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Eric Oksenhendler - One of the best experts on this subject based on the ideXlab platform.

  • Human Herpesvirus 8 polyclonal igmλ b cell lymphocytosis mimicking plasmablastic leukemia lymphoma in hiv infected patients
    European Journal of Haematology, 2013
    Co-Authors: Eric Oksenhendler, Félix Agbalika, Veronique Meignin, Claire Fieschi, David Boutboul, Kheira Beldjord, Adrienne De Labarthe, Antoine Dossier, Carlo Parravicini, Giovanna Tosato
    Abstract:

    Purpose Multicentric Castleman disease (MCD) is a distinct lymphoproliferative disorder characterized by inflammatory symptoms, lymphadenopathy, splenomegaly, and cytopenia. Kaposi's sarcoma-associated Herpesvirus (KSHV), also called Human Herpesvirus-8 (HHV-8), is the cause of virtually all cases of MCD occurring in patients with HIV infection. MCD lesions characteristically contain HHV-8-infected polyclonal IgMλ plasmablasts. A high frequency of HHV-8-related non-Hodgkin lymphoma has been reported in these patients. Patients and methods We now report on three patients who presented with severe symptoms of MCD, extreme splenomegaly, and rapid expansion of B-cell lymphocytosis (44–81%) attributable to circulating HHV-8 positive plasmablasts. Results The circulating plasmablastic cells shared the phenotype (IgMλ, CD19+, CD20− CD138−) of HHV-8-infected cells from MCD lesions, mimicking the leukemic phase of large B-cell lymphoma occurring in HHV-8-related MCD. These patients displayed a very high HHV-8 viral load in blood (>7 logs HHV-8 DNA copies/ml) and high levels of serum vIL-6, the viral homolog of Human interleukin 6. Serum IL-6 and IL-10 were also abnormally elevated. HHV-8-infected cells were demonstrated by immunoglobulin gene rearrangement analysis, to be polyclonal and likely represent an expansion of HHV-8-infected cells similar to those found in MCD lesions. Conclusion Thus, the spectrum of HHV-8-related plasmablastic lymphoproliferative disorders in patients with HIV infection is expanded to include HHV-8+ polyclonal IgMλ B-cell lymphocytosis. At onset, this lymphoproliferative disorder may mimic plasmablastic leukemia/lymphoma. Recognizing this unusual complication may have important implications in treatment decision avoiding unnecessary toxicity to the patients.

  • Human Herpesvirus 8 related castleman disease in the absence of hiv infection
    Clinical Infectious Diseases, 2013
    Co-Authors: A Dossier, Eric Oksenhendler, Veronique Meignin, Claire Fieschi, David Boutboul, Lionel Galicier
    Abstract:

    Background. Castleman disease (CD) in the context of Human immunodeficiency virus (HIV) infection is well described. It is almost always multicentric (MCD) and linked to Human Herpesvirus 8 (HHV-8). There are limited published data surrounding HHV-8–related CD among HIV-negative patients. Methods. From January 1995 through June 2012, we identified in a single center 18 HIV-seronegative patients with HHV-8–related CD. We report on their clinical, pathological, and laboratory features. Results. All cases were multicentric. Patients were aged 42–83 years and were referred with a relapsing remitting syndrome of fever (94%), constitutional symptoms (100%), peripheral lymphadenopathy (100%), splenomegaly (72%), hepatomegaly (50%), and edema (28%). Kaposi sarcoma was observed in 9 cases. Anemia and serum markers of inflammation were present in all cases. Polymerase chain reaction for HHV-8 DNA was positive on blood samples in all cases, whereas only 12 of 16 patients tested had positive HHV-8 serology at diagnosis. All cases showed the classic histological features of MCD, and LANA-1 immunostaining identified HHV-8–infected plasmablasts in 16 of 16 tested cases. Reactive hemophagocytic syndrome (44%), autoimmune hemolytic anemia (33%), and lymphoma (22%) were the commonest associated complications. Remission was obtained with etoposide in 13 of 15 cases. Rituximab allowed prolonged remission off therapy in 10 cases. Death occurred in 3 patients not treated with rituximab. These features were similar to those described in HIV-positive HHV-8–related MCD. Comparison between these 18 cases and 12 HIV-negative HHV-8–unrelated MCD cases showed marked discrepancies. Conclusions. HHV-8–associated MCD may be considered as a single clinicopathological entity regardless of HIV status.

