scholarly journals HHV-8-Associated Lymphoproliferative Disorders and Pathogenesis in an HIV-Positive Patient

2019 ◽  
Vol 2019 ◽  
pp. 1-6 ◽  
Author(s):  
Carlo Guerrero ◽  
Tania Jain ◽  
Katalin Kelemen
Keyword(s):  
Kaposi's Sarcoma ◽  
Primary Effusion Lymphoma ◽  
Clinical Manifestations ◽  
Human Herpesvirus ◽  
Kaposi’S Sarcoma ◽  
B Cell Lymphoma ◽  
Lymphoproliferative Disorders ◽  
World Health ◽  
Hiv Positive ◽  
Health Organization

Human herpesvirus 8 (HHV-8), also known as Kaposi’s sarcoma-associated herpesvirus, is a DNA oncovirus known for its role in the development of Kaposi’s sarcoma (KS) and several lymphoproliferative disorders (LPDs). HHV-8 promotes lymphoproliferation via the activation of the interleukin-6 receptor signaling pathway, as well as a host of other regulatory mechanisms. The spectrum of HHV-8-associated LPDs is increasing. The World Health Organization has recently updated the classification of HHV-8-associated LPDs by introducing HHV-8-positive germinotropic LPD (GLPD) in addition to the previously recognized entities of HHV-8-positive diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS), primary effusion lymphoma (PEL), and HHV-8-positive multicentric Castleman’s disease (MCD). We present here a case of an HIV-positive woman with a history of KS, who later developed three HHV-8-associated LPDs, including HHV-8-positive MCD, PEL, and GLPD. To the best of our knowledge, this is the first reported case of a patient with this combination of individually rare HHV-8-associated LPDs. This case illustrates the spectrum and the sequential development of the different clinical manifestations of HHV-8-associated diseases. Detection of HHV-8 can have clinical significance in the diagnosis and management of certain HHV-8-associated conditions. Recently discovered variants of HHV-8-associated LPDs indicate that this group represents a diverse spectrum of disorders, whose classification may require further refinement beyond the currently recognized entities.

scholarly journals Spectrum of Kaposi's Sarcoma-Associated Herpesvirus, or Human Herpesvirus 8, Diseases

2002 ◽  
Vol 15 (3) ◽  
pp. 439-464 ◽  
Author(s):  
Dharam V. Ablashi ◽  
Louise G. Chatlynne ◽  
James E. Whitman, ◽  
Ethel Cesarman
Keyword(s):  
Dna Sequences ◽  
Kaposi's Sarcoma ◽  
Primary Effusion Lymphoma ◽  
Human Herpesvirus ◽  
Kaposi’S Sarcoma ◽  
B Cell Lymphoma ◽  
Human Herpesvirus 8 ◽  
Herpesvirus 8 ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Kaposi’S Sarcoma Associated Herpesvirus

SUMMARY Human herpesvirus 8 (HHV-8), also known as Kaposi's sarcoma-associated herpesvirus (KSHV), discovered in 1994, is a human rhadinovirus (gamma-2 herpesvirus). Unlike other human herpesviruses (herpes simplex virus, Epstein-Barr virus, varicella-zoster virus, cytomegalovirus, HHV-6, and HHV-7), it is not widespread in the general population and has many unique proteins. HHV-8 is strongly associated with all subtypes of Kaposi's sarcoma (KS), multicentric Castleman's disease, and a rare form of B-cell lymphoma, primary effusion lymphoma. In addition, HHV-8 DNA sequences have been found in association with other diseases, but the role of the virus in these diseases is largely unconfirmed and remains controversial. The seroprevalence of HHV-8, based on detection of latent and lytic proteins, is 2 to 5% in healthy donors except in certain geographic areas where the virus is endemic, 80 to 95% in classic KS patients, and 40 to 50% in HIV-1 patients without KS. This virus can be transmitted both sexually and through body fluids (e.g., saliva and blood). HHV-8 is a transforming virus, as evidenced by its presence in human malignancies, by the in vitro transforming properties of several of its viral genes, and by its ability to transform some primary cells in culture. It is not, however, sufficient for transformation, and other cofactors such as immunosuppressive cytokines are involved in the development of HHV-8-associated malignancies. In this article, we review the biology, molecular virology, epidemiology, transmission, detection methods, pathogenesis, and antiviral therapy of this newly discovered human herpesvirus.

