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Wang J, Brückner N, Weissmann S, Günther T, Zhu S, Vogt C, Sun G, Guo R, Bruno R, Ritter B, Steinbrück L, Kaufer BB, Depledge DP, Grundhoff A, Viejo-Borbolla A. Repression of varicella zoster virus gene expression during quiescent infection in the absence of detectable histone deposition. PLoS Pathog 2025; 21:e1012367. [PMID: 39928684 PMCID: PMC11838886 DOI: 10.1371/journal.ppat.1012367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 02/19/2025] [Accepted: 01/20/2025] [Indexed: 02/12/2025] Open
Abstract
Varicella zoster virus (VZV) is a human-specific herpesvirus that establishes latency in peripheral neurons. The only transcripts detected in infected human trigeminal ganglia (TG) obtained shortly after death correspond to the VZV latency-associated transcript (VLT) and associated VLT-ORF63 splice variants. In vitro studies showed that VLT-ORF63 is translated into a protein (pVLT-ORF63) that induces VZV transcription. The mechanisms that lead to this restricted gene expression and the transition to lytic replication remain unknown, partly due to the difficulty of working with human neurons. In this study, we addressed whether the neuroblastoma-derived cell line SH-SY5Y could serve as a model to investigate the mechanisms that lead to repression of VZV gene expression followed by reactivation. VZV productively infected differentiated SH-SY5Y (dSH-SY5Y) whereas incubation with acyclovir (ACV) inhibited virus replication and induced a progressive repression of the virus. Upon removal of ACV there was production of viral particles in a subset of cells, while others contained non-replicating VZV genomes and VLT-containing transcripts for at least 20 days post-infection (dpi). Exogenous expression of VLT-ORF63 induced productive infection, suggesting that the non-replicating and repressed genomes remained functional. Interestingly, histone deposition was undetectable at VZV genomes in quiescently infected dSH-SY5Y cells, pointing to a potential novel mechanism leading to VZV repression in this neuronal setting.
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Affiliation(s)
- Jiayi Wang
- Institute of Virology, Hannover Medical School, Hannover, Germany
| | - Nadine Brückner
- Institute of Virology, Hannover Medical School, Hannover, Germany
| | | | | | - Shuyong Zhu
- Institute of Virology, Hannover Medical School, Hannover, Germany
- Excellence Cluster RESIST, Hannover Medical School, Hannover, Germany
| | - Carolin Vogt
- Institute of Virology, Hannover Medical School, Hannover, Germany
- German Center for Infection Research (DZIF), Hannover, Germany
| | - Guorong Sun
- Institute of Virology, Hannover Medical School, Hannover, Germany
| | - Rongrong Guo
- Institute of Virology, Hannover Medical School, Hannover, Germany
| | - Renzo Bruno
- Institute of Virology, Hannover Medical School, Hannover, Germany
| | - Birgit Ritter
- Institute of Virology, Hannover Medical School, Hannover, Germany
| | - Lars Steinbrück
- Institute of Virology, Hannover Medical School, Hannover, Germany
| | | | - Daniel P. Depledge
- Institute of Virology, Hannover Medical School, Hannover, Germany
- Excellence Cluster RESIST, Hannover Medical School, Hannover, Germany
- German Center for Infection Research (DZIF), Hannover, Germany
| | | | - Abel Viejo-Borbolla
- Institute of Virology, Hannover Medical School, Hannover, Germany
- Excellence Cluster RESIST, Hannover Medical School, Hannover, Germany
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Cona A, Luppi M, Kodiyanplakkal RP, Perra S, Mularoni A, Malinis M. Riders on the Storm. Transpl Infect Dis 2025; 27:e14426. [PMID: 39731652 PMCID: PMC11827754 DOI: 10.1111/tid.14426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Accepted: 12/04/2024] [Indexed: 12/30/2024]
Abstract
This case involves a 52-year-old male, who underwent a deceased donor orthotopic liver transplant 7 months prior, presented with a 2-week history of persistent fever, anemia, thrombocytopenia, and mild elevation of liver enzymes. Upon hospital admission, the patient was febbrile, alert and oriented, hemodynamically stable. Laboratory exams revealed worsening leukopenia, anemia, thrombocytopenia, hyponatremia, and elevated ferritin. On hospital day 5, the general condition of the patient rapidly deteriorated with dyspnea, asthenia, and worsening fever and pancytopenia.Computed tomography revealed splenomegaly and minimal bilateral pleural effusion.
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Affiliation(s)
- Andrea Cona
- Unit of Infectious DiseasesIRCCS‐ISMETT Istituto Mediterraneo per i Trapianti e Terapie ad Alta SpecializzazionePalermoItaly
| | - Mario Luppi
- Section of Hematology, Department of Medical and Surgical SciencesUniversity of Modena and Reggio Emilia, AOU ModenaModenaItaly
| | | | - Simone Perra
- Unit of Infectious DiseasesIRCCS‐ISMETT Istituto Mediterraneo per i Trapianti e Terapie ad Alta SpecializzazionePalermoItaly
| | - Alessandra Mularoni
- Unit of Infectious DiseasesIRCCS‐ISMETT Istituto Mediterraneo per i Trapianti e Terapie ad Alta SpecializzazionePalermoItaly
| | - Maricar Malinis
- Division of Infectious DiseasesVanderbilt University Medical CenterNashvilleTennesseeUSA
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Yoshitomi Y, Kawashima A, Nakayama H, Nakamoto T, Ando N, Uemura H, Mizushima D, Aoki T, Tanuma J, Teruya K, Gatanaga H, Watanabe K. Local radiotherapy for chemotherapy-refractory Kaposi's sarcoma in an HIV-infected patient: A case report and literature review. J Infect Chemother 2024; 30:1061-1064. [PMID: 38387788 DOI: 10.1016/j.jiac.2024.02.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 01/08/2024] [Accepted: 02/19/2024] [Indexed: 02/24/2024]
Abstract
Human immunodeficiency virus-associated Kaposi's sarcoma (HIV-KS) is a well-documented vascular tumor with a pathogenesis involving human herpesvirus-8 (HHV-8) infection. While antiretroviral therapy (ART) and chemotherapy are effective for treating most KS cases, some become refractory. In this report, we present a case of a 58-year-old man with refractory HIV-KS treated with ART and chemotherapy. Chemotherapy was eventually discontinued due to an adverse reaction, and the patient presented with painful plantar lesions that impaired ambulation. With the exclusion of visceral metastases, localized radiotherapy was administered, which resulted in significant cosmetic and functional improvements. The patient regained ambulation and lived independently, receiving additional radiotherapy as needed. This case underscores the potential use of radiotherapy for the treatment of ART-resistant KS, particularly when the patient is unresponsive to conventional chemotherapy. It also highlights the need for future research in this area.
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Affiliation(s)
- Yutaro Yoshitomi
- AIDS Clinical Center, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku ku, Tokyo, Japan
| | - Akira Kawashima
- AIDS Clinical Center, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku ku, Tokyo, Japan; The Joint Research Center for Human Retrovirus Infection Kumamoto University Campus, Kumamoto City, Kumamoto, Japan.
| | - Hidetsugu Nakayama
- Department of Radiation Oncology, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku ku, Tokyo, Japan
| | - Takato Nakamoto
- AIDS Clinical Center, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku ku, Tokyo, Japan
| | - Naokatsu Ando
- AIDS Clinical Center, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku ku, Tokyo, Japan
| | - Haruka Uemura
- AIDS Clinical Center, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku ku, Tokyo, Japan
| | - Daisuke Mizushima
- AIDS Clinical Center, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku ku, Tokyo, Japan
| | - Takahiro Aoki
- AIDS Clinical Center, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku ku, Tokyo, Japan
| | - Junko Tanuma
- AIDS Clinical Center, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku ku, Tokyo, Japan
| | - Katsuji Teruya
- AIDS Clinical Center, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku ku, Tokyo, Japan
| | - Hiroyuki Gatanaga
- AIDS Clinical Center, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku ku, Tokyo, Japan; The Joint Research Center for Human Retrovirus Infection Kumamoto University Campus, Kumamoto City, Kumamoto, Japan
| | - Koji Watanabe
- AIDS Clinical Center, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku ku, Tokyo, Japan; The Joint Research Center for Human Retrovirus Infection Kumamoto University Campus, Kumamoto City, Kumamoto, Japan.
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4
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Okpara MO, Weaver F, Whitehouse A, Veale CGL, Edkins AL. Discovery of a small-molecule inhibitor of KSHV lytic replication from the MMV pandemic response box. Antiviral Res 2024; 230:105990. [PMID: 39154751 DOI: 10.1016/j.antiviral.2024.105990] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 08/02/2024] [Accepted: 08/14/2024] [Indexed: 08/20/2024]
Abstract
Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent for primary effusion lymphoma (PEL), multicentric Castleman's disease (MCD) and Kaposi's sarcoma (KS). KSHV is one of the oncoviruses that contribute to 1.5 million new infection-related cancer cases annually. Currently, there are no targeted therapies for KSHV-associated diseases. Through the development of a medium-throughput phenotype-based ELISA screening platform based on KSHV ORF57 protein detection, we screened the Medicines for Malaria Venture (MMV) Pandemic Response Box for non-cytotoxic inhibitors of KSHV lytic replication. MMV1645152 was identified as a promising inhibitor of KSHV lytic replication, suppressing KSHV immediate-early and late lytic gene expression and blocking the production of infectious KSHV virion particles at non-cytotoxic concentrations in cell line models of KSHV infection with or without EBV coinfection. MMV1645152 is a promising hit compound for the development of future therapeutic agents against KSHV-associated malignancies.
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Affiliation(s)
- Michael O Okpara
- Biomedical Biotechnology Research Unit (BioBRU), Department of Biochemistry and Microbiology, Rhodes University, Grahamstown, South Africa
| | - Frederick Weaver
- School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK
| | - Adrian Whitehouse
- Biomedical Biotechnology Research Unit (BioBRU), Department of Biochemistry and Microbiology, Rhodes University, Grahamstown, South Africa; School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK; Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, UK; LeedsOmics, University of Leeds, Leeds, LS2 9JT, UK
| | - Clinton G L Veale
- Department of Chemistry, University of Cape Town, Rondebosch, Cape Town, South Africa
| | - Adrienne L Edkins
- Biomedical Biotechnology Research Unit (BioBRU), Department of Biochemistry and Microbiology, Rhodes University, Grahamstown, South Africa; Centre for Chemico- and Biomedicinal Research (CCBR), Rhodes University, Grahamstown, South Africa.
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Najarro G, Brackett K, Woosley H, Dorman LC, Turon-Lagot V, Khadka S, Faeldonea C, Moreno OK, Negron AR, Love C, Ward R, Langelier C, McCarthy F, Gonzalez C, Elias JE, Gardner BM, Arias C. BiP/GRP78 is a pro-viral factor for diverse dsDNA viruses that promotes the survival and proliferation of cells upon KSHV infection. PLoS Pathog 2024; 20:e1012660. [PMID: 39471213 PMCID: PMC11548844 DOI: 10.1371/journal.ppat.1012660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 11/08/2024] [Accepted: 10/11/2024] [Indexed: 11/01/2024] Open
Abstract
The Endoplasmic Reticulum (ER)-resident HSP70 chaperone BiP (HSPA5) plays a crucial role in maintaining and restoring protein folding homeostasis in the ER. BiP's function is often dysregulated in cancer and virus-infected cells, conferring pro-oncogenic and pro-viral advantages. We explored BiP's functions during infection by the Kaposi's sarcoma-associated herpesvirus (KSHV), an oncogenic gamma-herpesvirus associated with cancers of immunocompromised patients. Our findings reveal that BiP protein levels are upregulated in infected epithelial cells during the lytic phase of KSHV infection. This upregulation occurs independently of the unfolded protein response (UPR), a major signaling pathway that regulates BiP availability. Genetic and pharmacological inhibition of BiP halts KSHV viral replication and reduces the proliferation and survival of KSHV-infected cells. Notably, inhibition of BiP limits the spread of other alpha- and beta-herpesviruses and poxviruses with minimal toxicity for normal cells. Our work suggests that BiP is a potential target for developing broad-spectrum antiviral therapies against double-stranded DNA viruses and a promising candidate for therapeutic intervention in KSHV-related malignancies.