  • low t cell responses to Human Herpesvirus 8 in patients with aids related and classic kaposi sarcoma
    The Journal of Infectious Diseases, 2006
    Co-Authors: Amelie Guihot, Eric Oksenhendler, Brigitte Autran, N Dupin, Annegenevieve Marcelin, Isabelle Gorin, Annesophie Bedin, Philippe Bossi, Lionel Galicier, Guislaine Carcelain
    Abstract:

    BACKGROUND Kaposi sarcoma (KS) occurs mainly in immunocompromised patients and is strongly associated with infection with Human Herpesvirus 8 (HHV-8; also known as "KS-associated Herpesvirus"). We hypothesized that KS is linked to deficiencies in specific anti-HHV-8 T cell immunity. METHODS We studied asymptomatic HHV-8 carriers coinfected with Human immunodeficiency virus (HIV; n = 23) and patients with HIV-related or classic KS (n = 29). We used an interferon- gamma enzyme-linked immunospot assay with 56 specific peptides distributed on 6 HHV-8 proteins (glycoprotein [gp] B, gpH, gp35/37, latent nuclear antigen 1 [LANA-1], K12, and K15) to detect HHV-8-specific T cell responses. RESULTS We found that patients with KS responded to these peptides less often and had much lower HHV-8-specific T cells counts than did asymptomatic HHV-8 carriers (P = .001 and P = .0004, respectively), regardless of CD4 T cell count or HHV-8 load. The frequency of Epstein-Barr virus-specific T cells was similar in both groups. CONCLUSIONS Our results suggest that HIV-related and classic KS are associated with a lack of HHV-8-specific T cells. Also, we have described 8 new HHV-8 T cell epitopes in LANA-1, K12, and K15, including 2 CD4 T cell epitopes. These data provide new insight into HHV-8 cellular immunity.

  • prognostic factors and outcome of Human Herpesvirus 8 associated primary effusion lymphoma in patients with aids
    Journal of Clinical Oncology, 2005
    Co-Authors: E Boulanger, J Gabarre, Laurence Gerard, Jeanmichel Molina, C Rapp, Jeanfrancois Abino, J Cadranel, Sylvie Chevret, Eric Oksenhendler
    Abstract:

    Purpose Primary effusion lymphoma (PEL) is a rare high-grade B-cell non-Hodgkin's lymphoma associated with Kaposi sarcoma–associated Herpesvirus/Human Herpesvirus 8 (KSHV/HHV-8) infection, and is mostly observed in the course of HIV infection. The prognosis is poor, with reported median survival time shorter than 6 months. To date, no prognostic factor has been identified in this subset of lymphoma. Patients and Methods We describe here a large series of HIV-infected patients with PEL, including 28 cases diagnosed in six centers during an 11-year time period. Prognosis analysis was performed using a Cox proportional hazard regression model. Statistically significant covariates were further analyzed in a forward, stepwise multivariate model. Results After a median follow-up of 3.8 years (range, 10 months to 10.8 years), nine patients (32%) were still alive, and eight of them remained progression free. The median survival was 6.2 months, and the 1-year overall survival rate was 39.3%. Fourteen patients (50%...

  • high levels of Human Herpesvirus 8 viral load Human interleukin 6 interleukin 10 and c reactive protein correlate with exacerbation of multicentric castleman disease in hiv infected patients
    Blood, 2000
    Co-Authors: Eric Oksenhendler, E Boulanger, Guislaine Carcelain, Yoshiyasu Aoki, Anne Maillard, Jeanpierre Clauvel, Félix Agbalika
    Abstract:

    Multicentric Castleman disease (MCD) is a distinct type of lymphoproliferative disorder associated with inflammatory symptoms and interleukin-6 (IL-6) dysregulation. In the context of Human immunodeficiency virus (HIV) infection, MCD is associated with Human Herpesvirus 8 (HHV8) infection. In a prospective study of 23 HIV-infected patients with MCD, clinical symptoms of MCD were present at 45 visits, whereas patients were in chemotherapy-induced clinical remission at 50 visits. Symptoms were associated with a high level of serum C reactive protein, high HHV8 viral load in peripheral blood mononuclear cells, and high plasma Human IL-6 and IL-10 levels. Strong correlations between plasma IL-6 and plasma IL-10 with the HHV8 viral load suggest that both cytokines may be involved in the pathogenesis of this virus-associated lymphoproliferative disorder.

Jose Fernando Valbernal - One of the best experts on this subject based on the ideXlab platform.

  • Human Herpesvirus 8 genes are expressed in pulmonary inflammatory myofibroblastic tumor inflammatory pseudotumor
    The American Journal of Surgical Pathology, 2001
    Co-Authors: Jose Javier Gomezroman, Pablo Sanchezvelasco, Gonzalo Ocejovinyals, Emilia Hernandeznieto, Francisco Leyvacobian, Jose Fernando Valbernal
    Abstract:

    The presence of Human Herpesvirus-8 DNA sequences, as well as an overexpression of Human interleukin-6 and Human cyclin D1 in myofibroblastic cells of inflammatory myofibroblastic tumor (inflammatory pseudotumor), has recently been reported. We describe the pattern of Human Herpesvirus-8 gene expression in five cases of pulmonary inflammatory myofibroblastic tumor. Reverse transcriptase-polymerase chain reaction (RT-PCR), with several positive and negative controls, was performed to detect mRNA of 11 open reading frames encoded by Human Herpesvirus-8 in lytic and latent stages of viral replicative cycle. We found molecular transcripts from ORF16, ORFK13, and ORF72 in the five cases and from ORFK2 in four of five neoplasms. The corresponding encoded proteins were Human homologous oncoproteins (viral cyclin-D), inflammatory cytokines (viral IL-6), and inhibitors of apoptotic pathways (viral FLIP and viral Bcl-2), mostly expressed in a latent viral replicative stage. The rest of open reading frames examined included mainly lytic-associated genes and showed no expression. The spectrum of expressed viral genes is not the same as can be observed in Kaposi's sarcoma or multicentric Castleman's disease, suggesting that Human Herpesvirus-8 plays a different role in the pathogenesis of its associated diseases. These differences may be related to either cell-specific or immunologic host factors.

  • presence of Human Herpesvirus 8 dna sequences and overexpression of Human il 6 and cyclin d1 in inflammatory myofibroblastic tumor inflammatory pseudotumor
    Laboratory Investigation, 2000
    Co-Authors: Jose Javier Gomezroman, Pablo Sanchezvelasco, Gonzalo Ocejovinyals, Francisco Leyvacobian, Emilia Hernandez Nieto, Jose Fernando Valbernal
    Abstract:

    Inflammatory myofibroblastic tumor (IMT) is composed of myofibroblasts, plasma cells, and lymphocytes. Cytokines are possibly involved in its pathogenesis. Human Herpesvirus-8 (HHV-8) encodes cell cycle regulatory and signaling proteins. A combination of nested PCR with several negative controls and Southern blot methods showed the presence of HHV-8 DNA in seven cases of IMT. Additionally, strong expression was demonstrated by in situ hybridization in many tumoral nuclei. Most of the myofibroblasts in all of the cases were immunoreactive for Human IL-6 and cyclin D1. These cytokines probably have a paracrine action and may sustain myofibroblastic growth. HHV-8 could play an essential role in triggering IMT development by a local reactivation of viral lytic replication. The relationship between HHV-8 and immunosuppression status as the only associated cause for tumorigenesis should be revised.

Don Ganem - One of the best experts on this subject based on the ideXlab platform.