scholarly journals The Kaposi's Sarcoma-Associated Herpesvirus G Protein-Coupled Receptor Has Broad Signaling Effects in Primary Effusion Lymphoma Cells

2003 ◽  
Vol 77 (1) ◽  
pp. 57-67 ◽  
Author(s):  
Mark Cannon ◽  
Nicola J. Philpott ◽  
Ethel Cesarman
Keyword(s):  
G Protein ◽  
Kaposi's Sarcoma ◽  
Primary Effusion Lymphoma ◽  
Cell Cycle Control ◽  
Human Herpesvirus ◽  
Kaposi’S Sarcoma ◽  
G Protein Coupled Receptor ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Kaposi’S Sarcoma Associated Herpesvirus ◽  
G Protein Coupled

ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV/human herpesvirus 8 [HHV-8]) is a gamma-2-herpesvirus responsible for Kaposi's sarcoma as well as primary effusion lymphoma (PEL). KSHV is a lymphotropic virus that has pirated many mammalian genes involved in inflammation, cell cycle control, and angiogenesis. Among these is the early lytic viral G protein-coupled receptor (vGPCR), a homologue of the human interleukin-8 (IL-8) receptor. When expressed, vGPCR is constitutively active and can signal via mitogen- and stress-activated kinases. In certain models it activates the transcriptional potential of NF-κB and activator protein 1 (AP-1) and induces vascular endothelial growth factor (VEGF) production. Despite its importance to the pathogenesis of all KSHV-mediated disease, little is known about vGPCR activity in hematopoietic cells. To study the signaling potential and downstream effects of vGPCR in such cells, we have developed PEL cell lines that express vGPCR under the control of an inducible promoter. The sequences required for tetracycline-mediated induction were cloned into a plasmid containing adeno-associated virus type 2 elements to enhance integration efficiency. This novel plasmid permitted studies of vGPCR activity in naturally infected KSHV-positive lymphocytes. We show that vGPCR activates ERK-2 and p38 in PEL cells. In addition, it increases the transcription of reporter genes under the control of AP-1, NF-κB, CREB, and NFAT, a Ca2+-dependent transcription factor important to KSHV lytic gene expression. vGPCR also increases the transcription of KSHV open reading frames 50 and 57, thereby displaying broad potential to affect viral transcription patterns. Finally, vGPCR signaling results in increased PEL cell elaboration of KSHV vIL-6 and VEGF, two growth factors involved in KSHV-mediated disease pathogenesis.

scholarly journals Differential Expression of Viral Bcl-2 Encoded by Kaposi's Sarcoma-Associated Herpesvirus and Human Bcl-2 in Primary Effusion Lymphoma Cells and Kaposi's Sarcoma Lesions

2002 ◽  
Vol 76 (5) ◽  
pp. 2551-2556 ◽  
Author(s):  
Isabelle Widmer ◽  
Marion Wernli ◽  
Felix Bachmann ◽  
Fred Gudat ◽  
Gieri Cathomas ◽  
...  
Keyword(s):  
Kaposi's Sarcoma ◽  
Mononuclear Cells ◽  
Primary Effusion Lymphoma ◽  
Human Herpesvirus ◽  
Kaposi’S Sarcoma ◽  
Human Herpesvirus 8 ◽  
Lymphoma Cells ◽  
Herpesvirus 8 ◽  
Primary Effusion Lymphoma Cell ◽  
Spindle Cells

ABSTRACT Expression of human herpesvirus 8 viral Bcl-2 protein was demonstrated in spindle cells of late-stage Kaposi's sarcoma lesions but not in primary effusion lymphoma cell lines. In contrast, strong expression of human Bcl-2 was found in stimulated primary effusion lymphoma cells, whereas in Kaposi's sarcoma lesions preferential mononuclear cells, and to a lesser extent spindle cells, stained positive.