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Affiliation(s)
- Guillermo Najarro
- University of California, Santa Barbara, California, United States of America
| | - Kevin Brackett
- University of California, Santa Barbara, California, United States of America
| | - Hunter Woosley
- Chan Zuckerberg BioHub, San Francisco, California, United States of America
| | - Leah C. Dorman
- Chan Zuckerberg BioHub, San Francisco, California, United States of America
| | | | - Sudip Khadka
- Chan Zuckerberg BioHub, San Francisco, California, United States of America
| | - Catya Faeldonea
- University of California, Santa Barbara, California, United States of America
| | | | | | - Christina Love
- Department of Medicine, University of California, San Francisco, California, United States of America
| | - Ryan Ward
- Department of Medicine, University of California, San Francisco, California, United States of America
| | - Charles Langelier
- Chan Zuckerberg BioHub, San Francisco, California, United States of America
- Department of Medicine, University of California, San Francisco, California, United States of America
| | - Frank McCarthy
- Chan Zuckerberg BioHub, San Francisco, California, United States of America
| | - Carlos Gonzalez
- Chan Zuckerberg BioHub, San Francisco, California, United States of America
| | - Joshua E. Elias
- Chan Zuckerberg BioHub, San Francisco, California, United States of America
| | - Brooke M. Gardner
- University of California, Santa Barbara, California, United States of America
| | - Carolina Arias
- University of California, Santa Barbara, California, United States of America
- Chan Zuckerberg BioHub, San Francisco, California, United States of America
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6
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Elamin S, Ibrahim SS, Mudawi H, Ali SEAM, Abdel-Satir A, Foad AFA. High malignancy rate in the absence of viral prophylaxis after kidney transplantation in Sudan. J Nephrol 2024; 37:1653-1659. [PMID: 38847938 DOI: 10.1007/s40620-024-01978-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Accepted: 04/26/2024] [Indexed: 10/15/2024]
Abstract
BACKGROUND Kidney transplantation in Sudan is funded by the government. Cytomegalovirus prophylaxis is provided for patients who receive biological induction or have recipient-negative donor-positive cytomegalovirus serology. Doctor Selma Center for Kidney Diseases joined the national kidney transplant program in May 2019. Since then, we observed the frequent occurrence of cancer in patients who received modest immunosuppression without viral prophylaxis. METHODS We retrospectively divided kidney transplant recipients between 2019 and 2021 into two groups according to cytomegalovirus prophylaxis and compared tumor occurrence rates. RESULTS The first group included 77 patients who did not receive biological induction or cytomegalovirus prophylaxis. The second group included 92 patients who received valganciclovir for 3-6 months. There was no other antiviral treatment except entecavir for chronic hepatitis B virus infection in eight patients. Five patients in the first group developed malignancy. The first patient presented eight months post-transplant with Kaposi sarcoma of the stomach and responded to treatment with sirolimus. The second patient presented nine months post-transplant with cutaneous Kaposi sarcoma and also responded to sirolimus. Two patients presented two and four months post-transplant with aggressive non-cutaneous Kaposi sarcoma that involved the gastrointestinal tract and lymphatic system and died soon afterwards. The fifth patient presented three years post-transplant with non-Hodgkin lymphoma of the duodenum and is currently receiving chemotherapy. Malignancy rate (6.5% vs 0.0%, P = 0.02) and Kaposi sarcoma rate (5.2% vs 0.0%, P = 0.04) were significantly higher in the first group. CONCLUSION In Sudan, omitting valganciclovir prophylaxis after kidney transplantation was associated with a high rate of virus-induced malignancy.
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Affiliation(s)
- Sarra Elamin
- Doctor Selma Center for Kidney Diseases, University of Khartoum, Khartoum, Sudan.
| | - Selma S Ibrahim
- Doctor Selma Center for Kidney Diseases, University of Khartoum, Khartoum, Sudan
| | - Hatim Mudawi
- Gastroenterology Unit, Soba University Hospital, University of Khartoum, Khartoum, Sudan
| | - Sara E A Mohamed Ali
- Gastroenterology Unit, Soba University Hospital, University of Khartoum, Khartoum, Sudan
| | | | - Ayman F A Foad
- Histopathology Department, National University, Khartoum, Sudan
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7
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Sin SH, Eason AB, Kim Y, Schneider JW, Damania B, Dittmer DP. The complete Kaposi sarcoma-associated herpesvirus genome induces early-onset, metastatic angiosarcoma in transgenic mice. Cell Host Microbe 2024; 32:755-767.e4. [PMID: 38653242 PMCID: PMC11305081 DOI: 10.1016/j.chom.2024.03.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 01/16/2024] [Accepted: 03/27/2024] [Indexed: 04/25/2024]
Abstract
Kaposi sarcoma (KS) is the most common cancer in persons living with HIV. It is caused by KS-associated herpesvirus (KSHV). There exists no animal model for KS. Pronuclear injection of the 170,000-bp viral genome induces early-onset, aggressive angiosarcoma in transgenic mice. The tumors are histopathologically indistinguishable from human KS. As in human KS, all tumor cells express the viral latency-associated nuclear antigen (LANA). The tumors transcribe most viral genes, whereas endothelial cells in other organs only transcribe the viral latent genes. The tumor cells are of endothelial lineage and exhibit the same molecular pattern of pathway activation as KS, namely phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR, interleukin-10 (IL-10), and vascular endothelial growth factor (VEGF). The KSHV-induced tumors are more aggressive than Ha-ras-induced angiosarcomas. Overall survival is increased by prophylactic ganciclovir. Thus, whole-virus KSHV-transgenic mice represent an accurate model for KS and open the door for the genetic dissection of KS pathogenesis and evaluation of therapies, including vaccines.
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Affiliation(s)
- Sang-Hoon Sin
- Lineberger Comprehensive Cancer Center and Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Anthony B Eason
- Lineberger Comprehensive Cancer Center and Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Yongbaek Kim
- Laboratory of Veterinary Clinical Pathology, College of Veterinary Medicine, Seoul National University, Seoul, Republic of Korea
| | - Johann W Schneider
- National Health Laboratory Service, Division of Anatomical Pathology, Faculty of Medicine and Health Sciences, Tygerberg Hospital, Stellenbosch University, Cape Town, South Africa
| | - Blossom Damania
- Lineberger Comprehensive Cancer Center and Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Dirk P Dittmer
- Lineberger Comprehensive Cancer Center and Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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Alsaeed A, AlKhalaf A, Alhudaifi A, Alwesaibi AA, Al Muhaif A, Alzaher W, Alsolami S. Castleman's Disease With Tongue Lesions in an HIV-Positive Patient From Saudi Arabia. Cureus 2023; 15:e50177. [PMID: 38186418 PMCID: PMC10771808 DOI: 10.7759/cureus.50177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/08/2023] [Indexed: 01/09/2024] Open
Abstract
Castleman's disease (CD) is a rare lymphoproliferative disorder that presents with heterogeneous clinical manifestations. We present a case report of a 34-year-old male patient co-infected with CD and HIV, who exhibited tongue lesions along with systemic symptoms. Prompt diagnosis and appropriate management, including antiretroviral therapy (ART) and targeted treatment for CD, resulted in significant clinical improvement. This case highlights the challenges faced in managing CD with tongue involvement in the setting of HIV infection and emphasizes the importance of comprehensive management strategies.
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Affiliation(s)
- Ali Alsaeed
- Internal Medicine, Dammam Medical Complex, Dammam, SAU
| | | | | | | | - Ali Al Muhaif
- Internal Medicine, Dammam Medical Complex, Dammam, SAU
| | - Waad Alzaher
- Internal Medicine, Dammam Medical Complex, Dammam, SAU
| | - Sana Alsolami
- Anatomical Pathology, Dammam Medical Complex, Dammam, SAU
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9
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Santos-Alonso C, Vaca Gallardo MA, Ferreira Bermejo M, López-Oliva MO, Afonso Ramos S, García EG, Santacruz Mancheno JC, García Fernández E, Ibarra Soraluce N, Jiménez Martín C. Multicentric Castleman's disease in kidney transplant: A case report and literature review. Nefrologia 2023; 43 Suppl 2:103-105. [PMID: 36564225 DOI: 10.1016/j.nefroe.2022.03.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 03/27/2022] [Indexed: 06/17/2023] Open
Affiliation(s)
| | | | | | | | - Sara Afonso Ramos
- Hospital Universitario La Paz, Department of Nephrology, Madrid, Spain
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10
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Volkow P, Chavez Galan L, Ramon-Luing L, Cruz-Velazquez J, Cornejo-Juarez P, Sada-Ovalle I, Perez-Padilla R, Islas-Muñoz B. Impact of valganciclovir therapy on severe IRIS-Kaposi Sarcoma mortality: An open-label, parallel, randomized controlled trial. PLoS One 2023; 18:e0280209. [PMID: 37195970 DOI: 10.1371/journal.pone.0280209] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 12/07/2022] [Indexed: 05/19/2023] Open
Abstract
INTRODUCTION High HHV-8 viral load (VL) in Kaposi Sarcoma (KS) has been associated with Severe Immune Reconstitution Inflammatory Syndrome (Severe-IRIS-KS), which can occur after initiating cART, and leads to high mortality, particularly in patients with pulmonary involvement. We investigate if valganciclovir (as an anti-HHV-8 agent) initiated before cART reduces the mortality associated with Severe-IRIS-KS and the incidence of Severe-IRIS-KS. METHODS Open-label parallel-group randomized clinical trial in AIDS cART naïve patients with disseminated KS (DKS) as defined by at least two of the following: pulmonary, lymph-node, or gastrointestinal involvement, lymphedema, or ≥30 skin lesions. In the experimental group (EG), patients received valganciclovir 900 mg BID four weeks before cART and continued until week 48; in the control group (CG), cART was initiated on week 0. Non-severe-IRIS-KS was defined as: an increase in the number of lesions plus a decrease of ≥one log10 HIV-VL, or an increase of ≥50cells/mm3 or ≥2-fold in baseline CD4+cells. Severe-IRIS-KS was defined as abrupt clinical worsening of KS lesions and/or fever after ruling out another infection following cART initiation, and at least three of the following: thrombocytopenia, anemia, hyponatremia, or hypoalbuminemia. RESULTS 40 patients were randomized and 37 completed the study. In the ITT analysis, at 48 weeks, total mortality was the same in both groups (3/20), severe-IRIS-KS attributable mortality was 0/20 in the EG, compared with 3/20 in the CG (p = 0.09), similar to the per-protocol analysis: 0/18 in the EG, and 3/19 in the control group (p = 0.09). The crude incidence rate of severe-IRIS-KS was four patients developed a total of 12 episodes of Severe-IRIS-KS in the CG and two patients developed one episode each in the EG. Mortality in patients with pulmonary KS was nil in the EG (0/5) compared with 3/4 in the CG (P = 0.048). No difference was found between groups in the number of non-S-IRIS-KS events. Among survivors at week 48, 82% achieved >80% remission. CONCLUSIONS Although mortality attributable to KS was lower in the EG the difference was not statistically significant.
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Affiliation(s)
- Patricia Volkow
- Infectious Disease Department, Instituto Nacional de Cancerología, Mexico City, Mexico
| | - Leslie Chavez Galan
- Integrative Inmunology Laboratory, Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico
| | - Lucero Ramon-Luing
- Integrative Inmunology Laboratory, Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico
| | | | | | - Isabel Sada-Ovalle
- Integrative Inmunology Laboratory, Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico
| | - Rogelio Perez-Padilla
- Department of Research on Tobacco and COPD, Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico
| | - Beda Islas-Muñoz
- Infectious Disease Department, Instituto Nacional de Cancerología, Mexico City, Mexico
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11
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Santos-Alonso C, Vaca Gallardo MA, Ferreira Bermejo M, López-Oliva MO, Afonso Ramos S, García EG, Santacruz Mancheno JC, García Fernández E, Ibarra Soraluce N, Jiménez Martín C. Multicentric Castleman's disease in kidney transplant: A case report and literature review. Nefrologia 2022. [DOI: 10.1016/j.nefro.2022.03.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
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Abstract
Kaposi's sarcoma-associated herpesvirus (KSHV)-associated primary effusion lymphomas (PEL) are traditionally viewed as homogenous regarding viral transcription and lineage of origin, but so far this contention has not been explored at the single-cell level. Single-cell RNA sequencing of latently infected PEL supports the existence of multiple subpopulations even within a single cell line. At most 1% of the cells showed evidence of near-complete lytic transcription. The majority of cells only expressed the canonical viral latent transcripts: those originating from the latency locus, the viral interferon regulatory factor locus, and the viral lncRNA nut-1/Pan/T1.1; however, a significant fraction of cells showed various degrees of more permissive transcription, and some showed no evidence of KSHV transcripts whatsoever. Levels of viral interleukin-6 (IL-6)/K2 mRNA emerged as the most distinguishing feature to subset KSHV-infected PEL. One newly uncovered phenotype is the existence of BCBL-1 cells that readily adhered to fibronectin and that displayed mesenchymal lineage-like characteristics. IMPORTANCE Latency is the defining characteristic of the Herpesviridae and central to the tumorigenesis phenotype of Kaposi's sarcoma-associated herpesvirus (KSHV). KSHV-driven primary effusion lymphomas (PEL) rapidly develop resistance to therapy, suggesting tumor instability and plasticity. At any given time, a fraction of PEL cells spontaneously reactivate KSHV, suggesting transcriptional heterogeneity even within a clonal cell line under optimal growth conditions. This study employed single-cell mRNA sequencing to explore the within-population variability of KSHV transcription and how it relates to host cell transcription. Individual clonal PEL cells exhibited differing patterns of viral transcription. Most cells showed the canonical pattern of KSHV latency (LANA, vCyc, vFLIP, Kaposin, and vIRFs), but a significant fraction evidenced extended viral gene transcription, including of the viral IL-6 homolog, open reading frame K2. This study suggests new targets of intervention for PEL. It establishes a conceptual framework to design KSHV cure studies analogous to those for HIV.