  • evidence for concurrent epidemics of Human Herpesvirus 8 and Human immunodeficiency virus type 1 in us homosexual men rates risk factors and relationship to kaposi s sarcoma
    The Journal of Infectious Diseases, 1999
    Co-Authors: Thomas R Obrien, Don Ganem, Dean H Kedes, Donald R Macrae, Philip S Rosenberg, Jaime Molden, James J Goedert
    Abstract:

    We examined Human Herpesvirus 8 (HHV-8) seroprevalence and seroincidence among 245 homosexual men from New York City (NYC) and Washington, DC (DC) who have been followed since 1982. An immunofluorescence assay measured antibodies to a latent HHV-8 nuclear antigen. Seroprevalence was 20.4% in 1982; seroincidence was approximately 15%/year during 1982-1983 but fell sharply thereafter. NYC men had a higher seroprevalence (odds ratio, 3.43; P<.001) and seroincidence (rate ratio, 2.13; P=.01) than DC men. Risk of Kaposi's sarcoma (KS) was increased in seropositive men (adjusted relative hazard, 3.58; P=.02). Among men who were seropositive for both Human immunodeficiency virus type 1 and HHV-8, the 10-year cumulative risk of KS was 39%; time from coinfection to KS diagnosis ranged from 15 to 154 months (median, 63.5 months). This study shows an epidemic of HHV-8 among US homosexual men in the early 1980s that was associated with a high risk of developing KS.

  • sexual transmission and the natural history of Human Herpesvirus 8 infection
    The New England Journal of Medicine, 1998
    Co-Authors: Jeffrey N Martin, Don Ganem, Dennis Osmond, Kimberly Pageshafer, Don Macrae, Dean H Kedes
    Abstract:

    Background Although Human Herpesvirus 8 (HHV-8) has been suspected to be the etiologic agent of Kaposi's sarcoma, little is known about its seroprevalence in the population, its modes of transmission, and its natural history. Methods The San Francisco Men's Health Study, begun in 1984, is a study of a population-based sample of men in an area with a high incidence of Human immunodeficiency virus (HIV) infection. We studied all 400 men infected at base line with HIV and a sample of 400 uninfected men. Base-line serum samples were assayed for antibodies to HHV-8 latency–associated nuclear antigen (anti-LANA). In addition to the seroprevalence and risk factors for anti-LANA seropositivity, we analyzed the time to the development of Kaposi's sarcoma. Results Anti-LANA antibodies were found in 223 of 593 men (37.6 percent) who reported any homosexual activity in the previous five years and in none of 195 exclusively heterosexual men. Anti-LANA seropositivity correlated with a history of sexually transmitted di...

  • characterization of ribonucleoprotein complexes containing an abundant polyadenylated nuclear rna encoded by kaposi s sarcoma associated Herpesvirus Human Herpesvirus 8
    Journal of Virology, 1997
    Co-Authors: Weidong Zhong, Don Ganem
    Abstract:

    Infection with Kaposi's sarcoma-associated Herpesvirus (KSHV) (also called Human Herpesvirus 8) is strongly linked to all forms of Kaposi's sarcoma. We have previously identified two polyadenylated KSHV transcripts that are actively transcribed in Kaposi's sarcoma (KS) tumors and in KSHV-infected B-lymphoma cells. One of these RNAs (termed T1.1 or nut-1 RNA) is a 1.1-kb transcript present in a subpopulation of KS tumor cells. This RNA is localized to the nucleus of infected cells and has no open reading frames longer than 62 codons, suggesting that it may not function as an mRNA in vivo. Here we demonstrate that nut-1 RNA is a lytic-cycle gene product that is found in high-molecular-weight ribonucleoprotein complexes in infected cell nuclei. The transcript lacks the trimethylguanosine (TMG) cap found in many U-like small nuclear RNAs, but a subpopulation of nut-1 RNAs can associate with Sm protein-containing small nuclear ribonucleoproteins, as judged by immunoprecipitation analyses using monoclonal anti-Sm and anti-TMG antibodies. This interaction does not require other viral gene products, and deletion of the sole candidate Sm binding site on nut-1 RNA does not ablate this association. This finding suggests an indirect interaction with Sm-containing structures, and models for such associations are presented.