Angiogenesis and Hematopoiesis Induced by Kaposi’s Sarcoma-Associated Herpesvirus-Encoded Interleukin-6

Blood ◽  
1999 ◽  
Vol 93 (12) ◽  
pp. 4034-4043 ◽  
Author(s):  
Yoshiyasu Aoki ◽  
Elaine S. Jaffe ◽  
Yuan Chang ◽  
Karen Jones ◽  
Julie Teruya-Feldstein ◽  
...  
Keyword(s):  
Lymph Nodes ◽  
Interleukin 6 ◽  
Kaposi's Sarcoma ◽  
Primary Effusion Lymphoma ◽  
Biological Activities ◽  
Human Herpesvirus ◽  
Kaposi’S Sarcoma ◽  
Nih3t3 Cells ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Kaposi’S Sarcoma Associated Herpesvirus

Kaposi’s sarcoma-associated herpesvirus (KSHV; also known as human herpesvirus 8 [HHV-8]) is a herpesvirus linked to the development of Kaposi’s sarcoma (KS), primary effusion lymphoma, and a proportion of Castleman’s disease. KSHV encodes viral interleukin-6 (vIL-6), which is structurally homologous to human and murine IL-6. The biological activities of vIL-6 are largely unknown. To gain insight into the biology of vIL-6, we expressed vIL-6 in murine fibroblasts NIH3T3 cells and inoculated stable vIL-6–producing clones into athymic mice. vIL-6 was detected selectively in the blood of mice injected with vIL-6–expressing clones. Compared with controls, vIL-6–positive mice displayed increased hematopoiesis in the myeloid, erythroid, and megakaryocytic lineages; plasmacytosis in spleen and lymph nodes; hepatosplenomegaly; and polyclonal hypergammaglobulinemia. vIL-6–expressing NIH3T3 cells gave rise to tumors more rapidly than did control cells, and vIL-6–positive tumors were more vascularized than controls. Vascular endothelial growth factor (VEGF) was detected at higher levels in the culture supernatant of vIL-6–expressing cells compared with controls, and immunohistochemical staining detected VEGF in spleen, lymph nodes, and tumor tissues from mice bearing vIL-6–producing tumors but not control tumors. Thus, vIL-6 is a multifunctional cytokine that promotes hematopoiesis, plasmacytosis, and angiogenesis. Through these functions, vIL-6 may play an important role in the pathogenesis of certain KSHV-associated disorders.

scholarly journals Kaposi’s Sarcoma-Associated Herpesvirus Increases PD-L1 and Proinflammatory Cytokine Expression in Human Monocytes

mBio ◽  
2017 ◽  
Vol 8 (5) ◽  
Author(s):  
Kurtis M. Host ◽  
Sarah R. Jacobs ◽  
John A. West ◽  
Zhigang Zhang ◽  
Lindsey M. Costantini ◽  
...  
Keyword(s):  
T Cells ◽  
Proinflammatory Cytokine ◽  
Kaposi's Sarcoma ◽  
Primary Effusion Lymphoma ◽  
Kaposi’S Sarcoma ◽  
Lymphoproliferative Disorders ◽  
Human Monocytes ◽  
Programmed Death Ligand 1 ◽  
Kshv Infection ◽  
Programmed Death