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13
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Valantin MA, Royston L, Hentzien M, Jary A, Makinson A, Veyri M, Ronot-Bregigeon S, Isnard S, Palich R, Routy JP. Therapeutic Perspectives in the Systemic Treatment of Kaposi's Sarcoma. Cancers (Basel) 2022; 14:484. [PMID: 35158752 PMCID: PMC8833559 DOI: 10.3390/cancers14030484] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 01/07/2022] [Accepted: 01/14/2022] [Indexed: 11/28/2022] Open
Abstract
In patients with Kaposi's sarcoma (KS), the therapeutic goal is to achieve a durable remission in the size and number of skin and visceral lesions. Although most patients show tumor regression in response to standard systemic chemotherapy regimens, alternative systemic treatments are needed for patients who develop refractory KS. Anti-angiogenic therapies represent attractive therapeutic targets in this context, due to the central role of angiogenesis in KS pathogenesis. Pomalidomide, which exhibits such anti-angiogenic activity through inhibition of VEGF, currently constitutes the most promising agent of this class and has been recently approved by the FDA. In addition, immune checkpoint blockade also represents an interesting alternative therapeutic approach through the restoration of immunity against HHV-8, the causative agent of KS, and improvement of tumor control. Although small series of cases treated successfully with these drugs have been reported, there is no marketing approval for anti-immune checkpoint antibodies for KS to date. In the present review, we will discuss potential therapeutic options for patients with recurrent or refractory KS, including systemic chemotherapies, immune checkpoint inhibitors, anti-herpesvirus agents, and anti-angiogenic drugs. Well-conducted clinical trials in this population are urgently needed to correctly address the efficacy of targeted agents and immunomodulators, while monitoring for adverse effects.
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Affiliation(s)
- Marc-Antoine Valantin
- Infectious Diseases Department, Pitié-Salpêtrière Hospital, AP-HP, Pierre Louis Epidemiology and Public Health Institute (iPLESP), INSERM U1136, Sorbonne University, 75013 Paris, France;
| | - Léna Royston
- Infectious Diseases and Immunity in Global Health Program & Chronic Viral Illness Service, McGill University Health Centre, Montréal, QC H4A3J1, Canada; (S.I.); (J.-P.R.)
- Division of Infectious Diseases, Geneva University Hospitals, 1205 Geneva, Switzerland
| | - Maxime Hentzien
- Service de Médecine Interne, Maladies Infectieuses, Immunologie Clinique, CHU Robert Debré, 51090 Reims, France;
| | - Aude Jary
- Service de Virologie, Pitié-Salpêtrière Hospital, AP-HP, Pierre Louis Epidemiology and Public Health Institute (iPLESP), INSERM U1136, Sorbonne University, 75013 Paris, France;
| | - Alain Makinson
- Infectious Diseases Department, INSERM U1175, University Hospital of Montpellier, 34000 Montpellier, France;
| | - Marianne Veyri
- Service d’Oncologie Médicale, Hôpitaux Universitaires Pitié Salpêtrière-Charles Foix, AP-HP, Pierre Louis Epidemiology and Public Health Institute (iPLESP), INSERM, Sorbonne University, 75013 Paris, France;
| | - Sylvie Ronot-Bregigeon
- Service d’Immuno-Hématologie Clinique, Hôpital Sainte-Marguerite, Aix Marseille Université, 13009 Marseille, France;
| | - Stéphane Isnard
- Infectious Diseases and Immunity in Global Health Program & Chronic Viral Illness Service, McGill University Health Centre, Montréal, QC H4A3J1, Canada; (S.I.); (J.-P.R.)
| | - Romain Palich
- Infectious Diseases Department, Pitié-Salpêtrière Hospital, AP-HP, Pierre Louis Epidemiology and Public Health Institute (iPLESP), INSERM U1136, Sorbonne University, 75013 Paris, France;
| | - Jean-Pierre Routy
- Infectious Diseases and Immunity in Global Health Program & Chronic Viral Illness Service, McGill University Health Centre, Montréal, QC H4A3J1, Canada; (S.I.); (J.-P.R.)
- Division of Hematology, McGill University Health Centre, Montréal, QC H4A3J1, Canada
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14
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Abstract
Human herpesviruses are large double-stranded DNA viruses belonging to the Herpesviridae family. The main characteristics of these viruses are their ability to establish a lifelong latency into the host with a potential to reactivate periodically. Primary infections and reactivations with herpesviruses are responsible for a large spectrum of diseases and may result in severe complications in immunocompromised patients. The viral DNA polymerase is a key enzyme in the replicative cycle of herpesviruses, and the target of most antiviral agents (i.e., nucleoside, nucleotide and pyrophosphate analogs). However, long-term prophylaxis and treatment with these antivirals may lead to the emergence of drug-resistant isolates harboring mutations in genes encoding viral enzymes that phosphorylate drugs (nucleoside analogs) and/or DNA polymerases, with potential cross-resistance between the different analogs. Drug resistance mutations mainly arise in conserved regions of the polymerase and exonuclease functional domains of these enzymes. In the polymerase domain, mutations associated with resistance to nucleoside/nucleotide analogs may directly or indirectly affect drug binding or incorporation into the primer strand, or increase the rate of extension of DNA to overcome chain termination. In the exonuclease domain, mutations conferring resistance to nucleoside/nucleotide analogs may reduce the rate of excision of incorporated drug, or continue DNA elongation after drug incorporation without excision. Mutations associated with resistance to pyrophosphate analogs may alter drug binding or the conformational changes of the polymerase domain required for an efficient activity of the enzyme. Novel herpesvirus inhibitors with a potent antiviral activity against drug-resistant isolates are thus needed urgently.
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Affiliation(s)
| | - Guy Boivin
- CHU de Québec-Université Laval, Quebec City, QC, Canada.
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15
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Naimo E, Zischke J, Schulz TF. Recent Advances in Developing Treatments of Kaposi's Sarcoma Herpesvirus-Related Diseases. Viruses 2021; 13:1797. [PMID: 34578378 PMCID: PMC8473310 DOI: 10.3390/v13091797] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 08/30/2021] [Accepted: 09/01/2021] [Indexed: 12/27/2022] Open
Abstract
Kaposi-sarcoma-associated herpesvirus (KSHV) or human herpesvirus 8 (HHV-8) is the causative agent of several malignancies, including Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD). Active KSHV replication has also been associated with a pathological condition called KSHV inflammatory cytokine syndrome (KICS), and KSHV may play a role in rare cases of post-transplant polyclonal lymphoproliferative disorders. Several commonly used herpesviral DNA polymerase inhibitors are active against KSHV in tissue culture. Unfortunately, they are not always efficacious against KSHV-induced diseases. To improve the outcome for the patients, new therapeutics need to be developed, including treatment strategies that target either viral proteins or cellular pathways involved in tumor growth and/or supporting the viral life cycle. In this review, we summarize the most commonly established treatments against KSHV-related diseases and review recent developments and promising new compounds that are currently under investigation or on the way to clinical use.
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Affiliation(s)
- Eleonora Naimo
- Institute of Virology, Hannover Medical School, 30625 Hannover, Germany; (E.N.); (J.Z.)
- German Centre for Infection Research, Hannover-Braunschweig Site, 38023 Braunschweig, Germany
| | - Jasmin Zischke
- Institute of Virology, Hannover Medical School, 30625 Hannover, Germany; (E.N.); (J.Z.)
- German Centre for Infection Research, Hannover-Braunschweig Site, 38023 Braunschweig, Germany
| | - Thomas F. Schulz
- Institute of Virology, Hannover Medical School, 30625 Hannover, Germany; (E.N.); (J.Z.)
- German Centre for Infection Research, Hannover-Braunschweig Site, 38023 Braunschweig, Germany
- Cluster of Excellence 2155 RESIST, Institute of Virology, Hannover Medical School, 30625 Hannover, Germany
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16
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Kaposi's Sarcoma-Associated Herpesvirus Processivity Factor, ORF59, Binds to Canonical and Linker Histones, and Its Carboxy Terminus Is Dispensable for Viral DNA Synthesis. J Virol 2021; 95:JVI.02169-20. [PMID: 33361421 DOI: 10.1128/jvi.02169-20] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 12/14/2020] [Indexed: 12/19/2022] Open
Abstract
Kaposi's sarcoma-associated herpesvirus (KSHV) is a human oncogenic virus and the causative agent of Kaposi's sarcoma, multicentric Castleman's disease, and primary effusion lymphoma. During lytic reactivation, there is a temporal cascade of viral gene expression that results in the production of new virions. One of the viral factors that is expressed during reactivation is open reading frame 59 (ORF59), the viral DNA polymerase processivity factor. ORF59 plays an essential role for DNA synthesis and is required for the nuclear localization of the viral DNA polymerase (ORF9) to the origin of lytic replication (oriLyt). In addition to its functions in viral DNA synthesis, ORF59 has been shown to interact with chromatin complexes, including histones and cellular methyltransferases. In this study, a series of KSHV BACmids containing 50-amino acid (aa) deletions within ORF59 were generated to determine the interaction domains between ORF59 and histones, as well as to assess the effects on replication fitness as a result of these interactions. These studies show that in the context of infection, ORF59 51 to 100 and 151 to 200 amino acids (aa) are required for interaction with histones, and ORF59 301 to 396 aa are not required for DNA synthesis. Since full-length ORF59 is known to localize to the nucleus, we performed an immunofluorescent assay (IFA) with the ORF59 deletion mutants and showed that all deletions are localized to the nucleus; this includes the ORF59 deletion without the previously identified nuclear localization signal (NLS). These studies further characterize ORF59 and demonstrate its essential role during lytic replication.IMPORTANCE Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic virus and the causative agent of potentially fatal malignancies. Lytic replication of KSHV is an essential part of the viral life cycle, allowing for virus dissemination within the infected host and shedding to infect naive hosts. Viral DNA synthesis is a critical step in the production of new infectious virions. One of the proteins that is vital to this process is open reading frame 59 (ORF59), the viral encoded polymerase processivity factor. Previous work has demonstrated that the function of ORF59 is closely connected to its association with other viral and cellular factors. The studies presented here extend that work to include the interaction between ORF59 and histones. This interaction offers an additional level of regulation of the chromatinized viral genome, ultimately influencing DNA synthesis and transcription dynamics.
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17
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Parthasarathy A, Borrego EJ, Savka MA, Dobson RCJ, Hudson AO. Amino acid-derived defense metabolites from plants: A potential source to facilitate novel antimicrobial development. J Biol Chem 2021; 296:100438. [PMID: 33610552 PMCID: PMC8024917 DOI: 10.1016/j.jbc.2021.100438] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 02/16/2021] [Accepted: 02/17/2021] [Indexed: 12/23/2022] Open
Abstract
For millennia, humanity has relied on plants for its medicines, and modern pharmacology continues to reexamine and mine plant metabolites for novel compounds and to guide improvements in biological activity, bioavailability, and chemical stability. The critical problem of antibiotic resistance and increasing exposure to viral and parasitic diseases has spurred renewed interest into drug treatments for infectious diseases. In this context, an urgent revival of natural product discovery is globally underway with special attention directed toward the numerous and chemically diverse plant defensive compounds such as phytoalexins and phytoanticipins that combat herbivores, microbial pathogens, or competing plants. Moreover, advancements in “omics,” chemistry, and heterologous expression systems have facilitated the purification and characterization of plant metabolites and the identification of possible therapeutic targets. In this review, we describe several important amino acid–derived classes of plant defensive compounds, including antimicrobial peptides (e.g., defensins, thionins, and knottins), alkaloids, nonproteogenic amino acids, and phenylpropanoids as potential drug leads, examining their mechanisms of action, therapeutic targets, and structure–function relationships. Given their potent antibacterial, antifungal, antiparasitic, and antiviral properties, which can be superior to existing drugs, phytoalexins and phytoanticipins are an excellent resource to facilitate the rational design and development of antimicrobial drugs.