  • the seroepidemiology of Human Herpesvirus 8 kaposi s sarcoma associated Herpesvirus distribution of infection in ks risk groups and evidence for sexual transmission
    Nature Medicine, 1996
    Co-Authors: Dean H Kedes, Eva Operskalski, Michael P Busch, Robert Kohn, Jennifer Flood, Don Ganem
    Abstract:

    Striking differences in Kaposi's sarcoma (KS) risk for AIDS patients who acquire HIV via homosexual activity and those whose HIV infections derive from blood product exposure suggest the presence of a sexually transmitted agent other than HIV in the development of KS. Using an immunofluorescence assay, we examined serum samples from 913 patients for the presence of antibody specific for infection by Human Herpesvirus 8 (HHV8), an agent whose genome is regularly found in KS tissue. The distribution of HHV8 seropositivity conforms to that expected for a sexually transmitted pathogen and tracks closely with the risk for KS development. Our data support the inference that this virus is the etiologic cofactor predicted by the epidemiology of KS.

  • restricted expression of kaposi sarcoma associated Herpesvirus Human Herpesvirus 8 genes in kaposi sarcoma
    Proceedings of the National Academy of Sciences of the United States of America, 1996
    Co-Authors: Weidong Zhong, Hao Wang, Brian Herndier, Don Ganem
    Abstract:

    Kaposi sarcoma (KS) is the leading neoplasm of HIV-infected patients and is also found in several HIV-negative populations. Recently, DNA sequences from a novel Herpesvirus, termed KS-associated Herpesvirus (KSHV), or Human Herpesvirus 8 (HHV-8) have been identified within KS tissue from both HIV-positive and HIV-negative cases; infection with this agent has been proposed as a possible factor in the etiology or pathogenesis of the tumor. Here we have examined the pattern of KSHV/HHV-8 gene expression in KS and find it to be highly restricted. We identify and characterize two small transcripts that represent the bulk of the virus-specific RNA transcribed from over 120 kb of the KSHV genome in infected cells. One transcript is predicted to encode a small membrane protein; the other is an unusual polyadenylylated RNA that accumulates in the nucleus to high copy number. This pattern of viral gene expression suggests that most infected cells in KS are latently infected, with lytic viral replication likely restricted to a much smaller subpopulation of cells. These findings have implications for the therapeutic utility of currently available antiviral drugs targeted against the lytic replication cycle.

John Nicholas - One of the best experts on this subject based on the ideXlab platform.

  • Human Herpesvirus 8 interleukin 6 interacts with calnexin cycle components and promotes protein folding
    Journal of Virology, 2017
    Co-Authors: Daming Chen, Qiwang Xiang, John Nicholas
    Abstract:

    ABSTRACT Viral interleukin-6 (vIL-6) encoded by Human Herpesvirus 8 (HHV-8) is believed to contribute via mitogenic, survival, and angiogenic activities to HHV-8-associated Kaposi9s sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman9s disease through autocrine or paracrine mechanisms during latency or productive replication. There is direct evidence that vIL-6 promotes latently infected PEL cell viability and proliferation and also viral productive replication in PEL and endothelial cells. These activities are mediated largely through endoplasmic reticulum (ER)-localized vIL-6, which can induce signal transduction via the gp130 signaling receptor, activating mitogen-activated protein kinase and signal transducer and activator of transcription signaling, and interactions of vIL-6 with the ER membrane protein vitamin K epoxide reductase complex subunit 1 variant 2 (VKORC1v2). The latter functional axis involves suppression of proapoptotic lysosomal protein cathepsin D by promotion of the ER-associated degradation of ER-transiting, preproteolytically processed procathepsin D. Other interactions of VKORC1v2 and activities of vIL-6 via the receptor have not been reported. We show here that both vIL-6 and VKORC1v2 interact with calnexin cycle proteins UDP-glucose:glycoprotein glucosyltransferase 1 (UGGT1), which catalyzes monoglucosylation of N-glycans, and oppositely acting glucosidase II (GlucII), and that vIL-6 can promote protein folding. This activity was found to require VKORC1v2 and UGGT1, to involve vIL-6 associations with VKORC1v2, UGGT1, and GlucII, and to operate in the context of productively infected cells. These findings document new VKORC1v2-associated interactions and activities of vIL-6, revealing novel mechanisms of vIL-6 function within the ER compartment. IMPORTANCE HHV-8 vIL-6 prosurvival (latent) and proreplication functions are mediated from the ER compartment through both gp130 receptor-mediated signal transduction and interaction of vIL-6 with the ER membrane protein VKORC1v2. This report identifies interactions of vIL-6 and VKORC1v2 with calnexin cycle enzymes GlucII and UGGT1, which are involved in glycan processing and nascent protein folding. The presented data show that vIL-6 and VKORC1v2 can cocomplex with GlucII and UGGT1, that vIL-6 promotes protein folding, and that VKORC1v2, UGGT1, and vIL-6 interactions with GlucII and UGGT1 are important for the profolding activity of vIL-6, which can be detected in the context of infected cells. This newly identified ER activity of vIL-6 involving VKORC1v2 may promote viral latency (in PEL cells) and productive replication by limiting the damaging effects of unfolded protein response signaling in addition to enhancing viral protein folding. This is the first report of such a function for a cytokine.