ABSTRACTKaposi’s sarcoma-associated herpesvirus (KSHV) is associated with the human malignancy Kaposi’s sarcoma and the lymphoproliferative disorders primary effusion lymphoma and multicentric Castleman’s disease. KSHV establishes lytic infection of monocytesin vivo, which may represent an important cellular reservoir during KS disease progression. KS tumors consist of latently infected endothelial cells; however, lytic phase gene products are important for KS onset. Early KS lesion progression is driven by proinflammatory cytokines supplied by immune cell infiltrates including T cells and monocytes. KSHV-infected monocytes may supply the lytic viral products and the inflammatory milieu conducive to KS tumor progression. To establish successful infection, KSHV extensively modulates the host immune system. KSHV antigens activate both innate and adaptive immune responses including KSHV-specific T cells, but lifelong infection is still established. Programmed death ligand 1 (PD-L1) is a prosurvival cell surface protein that suppresses T-cell-mediated killing. PD-L1 is variably present on various tumor cells and is a targetable marker for cancer treatment. We show that KSHV infection of human monocytes increases PD-L1 expression and transcription in a dose-dependent manner. We also saw evidence of lytic gene expression in the KSHV-infected monocytes. Intact KSHV is needed for full PD-L1 response in human monocytes. KSHV induces a general proinflammatory cytokine milieu including interleukins 1α, 1β, and 6, which have been implicated in early KS lesion progression. KSHV-mediated PD-L1 increase may represent a novel mechanism of KSHV-mediated immune modulation to allow for virus survival and eventually malignant progression.IMPORTANCEKSHV is the etiologic agent of Kaposi’s sarcoma and the lymphoproliferative disorders primary effusion lymphoma and multicentric Castleman’s disease. Programmed death ligand 1 (PD-L1) is an immunosuppressive cell surface marker that inhibits T cell activation. We report that KSHV infection of primary human monocytes upregulates PD-L1 transcription and protein expression. Analysis of the cytokine and chemokine milieu following KSHV infection of monocytes revealed that KSHV induces interleukins 1α, 1β, and 6, all of which have been implicated in KS development. Our work has identified another potential immune evasion strategy for KSHV and a potential target for immunotherapy of KSHV-derived disease.

scholarly journals Kaposi's Sarcoma-Associated Herpesvirus LANA2 Is a B-Cell-Specific Latent Viral Protein That Inhibits p53

2001 ◽  
Vol 75 (1) ◽  
pp. 429-438 ◽  
Author(s):  
Carmen Rivas ◽  
Ai-En Thlick ◽  
Carlo Parravicini ◽  
Patrick S. Moore ◽  
Yuan Chang
Keyword(s):  
Kaposi's Sarcoma ◽  
Primary Effusion Lymphoma ◽  
Blot Hybridization ◽  
Human Herpesvirus ◽  
Kaposi’S Sarcoma ◽  
Nuclear Antigen ◽  
P53 Overexpression ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Kaposi’S Sarcoma Associated Herpesvirus

ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV), or human herpesvirus 8, is associated with three proliferative diseases ranging from viral cytokine-induced hyperplasia to monoclonal neoplasia: multicentric Castleman's disease (CD), Kaposi's sarcoma (KS), and primary effusion lymphoma (PEL). Here we report a new latency-associated 1,704-bp KSHV spliced gene belonging to a cluster of KSHV sequences having homology to the interferon regulatory factor (IRF) family of transcription factors. ORFK10.5 encodes a protein, latency-associated nuclear antigen 2 (LANA2), which is expressed in KSHV-infected hematopoietic tissues, including PEL and CD but not KS lesions. LANA2 is abundantly expressed in the nuclei of cultured KSHV-infected B cells. Transcription of K10.5 in PEL cell cultures is not inhibited by DNA polymerase inhibitors nor significantly induced by phorbol ester treatment. Unlike LANA1, LANA2 does not elicit a serologic response from patients with KS, PEL, or CD as measured by Western blot hybridization. Both KSHV vIRF1 (ORFK9) and LANA2 (ORFK10.5) appear to have arisen through gene duplication of a captured cellular IRF gene. LANA2 is a potent inhibitor of p53-induced transcription in reporter assays. LANA2 antagonizes apoptosis due to p53 overexpression in p53-null SAOS-2 cells and apoptosis due to doxorubicin treatment of wild-type p53 U2OS cells. While LANA2 specifically interacts with amino acids 290 to 393 of p53 in glutathione S-transferase pull-down assays, we were unable to demonstrate LANA2-p53 interaction in vivo by immunoprecipitation. These findings show that KSHV has tissue-specific latent gene expression programs and identify a new latent protein which may contribute to KSHV tumorigenesis in hematopoietic tissues via p53 inhibition.