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Affiliation(s)
- Anutthaman Parthasarathy
- Rochester Institute of Technology, Thomas H. Gosnell School of Life Sciences, Rochester, New York, USA
| | - Eli J Borrego
- Rochester Institute of Technology, Thomas H. Gosnell School of Life Sciences, Rochester, New York, USA
| | - Michael A Savka
- Rochester Institute of Technology, Thomas H. Gosnell School of Life Sciences, Rochester, New York, USA
| | - Renwick C J Dobson
- Biomolecular Interaction Centre and School of Biological Sciences, University of Canterbury, Christchurch, New Zealand; Bio21 Molecular Science and Biotechnology Institute, Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia
| | - André O Hudson
- Rochester Institute of Technology, Thomas H. Gosnell School of Life Sciences, Rochester, New York, USA.
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18
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Dubich T, Dittrich A, Bousset K, Geffers R, Büsche G, Köster M, Hauser H, Schulz TF, Wirth D. 3D culture conditions support Kaposi's sarcoma herpesvirus (KSHV) maintenance and viral spread in endothelial cells. J Mol Med (Berl) 2021; 99:425-438. [PMID: 33484281 PMCID: PMC7900040 DOI: 10.1007/s00109-020-02020-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 11/17/2020] [Accepted: 12/04/2020] [Indexed: 12/27/2022]
Abstract
Kaposi's sarcoma-associated herpesvirus (KSHV) is a human tumorigenic virus and the etiological agent of an endothelial tumor (Kaposi's sarcoma) and two B cell proliferative diseases (primary effusion lymphoma and multicentric Castleman's disease). While in patients with late stage of Kaposi's sarcoma the majority of spindle cells are KSHV-infected, viral copies are rapidly lost in vitro, both upon culture of tumor-derived cells or from newly infected endothelial cells. We addressed this discrepancy by investigating a KSHV-infected endothelial cell line in various culture conditions and in tumors of xenografted mice. We show that, in contrast to two-dimensional endothelial cell cultures, KSHV genomes are maintained under 3D cell culture conditions and in vivo. Additionally, an increased rate of newly infected cells was detected in 3D cell culture. Furthermore, we show that the PI3K/Akt/mTOR and ATM/γH2AX pathways are modulated and support an improved KSHV persistence in 3D cell culture. These mechanisms may contribute to the persistence of KSHV in tumor tissue in vivo and provide a novel target for KS specific therapeutic interventions. KEY MESSAGES: In vivo maintenance of episomal KSHV can be mimicked in 3D spheroid cultures 3D maintenance of KSHV is associated with an increased de novo infection frequency PI3K/Akt/mTOR and ATM/ γH2AX pathways contribute to viral maintenance.
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Affiliation(s)
- Tatyana Dubich
- Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Anne Dittrich
- Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Kristine Bousset
- Gynaecology Research Unit, Hannover Medical School, Hannover, Germany
| | - Robert Geffers
- Genome Analytics, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Guntram Büsche
- Hematopathology Institute of Pathology, Hannover Medical School, Hannover, Germany
| | - Mario Köster
- Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Hansjörg Hauser
- Staff Unit Scientific Strategy, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Thomas F Schulz
- Institute of Virology, Hannover Medical School, Hannover, Germany
- Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany
- German Center for Infection Research (DZIF), partner site Hannover-Braunschweig, Hannover, Germany
| | - Dagmar Wirth
- Model Systems for Infection and Immunity, Helmholtz Centre for Infection Research, Braunschweig, Germany.
- Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany.
- Cluster of Excellence REBIRTH (EXC 62), Hannover Medical School, Hannover, Germany.
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19
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Piret J, Boivin G. Antiviral Drugs Against Herpesviruses. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1322:1-30. [PMID: 34258735 DOI: 10.1007/978-981-16-0267-2_1] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The discovery of the nucleoside analogue, acyclovir, represented a milestone in the management of infections caused by herpes simplex virus and varicella-zoster virus. Ganciclovir, another nucleoside analogue, was then used for the management of systemic and organ-specific human cytomegalovirus diseases. The pyrophosphate analogue, foscarnet, and the nucleotide analogue, cidofovir, have been approved subsequently and constitute the second-line antiviral drugs. However, the viral DNA polymerase is the ultimate target of all these antiviral agents with a possible emergence of cross-resistance between these drugs. Recently, letermovir that targets the viral terminase complex was approved for the prophylaxis of human cytomegalovirus infections in hematopoietic stem cell transplant recipients. Other viral targets such as the protein kinase and the helicase-primase complex are also evaluated for the development of novel potent inhibitors against herpesviruses.
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Affiliation(s)
| | - Guy Boivin
- CHU de Québec-Laval University, Quebec City, QC, Canada.
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20
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Hu J, Wang Y, Yuan Y. Inhibitors of APE1 redox function effectively inhibit γ-herpesvirus replication in vitro and in vivo. Antiviral Res 2020; 185:104985. [PMID: 33271272 DOI: 10.1016/j.antiviral.2020.104985] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 11/12/2020] [Accepted: 11/17/2020] [Indexed: 12/12/2022]
Abstract
APE1 is a multi-functional protein with a redox function in its N-terminal domain and an apurinic/apyrimidinic endonuclease activity in the C-terminal domain. APE1 redox function plays an important role in regulating cell proliferation and survival through activating specific transcriptional activators. APE1 redox function is also found to be associated with some cancer occurrence. In this study, we demonstrated that APE1 redox function is essential for Epstein-Barr virus (EBV) lytic replication as the silencing of APE1 expression or treatment with APE1 redox inhibitors C10 and E3330 can inhibit EBV lytic replication and virion production. Furthermore, C10 and E3330 also inhibit MHV-68 replication in vitro and in vivo. C10 and E3330 were able to significantly reduce the loss of pulmonary alveoli and thickening of alveolar septa in mice caused by MHV-68 infection. Altogether, (i) APE1 redox function is validated as a new antiviral target; (ii) APE1 redox inhibitors, especially C10, have potentials to be used for the treatment of γ-herpesvirus infection and associated diseases; (iii) MHV-68 is validated to be a surrogate for the study of the pathogenesis and therapy of EBV and KSHV infection in vivo.
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Affiliation(s)
- Jiayuan Hu
- Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Yan Wang
- Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Yan Yuan
- Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; Department of Basic and Translational Sciences, University of Pennsylvania School of Dental Medicine, Philadelphia, PA, 19104, USA.
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21
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Donia AF, Fouda MA, Ghoneim ME, Refaie AF, Ali-El-Dein B. The previously common post-kidney transplant Kaposi sarcoma has become non-existent for a decade: an Egyptian experience. J Cancer Res Clin Oncol 2020; 147:1493-1498. [PMID: 33130940 DOI: 10.1007/s00432-020-03433-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Accepted: 10/19/2020] [Indexed: 10/23/2022]
Abstract
BACKGROUND De novo malignancy is a worrying complication after kidney transplantation; the type of which may vary due to factors such as the prevalence of viral infection and race. Kaposi sarcoma used to be the most common malignancy among our patients constituting more than one-third of cancers. Nevertheless, we noticed that Kaposi sarcoma has not been observed for a long period. Therefore, we conducted this study to explore such observation. METHODS Data of all kidney transplant recipients were retrieved and retrospectively analyzed. Their total number was 3126 patients. Their mean age was 28.71 ± 10.97 years and of them, 823 (26.3%) were females. The pattern of Kaposi sarcoma throughout the last decade as well as the preceding three decades was studied. The possible relation between the disappearance of Kaposi sarcoma and three paradigm shifts in our practice, namely the use of mTOR inhibitors, steroid-free regimen and CMV prophylaxis was explored. RESULTS Since 2010, no new cases of Kaposi sarcoma have been observed. In addition, patients who have been transplanted after 2006 did not develop such malignancy. Patients who received CMV prophylaxis and/or were maintained on mTOR inhibitor or steroid-free regimens have not developed Kaposi sarcoma. Moreover, CMV prophylaxis had a statistically significant difference when compared to a homogenous group without CMV prophylaxis. However, Kaplan-Meier analysis of patients of the three policies and their counterpart groups showed comparable results. CONCLUSION Kaposi sarcoma, which was previously the most common malignancy, is no longer observed for almost a decade among our kidney transplant recipients. m-TOR inhibitors, steroid-free regimen and CMV prophylaxis policy are possible contributing factors. Nevertheless, only CMV prophylaxis policy had a statistically significant relation to the disappearance of Kaposi sarcoma.
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Affiliation(s)
- Ahmed Farouk Donia
- Nephrology and Transplantation Unit, Urology and Nephrology Center, Mansoura University, Mansoura, Egypt.
| | - Mohammed Ashraf Fouda
- Nephrology and Transplantation Unit, Urology and Nephrology Center, Mansoura University, Mansoura, Egypt
| | - Moatasem Elsayed Ghoneim
- Nephrology and Transplantation Unit, Urology and Nephrology Center, Mansoura University, Mansoura, Egypt
| | - Ayman Fathi Refaie
- Nephrology and Transplantation Unit, Urology and Nephrology Center, Mansoura University, Mansoura, Egypt
| | - Bedeir Ali-El-Dein
- Department of Urology, Faculty of Medicine, Urology and Nephrology Center, Mansoura University, Mansoura, Egypt
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22
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DiMaio TA, Vogt DT, Lagunoff M. KSHV requires vCyclin to overcome replicative senescence in primary human lymphatic endothelial cells. PLoS Pathog 2020; 16:e1008634. [PMID: 32555637 PMCID: PMC7326280 DOI: 10.1371/journal.ppat.1008634] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 06/30/2020] [Accepted: 05/14/2020] [Indexed: 12/13/2022] Open
Abstract
Kaposi's Sarcoma Herpesvirus (KSHV) is present in the main tumor cells of Kaposi's Sarcoma (KS), the spindle cells, which are of endothelial origin. KSHV is also associated with two B-cell lymphomas, Primary Effusion Lymphoma (PEL) and Multicentric Castleman's Disease. In KS and PEL, KSHV is primarily latent in the infected cells, expressing only a few genes. Although KSHV infection is required for KS and PEL, it is unclear how latent gene expression contributes to their formation. Proliferation of cancer cells occurs despite multiple checkpoints intended to prevent dysregulated cell growth. The first of these checkpoints, caused by shortening of telomeres, results in replicative senescence, where cells are metabolically active, but no longer divide. We found that human dermal lymphatic endothelial cells (LECs) are more susceptible to KSHV infection than their blood-specific endothelial cell counterparts and maintain KSHV latency to higher levels during passage. Importantly, KSHV infection of human LECs but not human BECs promotes their continued proliferation beyond this first checkpoint of replicative senescence. The latently expressed viral cyclin homolog is essential for KSHV-induced bypass of senescence in LECs. These data suggest that LECs may be an important reservoir for KSHV infection and may play a role during KS tumor development and that the viral cyclin is a critical oncogene for this process.