  • role of Human Herpesvirus 8 interleukin 6 activated gp130 signal transducer in primary effusion lymphoma cell growth and viability
    Journal of Virology, 2013
    Co-Authors: Emily Cousins, John Nicholas
    Abstract:

    Human Herpesvirus 8 (HHV-8) infection is associated with Kaposi's sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman's disease. HHV-8-encoded viral interleukin-6 (vIL-6) is believed to contribute to pathogenesis via proproliferative, antiapoptotic, and proangiogenic activities. In PEL cells, vIL-6 is produced in functional amounts during viral latency and promotes the growth of these cells, mediating its activity from the endoplasmic reticulum (ER), where it is predominantly localized. This vIL-6 activity is dependent, in part, on its interaction with a splice variant of vitamin K epoxide reductase complex subunit 1 (VKORC1), termed VKORC1 variant 2 (VKORC1v2). Here we report that the IL-6 signal transducer, gp130, which can support vIL-6 signaling from the ER, is also required for optimal PEL cell growth and viability. Levels of activated extracellular regulated kinases (ERKs) 1 and 2 and signal transducer and activator of transcription 1 (STAT1) and STAT3, phosphorylated following gp130 stimulation, were reduced in gp130-depleted BCBL-1 and BC-1 cells. Diminished STAT activation was also detected in JSC-1 and BC-3 cells. Effects of gp130 depletion on growth could be mimicked by short hairpin RNA targeting of ERKs 1 and 2 or by depletion of STAT3. Finally, inhibition of vIL-6–gp130 association specifically within the ER compartment suppressed cell proliferation and viability, mirroring the effects of gp130 depletion. Combined, these data demonstrate that gp130, in addition to VKORC1v2, is essential for normal PEL cell growth and survival and that ER-localized vIL-6–gp130 interactions are critical for these activities. Targeting of intracellular vIL-6–gp130 interactions could potentially provide a means of PEL therapy.

  • kaposi s sarcoma associated Human Herpesvirus 8 encodes homologues of macrophage inflammatory protein 1 and interleukin 6
    Nature Medicine, 1997
    Co-Authors: John Nicholas, Vivian R Ruvolo, William H Burns, Gordon R Sandford, Dolores M Ciufo, Sara B Hendrickson, Gary S Hayward, Marvin S Reitz
    Abstract:

    Human Herpesvirus-8 (HHV-8) has been detected in Kaposi's sarcoma (KS) lesions of all types (AIDS-related, classical and endemic), in body-cavity-based B-cell lymphomas (BCBLs) and in le-sions of multicentric Castleman's disease (MCD). We have identified a major gamma-Herpesvirus-divergent locus (DL-B) in HHV-8 DNA encoding several HHV-8 unique open reading frames (ORFs), including a homologue of interleukin-6 (IL-6) and two homologues of macrophage inflammatory protein MIP-1. We show that the HHV-8-encoded IL-6 homologue (vlL-6) shares functional properties with endogenous IL-6 proteins and that both vlL-6 and vMIP-1 transcripts are present at high levels following butyrate induction of an HHV-8+ BCBL cell line. Low amounts of constitutive vlL-6, but not vMIP-1, mRNA were also detected. The presence of a functional IL-6 homologue encoded by HHV-8 may provide a mechanistic model for the hypothesized role of HHV-8 in KS, MCD and BCBL that involves the mitogenic effects of vlL-6 on surrounding cells. MIP-1 proteins may enhance these effects through the chemotactic recruitment of endogenous cy-tokine-producing cells into affected tissues and could potentially influence HIV disease progression in coinfected individuals through interactions with the HIV co-receptor CCR-5.