scholarly journals Pathology Characteristics of Lymphomas in Rwanda: A Retrospective Study

2021 ◽  
Vol 5 (2) ◽  
pp. 170-173
Author(s):  
Fiacre Mugabe Byiringiro ◽  
Felix Manirakiza ◽  
Déogratias Ruhangaza ◽  
Thierry Zawadi Muvunyi ◽  
Belson Rugwizangoga
Keyword(s):  
Hodgkin Lymphoma ◽  
B Cell Lymphoma ◽  
World Health ◽  
Hiv Positive ◽  
Stained Glass ◽  
Global Challenge ◽  
Glass Slides ◽  
Hematoxylin And Eosin ◽  
Health Organization ◽  
Hodgkin's Lymphomas

Background: Lymphomas have been a global challenge for many decades and despite measures for prevention and management, the incidence continues to increase. There are two main categories, which are Non-Hodgkin’s Lymphomas and Hodgkin’s Lymphomas and most common etiologies are environmental, genetic alteration, radiation and some viruses. Objective: To describe pathology characteristics of lymphomas in Rwanda based on Hematoxylin and Eosin stained glass slides and immuno histo chemistry, and classify them according to clinical aggressiveness. Patients and Methods: We conducted a retrospective observational and descriptive study from January 2013 to December 2019. Lymphoma cases were retrieved together with relevant clinical and pathological information, and reviewed by independent pathologists. Histological diagnosis was classified according to the 2008 World Health Organization system in order to assign clinical aggressiveness of the lymphoma. Results: Three hundred and six lymphoma cases were enrolled. Males contributed to 57% of all reviewed case, and slightly over 50% were young aged ≤35 years. Approximately 191 (62%) of cases were nodal lymphomas. Approximately one fifth (18%) of lymphoma cases were HIV positive. Most 213(70%) cases were Non-Hodgkin’s Lymphomas of aggressive forms 164(77%). Among 164 cases of aggressive Non-Hodgkin’s Lymphomas, diffuse large B cell lymphoma was the leading subtype 91(55.5%), followed by solid lymphoblastic lymphoma 32(19.5%) and Burkitt lymphoma 17(10.4%). Among all Hodgkin lymphoma cases, 90(97%) were classical Hodgkin lymphomaof nodular sclerosis subtype. Hodgkin lymphoma patients were younger compared to Non-Hodgkin’s Lymphomas patients (mean age of 24.78±16.3 years versus 38.6±22. 5years, p=.000). Conclusion: Substantial proportion of Lymphomapatients in Rwanda were also HIV positive. Interestingly, Non-Hodgkin’s Lymphomas in Rwanda are predominated by the most aggressive forms, and these mostly affect a younger population. Optimal characterisation of such cases, using advanced methods, is recommended.

scholarly journals Kaposi's Sarcoma-Associated Herpesvirus Latent and Lytic Gene Expression as Revealed by DNA Arrays

2001 ◽  
Vol 75 (2) ◽  
pp. 891-902 ◽  
Author(s):  
Richard G. Jenner ◽  
M. Mar Albà ◽  
Chris Boshoff ◽  
Paul Kellam
Keyword(s):  
Gene Expression ◽  
Kaposi's Sarcoma ◽  
Primary Effusion Lymphoma ◽  
Human Herpesvirus ◽  
Kaposi’S Sarcoma ◽  
Lytic Replication ◽  
Dna Arrays ◽  
Nylon Membrane ◽  
Kaposi's Sarcoma Associated Herpesvirus ◽  
Kaposi’S Sarcoma Associated Herpesvirus

ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV; human herpesvirus 8) is associated with three human tumors, Kaposi's sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman's disease. KSHV encodes a number of homologs of cellular proteins involved in the cell cycle, signal transduction, and modulation of the host immune response. Of the virus complement of over 85 open reading frames (ORFs), the expression of only a minority has been characterized individually. We have constructed a nylon membrane-based DNA array which allows the expression of almost every ORF of KSHV to be measured simultaneously. A PEL-derived cell line, BC-3, was used to study the expression of KSHV during latency and after the induction of lytic replication. Cluster analysis, which arranges genes according to their expression profile, revealed a correlation between expression and assigned gene function that is consistent with the known stages of the herpesvirus life cycle. Furthermore, latent and lytic genes thought to be functionally related cluster into groups. The correlation between gene expression and function also infers possible roles for KSHV genes yet to be characterized.

scholarly journals Unique Circulating microRNA Profiles in Epidemic Kaposi’s Sarcoma

2020 ◽  
Author(s):  
Haruna Muwonge ◽  
Hassan Kasujja ◽  
Carolyne Atugonza ◽  
Josephine Kasolo ◽  
Allan Lugaajju ◽  
...  
Keyword(s):  
Kaposi's Sarcoma ◽  
Early Stage ◽  
Human Herpesvirus ◽  
Kaposi’S Sarcoma ◽  
Hiv Positive ◽  
Circulating Microrna ◽  
Early Stage Disease ◽  
Circulating Mirna ◽  
Serum Mirnas ◽  
Potential Biomarkers

Abstract BackgroundThe Human herpesvirus 8 (HHV-8), causes Kaposi's sarcoma (KS). Kaposi sarcoma in HIV/AIDS patients is referred to as epidemic KS, and is the most common HIV-related malignancy worldwide. Lack of a diagnostic assay to detect latent and early stage disease has increased disease morbidity and mortality. Serum miRNAs have previously been used as potential biomarkers of normal physiology and disease. In the current study, we profiled the unique serum miRNAs in patients with epidemic KS to generate baseline data to aid in developing a miRNA-based non-invasive biomarker assay for Epidemic KS. MethodsThis was a comparative cross-sectional study involving 27 patients with epidemic KS, and 27 HIV-positive adults with no prior diagnosis, or clinical manifestation of KS. DNA and RNA were isolated from blood and serum collected from study participants respectively. Nested PCR for circulating HHV-8 DNA was performed on the isolated DNA, whereas miRNA library preparation and sequencing for circulating miRNA was performed on the RNA samples. The miRge2 pipeline and EdgeR were used to analyze the sequencing data. Results Fifteen out of the 27 epidemic KS positive subjects (55.6%) tested positive for HHV-8 DNA, whereas only 3 (11.1%) out of the 27 HIV positive, KS negative subjects tested positive for HHV-8 DNA. Additionally, we found a unique miRNA expression signature in 49 circulating miRNAs in epidemic KS subjects compared to subjects with no epidemic KS, with 41 miRNAs upregulated and 8 miRNAs down regulated. Subjects with latent KS infection had a differential upregulation of circulating miR-193a compared to HIV-positive, KS negative subjects for whom circulating HHV-8 DNA was not detected. Further analysis of serum from epidemic KS patients revealed a miRNA signature according to KS tumor status and time since first HIV diagnosis. ConclusionsThis study reveals unique circulating miRNA profiles in the serum of patients with epidemic KS versus HIV-infected subjects with no KS, as well as in subjects with latent KS. Many of the dysregulated miRNAs in epidemic KS patients were previously reported to have crucial roles in KS infection and latency, highlighting their promising roles as potential biomarkers of latent or active KS infection.

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