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Affiliation(s)
- Terri A. DiMaio
- Department of Microbiology, University of Washington, Seattle, Washington, United States of America
| | - Daniel T. Vogt
- Department of Microbiology, University of Washington, Seattle, Washington, United States of America
| | - Michael Lagunoff
- Department of Microbiology, University of Washington, Seattle, Washington, United States of America
- * E-mail:
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23
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Choi D, Park E, Kim KE, Jung E, Seong YJ, Zhao L, Madhavan S, Daghlian G, Lee HH, Daghlian PT, Daghlian S, Bui K, Koh CJ, Wong AK, Cho IT, Hong YK. The Lymphatic Cell Environment Promotes Kaposi Sarcoma Development by Prox1-Enhanced Productive Lytic Replication of Kaposi Sarcoma Herpes Virus. Cancer Res 2020; 80:3130-3144. [PMID: 32518204 DOI: 10.1158/0008-5472.can-19-3105] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 03/13/2020] [Accepted: 06/04/2020] [Indexed: 12/17/2022]
Abstract
Kaposi sarcoma is the most common cancer in human immunodeficiency virus-positive individuals and is caused by Kaposi sarcoma-associated herpesvirus (KSHV). It is believed that a small number of latently infected Kaposi sarcoma tumor cells undergo spontaneous lytic reactivation to produce viral progeny for infection of new cells. Here, we use matched donor-derived human dermal blood and lymphatic endothelial cells (BEC and LEC, respectively) to show that KSHV-infected BECs progressively lose viral genome as they proliferate. In sharp contrast, KSHV-infected LECs predominantly entered lytic replication, underwent cell lysis, and released new virus. Continuous lytic cell lysis and de novo infection allowed LEC culture to remain infected for a prolonged time. Because of the strong propensity of LECs toward lytic replication, LECs maintained virus as a population, despite the death of individual host cells from lytic lysis. The master regulator of lymphatic development, Prox1, bound the promoter of the RTA gene to upregulate its expression and physically interacted with RTA protein to coregulate lytic genes. Thus, LECs may serve as a proficient viral reservoir that provides viral progeny for continuous de novo infection of tumor origin cells, and potentially BECs and mesenchymal stem cells, which give rise to Kaposi sarcoma tumors. Our study reveals drastically different host cell behaviors between BEC and LEC and defines the underlying mechanisms of the lymphatic cell environment supporting persistent infection in Kaposi sarcoma tumors. SIGNIFICANCE: This study defines the mechanism by which Kaposi's sarcoma could be maintained by virus constantly produced by lymphatic cells in HIV-positive individuals.
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Affiliation(s)
- Dongwon Choi
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.,Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Eunkyung Park
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.,Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Kyu Eui Kim
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.,Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Eunson Jung
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.,Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Young Jin Seong
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.,Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Luping Zhao
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.,Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Shrimika Madhavan
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.,Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - George Daghlian
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.,Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Hansuh H Lee
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.,Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Patill T Daghlian
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.,Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Saren Daghlian
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.,Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Khoa Bui
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.,Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Chester J Koh
- Division of Pediatric Urology, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas
| | - Alex K Wong
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Il-Taeg Cho
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.,Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Young-Kwon Hong
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California. .,Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
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Allicin and Glycyrrhizic Acid Display Antiviral Activity Against Latent and Lytic Kaposi Sarcoma-associated Herpesvirus. ACTA ACUST UNITED AC 2020. [DOI: 10.1097/im9.0000000000000016] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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25
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Reid EG, Suazo A, Lensing SY, Dittmer DP, Ambinder RF, Maldarelli F, Gorelick RJ, Aboulafia D, Mitsuyasu R, Dickson MA, Wachsman W. Pilot Trial AMC-063: Safety and Efficacy of Bortezomib in AIDS-associated Kaposi Sarcoma. Clin Cancer Res 2020; 26:558-565. [PMID: 31624104 PMCID: PMC7034393 DOI: 10.1158/1078-0432.ccr-19-1044] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Revised: 06/10/2019] [Accepted: 10/14/2019] [Indexed: 11/16/2022]
Abstract
PURPOSE AIDS-related Kaposi sarcoma is often incompletely controlled, requiring serial therapies. Kaposi sarcoma herpesvirus (KSHV) induces transformation of endothelial cells, where it resides in a predominately latent state. We hypothesized proteasome inhibition would have direct antitumor activity, induce lytic activation of KSHV, and inhibit HIV infectivity, improving control of both Kaposi sarcoma and HIV. The primary objective was determining the MTD of bortezomib in AIDS-Kaposi sarcoma. Secondary objectives included estimating the impact of bortezomib on Kaposi sarcoma response, KSHV plasma DNA copy number (PDCN), and HIV viral loads (VL). PATIENTS AND METHODS A 3+3 dose escalation design was employed evaluating four dose levels of bortezomib (0.75, 1, 1.2, or 1.6 mg/m2) administered intravenously on days 1, 8, and 15 of 28-day cycles in patients with relapsed/refractory (r/r) AIDS-Kaposi sarcoma taking antiretroviral therapy. RESULTS Seventeen patients enrolled. No dose-limiting toxicities occurred and the MTD was not reached. The most common adverse events included diarrhea, fatigue and nausea. Among 15 evaluable patients, partial response (PR) occurred in nine (60%), with a PR rate of 83% in the 1.6 mg/m2 cohort; the remainder had stable disease (SD). Median time to response was 2.1 months. Median change in KSHV PDCN was significantly different between those with PR versus SD. During cycle 1, seven of 11 evaluable patients had decreases in HIV VL. CONCLUSIONS Bortezomib is well-tolerated and active in AIDS-Kaposi sarcoma. The 60% PR rate is notable given the dose-finding nature of the study in a r/r population. Changes in KSHV PDCN and HIV VL trended as hypothesized.
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Affiliation(s)
- Erin G Reid
- University of California, San Diego Moores Cancer Center, La Jolla, California.
| | - Adrienne Suazo
- University of California, San Diego Moores Cancer Center, La Jolla, California
| | - Shelly Y Lensing
- University of Arkansas for Medical Sciences, Little Rock, Arkansas
| | - Dirk P Dittmer
- Lineberger Comprehensive Cancer Center at the University of North Carolina at Chapel Hill, North Carolina
| | | | - Frank Maldarelli
- HIV Dynamics and Replication Program, National Cancer Institute, Frederick, Maryland
| | - Robert J Gorelick
- AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland
| | - David Aboulafia
- Floyd and Delores Jones Cancer Institute at Virginia Mason Medical Center, Seattle, Washington
| | - Ronald Mitsuyasu
- Center for AIDS Research and Education, University of California, Los Angeles, Los Angeles, California
| | - Mark A Dickson
- Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York
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Abstract
Kaposi’s sarcoma (KS) is a vascular tumour of endothelial origin that is associated with human herpes virus-8 infection. In sub-Saharan Africa, AIDS-KS remains the most common HIV-associated malignancy, and hence it poses a huge burden to the already constrained health-care systems. KS has four clinical variants, namely, classic, endemic, iatrogenic and epidemic KS. The histopathology in these different KS forms is essentially identical; however, they have different clinical patterns. Expanding knowledge of KS biology increases hope for prevention, disease control, and hence better quality of life among patients. Primary prevention strategy for KS-associated herpes virus and management of disease complication, such as lymphoedema should be the focus of disease-prevention and -control research.
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Affiliation(s)
- Jackson Orem
- Uganda Cancer Institute, Upper Mulago Hill Road, PO Box 3935, Kampala, Uganda
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27
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Campogiani L, Cerva C, Maffongelli G, Teti E, Pupo L, Vaccarini S, Cantonetti M, Pennica A, Andreoni M, Sarmati L. Remission of an HHV8-related extracavitary primary effusion lymphoma in an HIV-positive patient during antiretroviral treatment containing dolutegravir. AIDS Res Ther 2019; 16:15. [PMID: 31351487 PMCID: PMC6660660 DOI: 10.1186/s12981-019-0230-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2019] [Accepted: 07/17/2019] [Indexed: 12/12/2022] Open
Abstract
Background Human herpes virus 8 (HHV8) is the causative agent of Kaposi’s sarcoma and has been associated with an increasing number of hematologic diseases such as primary effusion lymphoma (PEL) (both classic and extracavitary form), multicentric Castleman disease and the germinotropic lymphoproliferative disorder. PEL is a rare B cell non-Hodgkin lymphoma that primarily affects immunocompromised patients; aggressive chemotherapy and antiretroviral therapy (ART) with protease inhibitors have been used, with poor results. We present a case of extracavitary PEL in an HIV-infected patient, regressed after ART initiation. Case presentation A 42-year-old male was admitted to the emergency room because of several months of malaise, fever and progressive deterioration of the general conditions. On physical examination soft non-painful subcutaneous masses were palpable at retronuchal, retroauricolar and thoracic regions. HIV serology resulted positive: HIV plasma viremia was 782,270 copies/mL, CD4 103 cells/mL. The excision of one of the masses, metabolically active at a positron emission tomography (PET-CT) scan, revealed an HHV8-related extracavitary PEL. HHV8 plasma viremia was 44,826 copies/mL. ART with tenofovir alafenamide/emtricitabine/dolutegravir was started together with ganciclovir for cytomegalovirus chorioretinitis. The progressive disappearance of the masses was seen after 6 weeks of ART, and a PET-CT scan resulted completely negative at 3 months. After 19 months of ART the patient was in remission of PEL, HIV viremia was undetectable (< 20 copies/mL), CD4 count was 766 cells/mL and HHV8 viremia was undetectable. Conclusions In this clinical case, the complete regression of PEL has been achieved after the immune recovery, as a consequence of ART introduction, without chemotherapy. It cannot be excluded that ganciclovir, used for the treatment of CMV chorioretinitis, may have contributed to the control of HHV8 replication. Whether to try or not a conservative approach in HIV-infected PEL patients must be carefully evaluated, considering the patient’s characteristics and the prognostic factors.
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Epstein-Barr virus enhances genome maintenance of Kaposi sarcoma-associated herpesvirus. Proc Natl Acad Sci U S A 2018; 115:E11379-E11387. [PMID: 30429324 DOI: 10.1073/pnas.1810128115] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Primary effusion lymphoma (PEL) is a B cell lymphoma that is always associated with Kaposi's sarcoma-associated herpesvirus (KSHV) and in many cases also with Epstein-Barr virus (EBV); however, the requirement for EBV coinfection is not clear. Here, we demonstrate that adding exogenous EBV to KSHV+ single-positive PEL leads to increased KSHV genome maintenance and KSHV latency-associated nuclear antigen (LANA) expression. To show that EBV was necessary for naturally coinfected PEL, we nucleofected KSHV+/EBV+ PEL cell lines with an EBV-specific CRISPR/Cas9 plasmid to delete EBV and observed a dramatic decrease in cell viability, KSHV genome copy number, and LANA expression. This phenotype was reversed by expressing Epstein-Barr nuclear antigen 1 (EBNA-1) in trans, even though EBNA-1 and LANA do not colocalize in infected cells. This work reveals that EBV EBNA-1 plays an essential role in the pathogenesis of PEL by increasing KSHV viral load and LANA expression.
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29
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Abstract
Primary effusion lymphoma (PEL) is a rare and aggressive disease, affecting a unique population of patients who are often elderly or immunocompromised. PEL is associated with human herpesvirus type-8 infection and most commonly presents as malignant effusions of the body cavities. Patients diagnosed with PEL often have a compromised immune system from secondary conditions such as HIV. Chemotherapy has traditionally been the cornerstone of treatment for patients with a good performance status and no significant comorbidities. However, an optimal regimen does not exist. Most patients with PEL experience a relapse after frontline therapy within 6-8 months and subsequently require further treatment. In recent years, our understanding of the molecular drivers and environmental factors affecting the pathogenesis of PEL has expanded. This review will discuss the pathogenesis of PEL and various management approaches available in the frontline and relapsed setting as well as targeted agents that have shown promise in this disease.
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Affiliation(s)
- Mayur Narkhede
- Lombardi Comprehensive Cancer Center, Georgetown University Hospital, Washington, DC, USA,
| | - Shagun Arora
- Division of Hematology and Oncology, University of California, San Francisco, CA, USA
| | - Chaitra Ujjani
- Lombardi Comprehensive Cancer Center, Georgetown University Hospital, Washington, DC, USA,
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30
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Oktafiani D, Megasari NLA, Fitriana E, Nasronudin, Lusida MI, Soetjipto. DETECTION OF HUMAN HERPESVIRUS-8 ANTIGEN IN HIV-INFECTED PATIENTS IN EAST JAVA, INDONESIA. Afr J Infect Dis 2018; 12:43-46. [PMID: 30109285 PMCID: PMC6085735 DOI: 10.21010/ajid.v12i2.7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2017] [Revised: 12/13/2017] [Accepted: 12/13/2017] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND Co-infection of human herpesvirus-8 (HHV-8) in HIV-positive people might cause Kaposi's sarcoma. Early detection of HHV-8 may prevent the onset of clinical manifestations. In Indonesia, detection of HHV-8 antigen in HIV-positive patients has yet to be reported. The intention of this research was to examine the presence of HHV-8 antigen in HIV-positive patients in East Java, Indonesia. MATERIAL AND METHODS 103 serum samples were collected from HIV-positive patients in Surabaya and Tulungagung, East Java, Indonesia. Serums were then tested for the presence of HHV-8 antigen by using sandwich ELISA. RESULTS Human Herpesvirus-8 antigen was detected in 15 samples (14.5%). The presence of HHV-8 infection in HIV-positive patients did not present differently in males and females and among different age groups. Human immunodeficiency virus-positive serum samples were collected from 23 homosexual men, 25 intravenous drug users (IVDUs) and 52 heterosexuals. In the male homosexual group, HHV-8 antigen was detected in 21.7% (5/23) of the samples, while in the intravenous drug user group (IVDUs), 16% (4/25) of the samples were found to have HHV-8 antigen. CONCLUSION This research found the presence of HHV-8 antigen in 14.5% of patients in East Java, Indonesia. It is recommended that patients with a positive result should receive further examination to detect any clinical manifestations related to HHV-8 infection, especially in the form of Kaposi's sarcoma lesions, so that the illness can be appropriately managed.