  • a bcl 2 homolog encoded by kaposi sarcoma associated virus Human Herpesvirus 8 inhibits apoptosis but does not heterodimerize with bax or bak
    Proceedings of the National Academy of Sciences of the United States of America, 1997
    Co-Authors: Emily H Cheng, John Nicholas, Gary S Hayward, Marvin S Reitz, David S Bellows, Hong Guano Guo, Marie J Hardwick
    Abstract:

    The Bcl-2 protein family is characterized by the ability to modulate cell death, and members of this family share two highly conserved domains called Bcl-2 homology 1 (BH1) and 2 (BH2) which have been shown to be critical for the death-repressor activity of Bcl-2 and Bcl-xL. Through sequence analysis we identified a novel viral Bcl-2 homolog, designated KSbcl-2, from Human Herpesvirus 8 (HHV8) or Kaposi sarcoma-associated Herpesvirus. The overall amino acid sequence identity between KSbcl-2 and other Bcl-2 homologs is low (15–20%) but concentrated within the BH1 and BH2 regions. Overexpression of KSbcl-2 blocked apoptosis as efficiently as Bcl-2, Bcl-xL, or another viral Bcl-2 homolog encoded by Epstein–Barr virus, BHRF1. Interestingly, KSbcl-2 neither homodimerizes nor heterodimerizes with other Bcl-2 family members, suggesting that KSbcl-2 may have evolved to escape any negative regulatory effects of the cellular Bax and Bak proteins. Furthermore, the Herpesvirus Bcl-2 homologs including KSbcl-2, BHRF1, and ORF16 of Herpesvirus saimiri contain poorly conserved Bcl-2 homology 3 (BH3) domains compared with other mammalian Bcl-2 homologs, implying that BH3 may not be essential for anti-apoptotic function. This is consistent with our observation that amino acid substitutions within the BH3 domain of Bcl-xL had no effect on its death-suppressor activity.

E Boulanger - One of the best experts on this subject based on the ideXlab platform.

  • Human Herpesvirus 8 hhv 8 associated primary effusion lymphoma in two renal transplant recipients receiving rapamycin
    American Journal of Transplantation, 2008
    Co-Authors: E Boulanger, Philippe V Afonso, Y Yahiaoui, H Adlebiassette, J Gabarre, Félix Agbalika
    Abstract:

    The Akt/mammalian target of rapamycin (mTOR) signaling cascade has been demonstrated to be constitutively activated in several malignancies, including Kaposi sarcoma (KS) and Human Herpesvirus-8 (HHV-8)-associated primary effusion lymphoma (PEL). In organ transplant recipients, therapeutic change from cyclosporin to the mTOR inhibitor rapamycin can lead to regression of KS lesions. Recent experiments using PEL cell lines and murine xenograft PEL models suggested that rapamycin could inhibit the growth of PEL cells. In the present report, we describe the cases of two HIV-1-negative males of African origin who underwent renal transplantation and developed PEL while receiving rapamycin as immunosuppressive treatment. Both patients were retrospectively found to be HHV-8 seropositive before renal transplantation. The present case report suggests that rapamycin may not protect HHV-8-infected renal transplant recipients from occurrence of PEL or progression of pre-existing PEL.

