESULTS Patients with inflammatory MCD-like symptoms but without MCD had elevated vIL-6 levels, comparable with levels in patients with symptomatic KSHV-MCD, and had levels that were significantly greater than those in control patients with KS (P = .003). Elevated hIL-6, IL-10, and KSHV viral loads were also comparable to patients with symptomatic KSHV-MCD and significantly greater than those with KS. CONCLUSIONS A subset of patients with HIV and KSHV co-infection, but without MCD, can develop severe systemic inflammatory symptoms associated with elevated levels of KSHV vIL-6, IL-6, and KSHV viral loads. Excess lytic activation of KSHV, production of the lytic gene product vIL6, and associated immunologic dysregulation may underlie the pathophysiology of these symptoms. This IL-6-related inflammatory syndrome is important to consider in critically ill patients with HIV and KSHV co-infection.
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Affiliation(s)
- Thomas S. Uldrick
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD
| | - Victoria Wang
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD
| | - Deirdre O’Mahony
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD
| | - Karen Aleman
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD
| | - Kathleen M. Wyvill
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD
| | - Vickie Marshall
- Viral Oncology Section, AIDS and Cancer Virus Program, SAIC-Frederick, National Cancer Institute–Frederick, Frederick, MD
| | - Seth M. Steinberg
- Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, Bethesda, MD
| | - Stefania Pittaluga
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD
| | - Irina Maric
- Hematology Service, National Institutes of Health Clinical Center, Bethesda, MD
| | - Denise Whitby
- Viral Oncology Section, AIDS and Cancer Virus Program, SAIC-Frederick, National Cancer Institute–Frederick, Frederick, MD
| | - Giovanna Tosato
- Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, MD
| | - Richard F. Little
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD
| | - Robert Yarchoan
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD
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