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Affiliation(s)
- Devi Oktafiani
- Doctoral Degree Program, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Ni Luh Ayu Megasari
- Doctoral Degree Program, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Elsa Fitriana
- Doctoral Degree Program, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Nasronudin
- Universitas Airlangga Hospital, Surabaya, Indonesia
| | - Maria Inge Lusida
- Institute of Tropical Disease, Universitas Airlangga, Surabaya, Indonesia
- Department of Medical Microbiology, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Soetjipto
- Universitas Airlangga Hospital, Surabaya, Indonesia
- Institute of Tropical Disease, Universitas Airlangga, Surabaya, Indonesia
- Department of Medical Biochemistry, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
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31
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Respiratory Viruses and Other Relevant Viral Infections in the Lung Transplant Recipient. LUNG TRANSPLANTATION 2018. [PMCID: PMC7123387 DOI: 10.1007/978-3-319-91184-7_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
As advances occur in surgical technique, postoperative care, and immunosuppressive therapy, the rate of mortality in the early postoperative period following lung transplantation continues to decline. With the improvements in immediate and early posttransplant mortality, infections and their sequel as well as rejection and chronic allograft dysfunction are increasingly a major cause of posttransplant mortality. This chapter will focus on infections by respiratory viruses and other viral infections relevant to lung transplantation, including data regarding the link between viral infections and allograft dysfunction.
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32
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Mariggiò G, Koch S, Schulz TF. Kaposi sarcoma herpesvirus pathogenesis. Philos Trans R Soc Lond B Biol Sci 2018; 372:rstb.2016.0275. [PMID: 28893942 PMCID: PMC5597742 DOI: 10.1098/rstb.2016.0275] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/09/2017] [Indexed: 12/15/2022] Open
Abstract
Kaposi sarcoma herpesvirus (KSHV), taxonomical name human gammaherpesvirus 8, is a phylogenetically old human virus that co-evolved with human populations, but is now only common (seroprevalence greater than 10%) in sub-Saharan Africa, around the Mediterranean Sea, parts of South America and in a few ethnic communities. KSHV causes three human malignancies, Kaposi sarcoma, primary effusion lymphoma, and many cases of the plasmablastic form of multicentric Castleman's disease (MCD) as well as occasional cases of plasmablastic lymphoma arising from MCD; it has also been linked to rare cases of bone marrow failure and hepatitis. As it has colonized humans physiologically for many thousand years, cofactors are needed to allow it to unfold its pathogenic potential. In most cases, these include immune defects of genetic, iatrogenic or infectious origin, and inflammation appears to play an important role in disease development. Our much improved understanding of its life cycle and its role in pathogenesis should now allow us to develop new therapeutic strategies directed against key viral proteins or intracellular pathways that are crucial for virus replication or persistence. Likewise, its limited (for a herpesvirus) distribution and transmission should offer an opportunity for the development and use of a vaccine to prevent transmission. This article is part of the themed issue ‘Human oncogenic viruses’.
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Affiliation(s)
- Giuseppe Mariggiò
- Institute of Virology, Hannover Medical School, Carl Neuberg Strasse 1, 30625 Hannover, Germany.,German Centre for Infection Research, Hannover-Braunschweig site, Hannover, Germany
| | - Sandra Koch
- Institute of Virology, Hannover Medical School, Carl Neuberg Strasse 1, 30625 Hannover, Germany.,German Centre for Infection Research, Hannover-Braunschweig site, Hannover, Germany
| | - Thomas F Schulz
- Institute of Virology, Hannover Medical School, Carl Neuberg Strasse 1, 30625 Hannover, Germany .,German Centre for Infection Research, Hannover-Braunschweig site, Hannover, Germany
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33
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Miralles P, Navarro JT, Berenguer J, Gómez Codina J, Kwon M, Serrano D, Díez-Martín JL, Villà S, Rubio R, Menárguez J, Ribera Santasusana JM. GESIDA/PETHEMA recommendations on the diagnosis and treatment of lymphomas in patients infected by the human immunodeficiency virus. Med Clin (Barc) 2018; 151:39.e1-39.e17. [PMID: 29357988 DOI: 10.1016/j.medcli.2017.11.037] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2017] [Revised: 10/21/2017] [Accepted: 11/02/2017] [Indexed: 01/20/2023]
Abstract
The incidence of non-Hodgkin's lymphoma and Hodgkin's lymphoma is higher in patients with HIV infection than in the general population. Following the introduction of combination antiretroviral therapy (cART), the prognostic significance of HIV-related variables has decreased, and lymphoma-related factors have become more pronounced. Currently, treatments for lymphomas in HIV-infected patients do not differ from those used in the general population. However, differentiating characteristics of seropositive patients, such as the need for cART and specific prophylaxis and treatment of certain opportunistic infections, should be considered. This document updates recommendations on the diagnosis and treatment of lymphomas in HIV infected patients published by GESIDA/PETHEMA in 2008.
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Affiliation(s)
- Pilar Miralles
- Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, España.
| | - José Tomás Navarro
- Institut Català d'Oncologia, Hospital Universitari Germans Trias i Pujol, Institut de Recerca Josep Carreras, Universitat Autónoma de Barcelona, Badalona, Barcelona, España
| | - Juan Berenguer
- Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, España
| | | | - Mi Kwon
- Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, España
| | - David Serrano
- Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, España
| | - José Luis Díez-Martín
- Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, España
| | - Salvador Villà
- Institut Català d'Oncologia, Hospital Universitari Germans Trias i Pujol, Institut de Recerca Josep Carreras, Universitat Autónoma de Barcelona, Badalona, Barcelona, España
| | | | - Javier Menárguez
- Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, España
| | - José-María Ribera Santasusana
- Institut Català d'Oncologia, Hospital Universitari Germans Trias i Pujol, Institut de Recerca Josep Carreras, Universitat Autónoma de Barcelona, Badalona, Barcelona, España
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34
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Basnayake BMDB, Wazil AWM, Kannangara T, Ratnatunga NVI, Hewamana S, Ameer AM. Multicentric Castleman disease of hyaline vascular variant presenting with unusual systemic manifestations: a case report. J Med Case Rep 2017; 11:135. [PMID: 28501028 PMCID: PMC5429940 DOI: 10.1186/s13256-017-1294-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Accepted: 04/07/2017] [Indexed: 12/04/2022] Open
Abstract
Background Castleman disease is a rare lymphoproliferative disorder presenting with localized or disseminated lymphadenopathy and systemic manifestations. It can be categorized in numerous ways, such as unicentric versus multicentric, histopathological variants (hyaline-vascular, plasma cell, and mixed), or subtypes based on causative viral infections (human immunodeficiency virus, human herpesvirus-8, or Kaposi sarcoma herpesvirus). Presentation ranges from asymptomatic to symptoms involving multiple organs. Even though the exact mechanism of pathogenesis is unknown, treatment is directed toward possible etiologies such as interleukin-6, cluster of differentiation 20, and viral agents. Case presentation A 36-year-old Sri Lankan woman presented with generalized body swelling and foamy urine of 2 weeks’ duration. Examination revealed pallor; generalized edema; axillary, cervical, and inguinal lymphadenopathy; hypertension; and hepatomegaly. Investigations showed bicytopenia, nephrotic range proteinuria with hypoalbuminemia, hypogammaglobulinemia, and features of hyaline-vascular type Castleman disease in a lymph node biopsy. She was managed with rituximab and had good clinical improvement. Conclusions Castleman disease has a broad spectrum of clinical manifestations, disease pathogeneses, and associations and/or complications. Medical professionals need to be familiar with this spectrum because timely diagnosis and aggressive targeted therapy are the cornerstones of managing these patients.
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Affiliation(s)
| | - A W M Wazil
- Department of Nephrology, Teaching Hospital Kandy, Kandy, Sri Lanka
| | - T Kannangara
- Department of Medicine, Teaching Hospital Kandy, Kandy, Sri Lanka
| | - N V I Ratnatunga
- Department of Pathology, Faculty of Medicine, University of Peradeniya, Peradeniya, Sri Lanka
| | - S Hewamana
- Department of Hematology and Hemato-oncology, Lanka Hospitals, Colombo, Sri Lanka
| | - A M Ameer
- Department of Medicine, Teaching Hospital Kandy, Kandy, Sri Lanka
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35
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Chen HS, De Leo A, Wang Z, Kerekovic A, Hills R, Lieberman PM. BET-Inhibitors Disrupt Rad21-Dependent Conformational Control of KSHV Latency. PLoS Pathog 2017; 13:e1006100. [PMID: 28107481 PMCID: PMC5287475 DOI: 10.1371/journal.ppat.1006100] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2016] [Revised: 02/01/2017] [Accepted: 11/29/2016] [Indexed: 12/11/2022] Open
Abstract
Kaposi’s Sarcoma-associated Herpesvirus (KSHV) establishes stable latent infection in B-lymphocytes and pleural effusion lymphomas (PELs). During latency, the viral genome persists as an epigenetically constrained episome with restricted gene expression programs. To identify epigenetic regulators of KSHV latency, we screened a focused small molecule library containing known inhibitors of epigenetic factors. We identified JQ1, a Bromodomain and Extended Terminal (BET) protein inhibitor, as a potent activator of KSHV lytic reactivation from B-cells carrying episomal KSHV. We validated that JQ1 and other BET inhibitors efficiently stimulated reactivation of KSHV from latently infected PEL cells. We found that BET proteins BRD2 and BRD4 localize to several regions of the viral genome, including the LANA binding sites within the terminal repeats (TR), as well as at CTCF-cohesin sites in the latent and lytic control regions. JQ1 did not disrupt the interaction of BRD4 or BRD2 with LANA, but did reduce the binding of LANA with KSHV TR. We have previously demonstrated a cohesin-dependent DNA-loop interaction between the latent and lytic control regions that restrict expression of ORF50/RTA and ORF45 immediate early gene transcripts. JQ1 reduced binding of cohesin subunit Rad21 with the CTCF binding sites in the latency and lytic control regions. JQ1 also reduced DNA-loop interaction between latent and lytic control regions. These findings implicate BET proteins BRD2 and BRD4 in the maintenance of KSHV chromatin architecture during latency and reveal BET inhibitors as potent activators of KSHV reactivation from latency. KSHV is an oncogenic human herpesvirus implicated as the causative agent of KS and cofactor in pleural effusion lymphomas (PELs). The latent virus persists in PELs as an epigenetically regulated episome. We found that small molecule inhibitors of BET family have potent activity in triggering the lytic switch during latent infection in PELs. The BET family inhibitor JQ1 disrupted the latent virus from maintaining a closed DNA loop conformation. These findings have implications for treatment of KSHV-associated malignancies with epigenetic modulators of the BET inhibitor family.