  • prognostic factors and outcome of Human Herpesvirus 8 associated primary effusion lymphoma in patients with aids
    Journal of Clinical Oncology, 2005
    Co-Authors: E Boulanger, J Gabarre, Laurence Gerard, Jeanmichel Molina, C Rapp, Jeanfrancois Abino, J Cadranel, Sylvie Chevret, Eric Oksenhendler
    Abstract:

    Purpose Primary effusion lymphoma (PEL) is a rare high-grade B-cell non-Hodgkin's lymphoma associated with Kaposi sarcoma–associated Herpesvirus/Human Herpesvirus 8 (KSHV/HHV-8) infection, and is mostly observed in the course of HIV infection. The prognosis is poor, with reported median survival time shorter than 6 months. To date, no prognostic factor has been identified in this subset of lymphoma. Patients and Methods We describe here a large series of HIV-infected patients with PEL, including 28 cases diagnosed in six centers during an 11-year time period. Prognosis analysis was performed using a Cox proportional hazard regression model. Statistically significant covariates were further analyzed in a forward, stepwise multivariate model. Results After a median follow-up of 3.8 years (range, 10 months to 10.8 years), nine patients (32%) were still alive, and eight of them remained progression free. The median survival was 6.2 months, and the 1-year overall survival rate was 39.3%. Fourteen patients (50%...

  • Human Herpesvirus 8 hhv 8 associated peritoneal primary effusion lymphoma pel in two hiv negative elderly patients
    American Journal of Hematology, 2004
    Co-Authors: E Boulanger, Veronique Meignin, Olivier Hermine, Jeanpaul Fermand, Isabelle Radfordweiss, N Brousse, Antoine Gessain
    Abstract:

    Human Herpesvirus 8 (KSHV/HHV-8) is associated with all forms of Kaposi sarcoma (KS), with a rare high-grade B-cell non-Hodgkin lymphoma characterized by serous effusions in body cavities called primary effusion lymphoma (PEL) and with some forms of multicentric Castleman disease (MCD). Although mostly observed during AIDS, such disorders have also been described with a lower incidence in Human immunodeficiency virus-negative patients. We describe here the features of two novel cases of AIDS-unrelated PEL. Two patients, a 78-year-old man (case 1) and a 86-year-old woman (case 2), both of French origin, presented exudative ascitic effusion containing numerous KSHV/HHV-8(+) EBV(-) large lymphomatous cells of B-cell clonal origin, characterized by a CD45(+) CD30(+) CD19(-) CD20(-) immunophenotype. The PEL tumor cells harbored a homogenous and isolated trisomy 12 in case 1 and an aberrant expression of the T-cell lineage antigen CD7 in case 2. Both patients were lymphopenic at the time of PEL diagnosis and rapidly died with progressive lymphoma. Moreover, patient 2 had a previous history of classic KS and MCD clinically improved after treatment with all-trans-retinoid acid and a concomitant metastatic breast adenocarcinoma. Compared to AIDS-related PEL, these two cases displayed distinct features in particular the advanced age of patients, as observed for Mediterranean KS, and the absence of EBV coinfection.

  • high levels of Human Herpesvirus 8 viral load Human interleukin 6 interleukin 10 and c reactive protein correlate with exacerbation of multicentric castleman disease in hiv infected patients
    Blood, 2000
    Co-Authors: Eric Oksenhendler, E Boulanger, Guislaine Carcelain, Yoshiyasu Aoki, Anne Maillard, Jeanpierre Clauvel, Félix Agbalika
    Abstract:

    Multicentric Castleman disease (MCD) is a distinct type of lymphoproliferative disorder associated with inflammatory symptoms and interleukin-6 (IL-6) dysregulation. In the context of Human immunodeficiency virus (HIV) infection, MCD is associated with Human Herpesvirus 8 (HHV8) infection. In a prospective study of 23 HIV-infected patients with MCD, clinical symptoms of MCD were present at 45 visits, whereas patients were in chemotherapy-induced clinical remission at 50 visits. Symptoms were associated with a high level of serum C reactive protein, high HHV8 viral load in peripheral blood mononuclear cells, and high plasma Human IL-6 and IL-10 levels. Strong correlations between plasma IL-6 and plasma IL-10 with the HHV8 viral load suggest that both cytokines may be involved in the pathogenesis of this virus-associated lymphoproliferative disorder.