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MESH Headings
- Antigens, Viral/genetics
- Antigens, Viral/metabolism
- Azepines/pharmacology
- B-Lymphocytes/virology
- Binding Sites/drug effects
- Cell Cycle Proteins
- Cell Line, Tumor
- DNA-Binding Proteins
- Gene Expression Regulation, Viral
- HEK293 Cells
- Herpesvirus 8, Human/drug effects
- Herpesvirus 8, Human/genetics
- Herpesvirus 8, Human/physiology
- Humans
- Immediate-Early Proteins/biosynthesis
- Immediate-Early Proteins/genetics
- Nuclear Proteins/antagonists & inhibitors
- Nuclear Proteins/genetics
- Nuclear Proteins/metabolism
- Phosphoproteins/metabolism
- Pleural Effusion, Malignant/virology
- Protein Binding/drug effects
- Protein Serine-Threonine Kinases/antagonists & inhibitors
- Protein Serine-Threonine Kinases/metabolism
- RNA Interference
- RNA, Small Interfering
- Sarcoma, Kaposi/virology
- Trans-Activators/biosynthesis
- Trans-Activators/genetics
- Transcription Factors/antagonists & inhibitors
- Transcription Factors/metabolism
- Triazoles/pharmacology
- Virus Activation/drug effects
- Virus Latency/drug effects
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Affiliation(s)
- Horng-Shen Chen
- The Wistar Institute, Philadelphia, PA, United States of America
| | | | - Zhuo Wang
- The Wistar Institute, Philadelphia, PA, United States of America
| | - Andrew Kerekovic
- The Wistar Institute, Philadelphia, PA, United States of America
| | - Robert Hills
- The Wistar Institute, Philadelphia, PA, United States of America
| | - Paul M. Lieberman
- The Wistar Institute, Philadelphia, PA, United States of America
- * E-mail:
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36
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A role for MALT1 activity in Kaposi's sarcoma-associated herpes virus latency and growth of primary effusion lymphoma. Leukemia 2016; 31:614-624. [PMID: 27538487 PMCID: PMC5339436 DOI: 10.1038/leu.2016.239] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Revised: 07/20/2016] [Accepted: 08/09/2016] [Indexed: 12/15/2022]
Abstract
Primary effusion lymphoma (PEL) is an incurable malignancy that develops in immunodeficient patients as a consequence of latent infection of B-cells with Kaposi's sarcoma-associated herpes virus (KSHV). Malignant growth of KSHV-infected B cells requires the activity of the transcription factor nuclear factor (NF)-κB, which controls maintenance of viral latency and suppression of the viral lytic program. Here we show that the KSHV proteins K13 and K15 promote NF-κB activation via the protease mucosa-associated lymphoid tissue lymphoma translocation protein-1 (MALT1), a key driver of NF-κB activation in lymphocytes. Inhibition of the MALT1 protease activity induced a switch from the latent to the lytic stage of viral infection, and led to reduced growth and survival of PEL cell lines in vitro and in a xenograft model. These results demonstrate a key role for the proteolytic activity of MALT1 in PEL, and provide a rationale for the pharmacological targeting of MALT1 in PEL therapy.
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The K1 Protein of Kaposi's Sarcoma-Associated Herpesvirus Augments Viral Lytic Replication. J Virol 2016; 90:7657-66. [PMID: 27307571 PMCID: PMC4988170 DOI: 10.1128/jvi.03102-15] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Accepted: 04/20/2016] [Indexed: 11/20/2022] Open
Abstract
UNLABELLED The K1 gene product of Kaposi's sarcoma-associated herpesvirus (KSHV) is encoded by the first open reading frame (ORF) of the viral genome. To investigate the role of the K1 gene during the KSHV life cycle, we constructed a set of recombinant viruses that contained either wild-type (WT) K1, a deleted K1 ORF (KSHVΔK1), stop codons within the K1 ORF (KSHV-K15×STOP), or a revertant K1 virus (KSHV-K1REV). We report that the recombinant viruses KSHVΔK1 and KSHV-K15×STOP displayed significantly reduced lytic replication compared to WT KSHV and KSHV-K1REV upon reactivation from latency. Additionally, cells infected with the recombinant viruses KSHVΔK1 and KSHV-K15×STOP also yielded smaller amounts of infectious progeny upon reactivation than did WT KSHV- and KSHV-K1REV-infected cells. Upon reactivation from latency, WT KSHV- and KSHV-K1REV-infected cells displayed activated Akt kinase, as evidenced by its phosphorylation, while cells infected with viruses deleted for K1 showed reduced phosphorylation and activation of Akt kinase. Overall, our results suggest that K1 plays an important role during the KSHV life cycle. IMPORTANCE Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of three human malignancies, and KSHV K1 is a signaling protein that has been shown to be involved in cellular transformation and to activate the phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR pathway. In order to investigate the role of the K1 protein in the life cycle of KSHV, we constructed recombinant viruses that were deficient for K1. We found that K1 deletion viruses displayed reduced lytic replication compared to the WT virus and also yielded smaller numbers of infectious progeny. We report that K1 plays an important role in the life cycle of KSHV.
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Heyrman B, De Becker A, Schots R. A case report of immunosuppression-related Kaposi's sarcoma after autologous stem cell transplantation. BMC Res Notes 2016; 9:188. [PMID: 27012530 PMCID: PMC4806455 DOI: 10.1186/s13104-016-1991-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2015] [Accepted: 03/15/2016] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Kaposi's sarcoma (KS) is a tumor formed by angioproliferations driven by Human herpes virus 8 also known as Kaposi's sarcoma-associated herpes virus (KSHV). It is best known as an acquired immune deficiency syndrome (AIDS) defining illness that may be fatal. There are only a few reports of KS after hematopoietic cell transplantation (HCT). This is the first case describing the disappearance of KS with immune recovery after autologous HCT. CASE PRESENTATION We present the case of a 61-year-old male heterosexual patient of Moroccan origin treated for primary mediastinal non-Hodgkin lymphoma. Because of refractory disease he received multiple lines of chemotherapy prior to autologous HCT. After the second course of low-dose bis-chloroethylnitrosourea, etoposide, cytarabine, melphalan (BEAM) the patient developed several round blue skin lesions. A biopsy was performed, showing many small vessels and positive immune histochemical staining for Human herpes virus 8 (HHV-8), confirming diagnosis of KS. Human immunodeficiency virus testing was negative and work-up showed that there were no visceral lesions. When KS are limited to the skin, prognosis is usually better. The extensive chemotherapy resulted in an important immunosuppression; on day 105 after autologous HCT CD4(+) count was 82/mm(3). Since KS were limited to the skin and attributed to severe immune suppression a watchful waiting strategy was adopted even though in the first months after autologous HCT new skin lesions appeared. With immune recovery (CD4(+) count > 200/mm(3)) 277 days after transplant, skin lesions faded. CONCLUSION Kaposi's sarcoma remains a rare tumor that should be thought of in any patient whose immunity is down. If immune recovery is expected and disease is limited to the skin, a watchful waiting strategy can be more rewarding than intensive chemotherapy.
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Affiliation(s)
- Bert Heyrman
- Department of Clinical Hematology, UZ Brussel-VUB, Laarbeeklaan 101, 1090 Jette-Brussels, Belgium
| | - Ann De Becker
- Department of Clinical Hematology, UZ Brussel-VUB, Laarbeeklaan 101, 1090 Jette-Brussels, Belgium
| | - Rik Schots
- Department of Clinical Hematology, UZ Brussel-VUB, Laarbeeklaan 101, 1090 Jette-Brussels, Belgium
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Broccolo F, Tassan Din C, Viganò MG, Rutigliano T, Esposito S, Lusso P, Tambussi G, Malnati MS. HHV-8 DNA replication correlates with the clinical status in AIDS-related Kaposi's sarcoma. J Clin Virol 2016; 78:47-52. [PMID: 26985593 DOI: 10.1016/j.jcv.2016.02.019] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2015] [Revised: 02/08/2016] [Accepted: 02/17/2016] [Indexed: 12/13/2022]
Abstract
BACKGROUND The value of plasma levels of human herpesvirus 8 (HHV-8) DNA as a marker of clinical status in acquired immunodeficiency syndrome-related Kaposi's sarcoma (AIDS-KS) remains to be elucidated. OBJECTIVES To investigate the relationship between the plasma HHV-8 DNA viral load and the clinical status of AIDS-KS. STUDY DESIGN A total of 378 blood samples were obtained from 62 patients with AIDS-KS followed longitudinally. All patients received antiretroviral therapy (ART) or anti-neoplastic therapy. The patients were divided into four groups according to their clinical status: onset disease (OD), progressive disease (PD), stable or partial remission (S/PR) and complete remission (CR). RESULTS Plasma HHV-8 DNAaemia was detected in all samples obtained from patients with OD or PD (100%); in contrast, HHV-8 DNAaemia was found only in a minority of patients with CR (8%) and was invariably undetectable in patients with stable CR. HHV-8 DNA detection in plasma was strongly associated with an unfavourable outcome (odds ratio=231.9; p<0.0001). Conversely, neither the HIV-1 viral load nor peripheral CD4(+) T-cell counts were associated with the KS clinical status, though both parameters did affect HHV-8 DNAaemia levels (p<0.0001). Multivariate analysis confirmed that HHV-8 DNAaemia was strongly and independently correlated with both clinical status (p<0.05) and HIV-1 plasma viraemia (p=0.027). CONCLUSIONS The strong association of plasma HHV-8 DNAaemia with onset or progressive disease is compatible with an active role of replicating virus in clinically active AIDS-KS. An accurate evaluation of the plasma HHV-8 load might be useful for monitoring AIDS-KS under antiretroviral or antineoplastic therapy.
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Affiliation(s)
- Francesco Broccolo
- Department of Health Sciences, University of Milano-Bicocca, Monza, Italy
| | | | | | - Teresa Rutigliano
- Unit Human Virology, San Raffaele Scientific Institute, Milan, Italy
| | - Susanna Esposito
- Pediatric Highly Intensive Care Unit, Department of Pathophysiology and Transplantation, Università Degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Paolo Lusso
- Laboratory of Immunoregulation, NIAID, NIH, Bethesda, MD 20892, USA
| | | | - Mauro S Malnati
- Unit Human Virology, San Raffaele Scientific Institute, Milan, Italy.
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Lee AJ, Brenner L, Mourad B, Monteiro C, Vega KJ, Munoz JC. Gastrointestinal Kaposi’s sarcoma: Case report and review of the literature. World J Gastrointest Pharmacol Ther 2015; 6:89-95. [PMID: 26261737 PMCID: PMC4526844 DOI: 10.4292/wjgpt.v6.i3.89] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Revised: 06/21/2015] [Accepted: 07/14/2015] [Indexed: 02/06/2023] Open
Abstract
Kaposi’s sarcoma (KS) of the gastrointestinal tract is not an uncommon disease among individuals with acquired immunodeficiency syndrome (AIDS). The majority is asymptomatic, and for this reason, gastrointestinal KS (GI-KS) remains undiagnosed. With continued tumor growth, considerable variation in clinical presentation occurs including abdominal pain, nausea, vomiting, iron deficiency anemia (either chronic or frank gastrointestinal bleeding), and rarely mechanical obstruction alone or combined with bowel perforation. Endoscopy with biopsy allows for histological and immunohistochemical testing to confirm the diagnosis of GI-KS among those with clinical symptoms. In previous studies, dual treatment with highly active antiretroviral therapy and systemic chemotherapy have been associated with improved morbidity and mortality in individuals with visceral KS. Therefore, investigators have suggested performing screening endoscopies in select patients for early detection and treatment to improve outcome. In this review, we describe a 44 years old man with AIDS and cutaneous KS who presented for evaluation of postprandial abdominal pain, vomiting, and weight loss. On upper endoscopy, an extensive, infiltrative, circumferential, reddish mass involving the entire body and antrum of the stomach was seen. Histologic examination later revealed spindle cell proliferation, and confirmatory immunohistochemical testing revealed human herpes virus 8 latent nuclear antigen expression consistent with a diagnosis of gastric KS. Following this, we present a comprehensive review of literature on KS with emphasis on gastrointestinal tract involvement and management.
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Klepfish A, Zuckermann B, Schattner A. Primary effusion lymphoma in the absence of HIV infection--clinical presentation and management. QJM 2015; 108:481-8. [PMID: 25413797 DOI: 10.1093/qjmed/hcu232] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Indexed: 01/13/2023] Open
Abstract
Primary Effusion Lymphoma (PEL) is a rare type of Non-Hodgkin's Lymphoma caused by human herpesvirus type 8, also termed Kaposi's sarcoma-associated herpesvirus. It usually occurs in human immunodeficiency virus (HIV)-infected patients. A subset of patients is not infected with HIV and their treatment remains poorly defined. To clarify treatment issues in HIV-negative PEL patients, we report on two such patients who represent two opposing ends in the spectrum of treatment and review the literature regarding treatment options and patient outcomes. Either repeated cycles of chemotherapy or, surprisingly, drainage of the malignant effusions alone, proved very effective in our patients. The literature reveals additional treatment options which may be effective including immunochemotherapy, stem cell transplantation, antiviral treatment and immunomodulatory and targeted biological therapy. However, no controlled trials were found due to the rarity of the condition. In the absence of controlled trials, treatment decisions in PEL not associated with HIV must remain individual and patient-tailored.
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Affiliation(s)
- A Klepfish
- From the Blood Bank and Department of Hematology, Department of Cardio-Thoracic Surgery, Edith Wolfson Medical Centre, Holon and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv and The Faculty of Medicine, Hebrew University Hadassah Medical School, Jerusalem, Israel
| | - B Zuckermann
- From the Blood Bank and Department of Hematology, Department of Cardio-Thoracic Surgery, Edith Wolfson Medical Centre, Holon and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv and The Faculty of Medicine, Hebrew University Hadassah Medical School, Jerusalem, Israel
| | - A Schattner
- From the Blood Bank and Department of Hematology, Department of Cardio-Thoracic Surgery, Edith Wolfson Medical Centre, Holon and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv and The Faculty of Medicine, Hebrew University Hadassah Medical School, Jerusalem, Israel
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Bhutani M, Polizzotto MN, Uldrick TS, Yarchoan R. Kaposi sarcoma-associated herpesvirus-associated malignancies: epidemiology, pathogenesis, and advances in treatment. Semin Oncol 2014; 42:223-46. [PMID: 25843728 DOI: 10.1053/j.seminoncol.2014.12.027] [Citation(s) in RCA: 97] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Kaposi sarcoma associated herpesvirus (KSHV), a γ2-herpesvirus, also known as human herpesvirus-8, is the etiologic agent of three virally associated tumors: Kaposi sarcoma, a plasmablastic form of multicentric Castleman disease (KSHV-MCD), and primary effusion lymphoma. These malignancies are predominantly seen in people with acquired immunodeficiencies, including acquired immunodeficiency syndrome and iatrogenic immunosuppression in the setting of organ transplantation, but can also develop in the elderly. Kaposi sarcoma (KS) is most frequent in regions with high KSHV seroprevalence, such as sub-Saharan Africa and some Mediterranean countries. In the era of combination antiviral therapy, inflammatory manifestations associated with KSHV-infection, including KSHV-MCD, a recently described KSHV-associated inflammatory cytokine syndrome and KS immune reconstitution syndrome also are increasingly appreciated. Our understanding of viral and immune mechanisms of oncogenesis continues to expand and lead to improved molecular diagnostics, as well as novel therapeutic strategies that employ immune modulatory agents, manipulations of the tumor microenvironment, virus-activated cytotoxic therapy, or agents that target interactions between specific virus-host cell signaling pathways. This review focuses on the epidemiology and advances in molecular and clinical research that reflects the current understanding of viral oncogenesis, clinical manifestations, and therapeutics for KSHV-associated tumors.
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Affiliation(s)
- Manisha Bhutani
- HIV and AIDS Malignancy Branch, Center for Cancer Research, NCI, Bethesda, MD
| | - Mark N Polizzotto
- HIV and AIDS Malignancy Branch, Center for Cancer Research, NCI, Bethesda, MD
| | - Thomas S Uldrick
- HIV and AIDS Malignancy Branch, Center for Cancer Research, NCI, Bethesda, MD
| | - Robert Yarchoan
- HIV and AIDS Malignancy Branch, Center for Cancer Research, NCI, Bethesda, MD.
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Gable J, Acker TM, Craik CS. Current and potential treatments for ubiquitous but neglected herpesvirus infections. Chem Rev 2014; 114:11382-412. [PMID: 25275644 PMCID: PMC4254030 DOI: 10.1021/cr500255e] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2014] [Indexed: 02/07/2023]
Affiliation(s)
- Jonathan
E. Gable
- Department
of Pharmaceutical Chemistry, University
of California, San Francisco, 600 16th Street, San Francisco, California 94158-2280, United States
- Graduate
Group in Biophysics, University of California,
San Francisco, 600 16th
Street, San Francisco, California 94158-2280, United States
| | - Timothy M. Acker
- Department
of Pharmaceutical Chemistry, University
of California, San Francisco, 600 16th Street, San Francisco, California 94158-2280, United States
| | - Charles S. Craik
- Department
of Pharmaceutical Chemistry, University
of California, San Francisco, 600 16th Street, San Francisco, California 94158-2280, United States
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Abstract
Kaposi’s sarcoma (KS), caused by KS-associated herpesvirus (KSHV), is the most common cancer among HIV-infected patients in Malawi and in the United States today. In Malawi, KSHV is endemic. We conducted a cross-sectional study of patients with HIV infection and KS with no history of chemo- or antiretroviral therapy (ART). Seventy patients were enrolled. Eighty-one percent had T1 (advanced) KS. Median CD4 and HIV RNA levels were 181 cells/mm3 and 138,641 copies/ml, respectively. We had complete information and suitable plasma and biopsy samples for 66 patients. For 59/66 (89%) patients, a detectable KSHV load was found in plasma (median, 2,291 copies/ml; interquartile range [IQR], 741 to 5,623). We utilized a novel KSHV real-time quantitative PCR (qPCR) array with multiple primers per open reading frame to examine KSHV transcription. Seventeen samples exhibited only minimal levels of KSHV mRNAs, presumably due to the limited number of infected cells. For all other biopsy samples, the viral latency locus (LANA, vCyc, vFLIP, kaposin, and microRNAs [miRNAs]) was transcribed abundantly, as was K15 mRNA. We could identify two subtypes of treatment-naive KS: lesions that transcribed viral RNAs across the length of the viral genome and lesions that displayed only limited transcription restricted to the latency locus. This finding demonstrates for the first time the existence of multiple subtypes of KS lesions in HIV- and KS-treatment naive patients. KS is the leading cancer in people infected with HIV worldwide and is causally linked to KSHV infection. Using viral transcription profiling, we have demonstrated the existence of multiple subtypes of KS lesions for the first time in HIV- and KS-treatment-naive patients. A substantial number of lesions transcribe mRNAs which encode the viral kinases and hence could be targeted by the antiviral drugs ganciclovir or AZT in addition to chemotherapy.
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Reinitiation after translation of two upstream open reading frames (ORF) governs expression of the ORF35-37 Kaposi's sarcoma-associated herpesvirus polycistronic mRNA. J Virol 2014; 88:6512-8. [PMID: 24623444 DOI: 10.1128/jvi.00202-14] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
The Kaposi's sarcoma-associated herpesvirus (KSHV) ORF36 protein kinase is translated as a downstream gene from the ORF35-37 polycistronic mRNA via a unique mechanism involving short upstream open reading frames (uORFs) located in the 5' untranslated region. Here, we confirm that ORF35-37 is functionally dicistronic during infection and demonstrate that mutation of the dominant uORF restricts KSHV replication. Leaky scanning past the uORFs facilitates ORF35 expression, while a reinitiation mechanism after translation of the uORFs enables ORF36 expression.
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Arruda É, Jacome AADA, Toscano ALDCC, Silvestrini AA, Rêgo ASB, Wiermann EG, Cunha GFD, Melo HRLD, Morejón KML, Goldani LZ, Pereira LC, Silva MH, Treistman MS, Pereira MCT, Romero PMBX, Schmerling RA, Guedes RAV, Camargo VPD. Consensus of the Brazilian Society of Infectious Diseases and Brazilian Society of Clinical Oncology on the management and treatment of Kaposi's sarcoma. Braz J Infect Dis 2014; 18:315-26. [PMID: 24525061 PMCID: PMC9427498 DOI: 10.1016/j.bjid.2014.01.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Accepted: 01/23/2014] [Indexed: 12/26/2022] Open
Abstract
Kaposi's sarcoma is a multifocal vascular lesion of low-grade potential that is most often present in mucocutaneous sites and usually also affects lymph nodes and visceral organs. The condition may manifest through purplish lesions, flat or raised with an irregular shape, gastrointestinal bleeding due to lesions located in the digestive system, and dyspnea and hemoptysis associated with pulmonary lesions. In the early 1980s, the appearance of several cases of Kaposi's sarcoma in homosexual men was the first alarm about a newly identified epidemic, acquired immunodeficiency syndrome. In 1994, it was finally demonstrated that the presence of a herpes virus associated with Kaposi's sarcoma called HHV-8 or Kaposi's sarcoma herpes virus and its genetic sequence was rapidly deciphered. The prevalence of this virus is very high (about 50%) in some African populations, but stands between 2% and 8% for the entire world population. Kaposi's sarcoma only develops when the immune system is depressed, as in acquired immunodeficiency syndrome, which appears to be associated with a specific variant of the Kaposi's sarcoma herpes virus. There are no treatment guidelines for Kaposi's sarcoma established in Brazil, and thus the Brazilian Society of Clinical Oncology and the Brazilian Society of Infectious Diseases developed the treatment consensus presented here.
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Affiliation(s)
- Érico Arruda
- Sociedade Brasileira de Infectologia Infectologia, Vila Mariana, SP, Brazil
| | | | | | | | | | | | | | | | | | | | | | | | - Mauro Sergio Treistman
- Serviço de Infectologia de Rede Hospitalar Privada e Câmara Técnica de Doenças Infecciosas do CREMERJ
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De Clercq E. Potential of acyclic nucleoside phosphonates in the treatment of DNA virus and retrovirus infections. Expert Rev Anti Infect Ther 2014; 1:21-43. [PMID: 15482100 DOI: 10.1586/14787210.1.1.21] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
The acyclic nucleoside phosphonates [HPMPC: cidofovir, Vistide; PMEA: adefovir dipivoxil, Hepsera; and PMPA: tenofovir, Viread] have proven to be effective in vitro (cell culture systems) and in vivo (animal models and clinical studies) against a wide variety of DNA virus and retrovirus infections, for example, cidofovir against herpesvirus [herpes simplex virus type 1 and 2, varicella-zoster virus, cytomegalovirus, Epstein-Barr virus, human herpesvirus type 6, 7 and 8), polyoma-, papilloma-, adeno- and poxvirus (variola virus, cowpox virus, vaccinia virus, molluscum contagiosum virus and orf) infections; adefovir against herpesvirus, hepadnavirus [human hepatitis B virus] and retrovirus [HIV type-1 and 2, simian immunodeficiency virus and feline immunodeficiency virus] infections; and tenofovir against both hepadna- and retrovirus infections. Cidofovir has been officially approved for the treatment of cytomegalovirus retinitis in AIDS patients, tenofovir disoproxil fumarate (Viread) for the treatment of HIV infections (i.e., AIDS) and adefovir dipivoxil for the treatment of chronic hepatitis B.
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Affiliation(s)
- Eric De Clercq
- Rega Institute for Medical Research, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
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Haas DA, Bala K, Büsche G, Weidner-Glunde M, Santag S, Kati S, Gramolelli S, Damas M, Dittrich-Breiholz O, Kracht M, Rückert J, Varga Z, Keri G, Schulz TF. The inflammatory kinase MAP4K4 promotes reactivation of Kaposi's sarcoma herpesvirus and enhances the invasiveness of infected endothelial cells. PLoS Pathog 2013; 9:e1003737. [PMID: 24244164 PMCID: PMC3820715 DOI: 10.1371/journal.ppat.1003737] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2013] [Accepted: 09/15/2013] [Indexed: 12/15/2022] Open
Abstract
Kaposi's sarcoma (KS) is a mesenchymal tumour, which is caused by Kaposi's sarcoma herpesvirus (KSHV) and develops under inflammatory conditions. KSHV-infected endothelial spindle cells, the neoplastic cells in KS, show increased invasiveness, attributed to the elevated expression of metalloproteinases (MMPs) and cyclooxygenase-2 (COX-2). The majority of these spindle cells harbour latent KSHV genomes, while a minority undergoes lytic reactivation with subsequent production of new virions and viral or cellular chemo- and cytokines, which may promote tumour invasion and dissemination. In order to better understand KSHV pathogenesis, we investigated cellular mechanisms underlying the lytic reactivation of KSHV. Using a combination of small molecule library screening and siRNA silencing we found a STE20 kinase family member, MAP4K4, to be involved in KSHV reactivation from latency and to contribute to the invasive phenotype of KSHV-infected endothelial cells by regulating COX-2, MMP-7, and MMP-13 expression. This kinase is also highly expressed in KS spindle cells in vivo. These findings suggest that MAP4K4, a known mediator of inflammation, is involved in KS aetiology by regulating KSHV lytic reactivation, expression of MMPs and COX-2, and, thereby modulating invasiveness of KSHV-infected endothelial cells. Kaposi's sarcoma (KS) is a tumour caused by Kaposi's sarcoma herpesvirus (KSHV) and dysregulated inflammation. Both factors contribute to the high angiogenicity and invasiveness of KS. Various cellular kinases have been reported to regulate the KSHV latent-lytic switch and thereby virus pathogenicity. In this study, we have identified a STE20 kinase family member – MAP4K4 – as a modulator of KSHV lytic cycle and invasive phenotype of KSHV-infected endothelial cells. Moreover, we were able to link MAP4K4 to a known mediator of inflammation and invasiveness, cyclooxygenase-2, which also contributes to KSHV lytic replication. Finally, we could show that MAP4K4 is highly expressed in KS lesions, suggesting an important role for this kinase in tumour development and invasion.
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Affiliation(s)
- Darya A Haas
- Institute of Virology, Hannover Medical School, Hannover, Germany
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