Human Herpesvirus 8 DNA in the Skin and Blood of Patients with Mediterranean Kaposi’s Sarcoma: Clinical Correlations

Boneschi, Vinicio; Brambilla, Lucia; Berti, Emilio; Ferrucci, Silvia; Corbellino, Mario; Parravicini, Carlo; Fossati, Silvia

doi:10.1159/000051697

Cited by 33 publications

(29 citation statements)

References 34 publications

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“…The presence of KSHVinfected B cells in the peripheral blood (13,138,340) and the ability of TPA-treated PEL cells to efficiently transmit KSHV to primary endothelial cells in culture (441) suggest that circulating B cells may help disseminate the virus to extralymphoid targets such as lymphatic endothelium, where the virus then establishes a secondary latent infection (483). Supporting this notion, active KSHV replication and increased viral load in the peripheral blood predicts the pathogenic outcome of the infection (410) and is strongly correlated with (i) increased risk of progression to KS (13,530) and (ii) increased severity of the pathogenic stage of KS (47,68). Furthermore, treatment of high-risk patients with the antiviral ganciclovir blocks lytic KSHV replication and reduces KS risk (324).…”

Section: Lytic Genes and Kshv Pathogenesismentioning

confidence: 92%

“…The lymphotropism of KSHV was demonstrated by PCR amplification of viral DNA from the CD19 ϩ B-cell subset of PBMCs from AIDS-associated KS patients (13,340), as well as in PEL specimens (80,161,245,267,366), suggesting a mechanism by which the virus may disseminate in the host. Active KSHV replication and increased detection by PCR of viral DNA in the peripheral blood are strongly correlated with (i) increased risk of progression to KS (13,530) and (ii) increased severity of pathogenic stage of KS (47,68); the peripheral viral load predicts the pathogenic outcome of the infection (410). KSHV has also been found in the neutrophil subset of PBMCs (285) (481).…”

Section: Histopathogenesis Of Ks and Its Relationship To Kshv Infectionmentioning

confidence: 99%

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Molecular Genetics of Kaposi's Sarcoma-Associated Herpesvirus (Human Herpesvirus 8) Epidemiology and Pathogenesis

Dourmishev

Palmeri

et al. 2003

Microbiol Mol Biol Rev

305

367

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Kaposi's sarcoma had been recognized as unique human cancer for a century before it manifested as an AIDS-defining illness with a suspected infectious etiology. The discovery of Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus-8, in 1994 by using representational difference analysis, a subtractive method previously employed for cloning differences in human genomic DNA, was a fitting harbinger for the powerful bioinformatic approaches since employed to understand its pathogenesis in KS. Indeed, the discovery of KSHV was rapidly followed by publication of its complete sequence, which revealed that the virus had coopted a wide armamentarium of human genes; in the short time since then, the functions of many of these viral gene variants in cell growth control, signaling apoptosis, angiogenesis, and immunomodulation have been characterized. This critical literature review explores the pathogenic potential of these genes within the framework of current knowledge of the basic herpesvirology of KSHV, including the relationships between viral genotypic variation and the four clinicoepidemiologic forms of Kaposi's sarcoma, current viral detection methods and their utility, primary infection by KSHV, tissue culture and animal models of latent- and lytic-cycle gene expression and pathogenesis, and viral reactivation from latency. Recent advances in models of de novo endothelial infection, microarray analyses of the host response to infection, receptor identification, and cloning of full-length, infectious KSHV genomic DNA promise to reveal key molecular mechanisms of the candidate pathogeneic genes when expressed in the context of viral infection

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Section: Lytic Genes and Kshv Pathogenesismentioning

confidence: 92%

Section: Histopathogenesis Of Ks and Its Relationship To Kshv Infectionmentioning

confidence: 99%

Molecular Genetics of Kaposi's Sarcoma-Associated Herpesvirus (Human Herpesvirus 8) Epidemiology and Pathogenesis

Dourmishev

Palmeri

et al. 2003

Microbiol Mol Biol Rev

305

367

View full text Add to dashboard Cite

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“…Clinicoepidemiologic studies indicate that KSHV lytic activation is a critical contributor to the pathogenesis of KS, PEL, and MCD (7)(8)(9)(10)(11)(12)(13). Lytic activation also correlates with disease progression and prognosis (14)(15)(16).…”

mentioning

confidence: 99%

STAT3 Regulates Lytic Activation of Kaposi's Sarcoma-Associated Herpesvirus

King

Barbachano-Guerrero

et al. 2015

J Virol

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Lytic activation of Kaposi's sarcoma-associated herpesvirus (KSHV) from latency is a critical contributor to pathogenesis and progression of KSHV-mediated disease. Development of targeted treatment strategies and improvement of lytic-phase-directed oncolytic therapies, therefore, hinge on gaining a better understanding of latency-to-lytic-phase transition. A key observation in that regard, also common to other herpesviruses, is the partial permissiveness of latently infected cells to lytic-cycle-inducing agents. Here, we address the molecular basis of why only some KSHV-infected cells respond to lytic stimuli. Since cellular signal transducer and activator of transcription 3 (STAT3) is constitutively active in KSHV-associated cancers, KSHV activates STAT3, and STAT3 has been found to regulate lytic activation of Epstein-Barr virus (EBV)-infected cells, we asked if STAT3 contributes similarly to the life cycle of KSHV. We found that high levels of STAT3 correlate with the refractory state at the single-cell level under conditions of both spontaneous and induced lytic activation; importantly, STAT3 also regulates lytic susceptibility. Further, knockdown of STAT3 suppresses the cellular transcriptional corepressor Krüppel-associated box domain-associated protein 1 (KAP1; also known as TRIM28), and suppression of KAP1 activates lytic genes, including the viral lytic switch RTA, thereby linking STAT3 via KAP1 to regulation of the balance between lytic and latent cells. These findings, taken together with those from EBV-infected and, more recently, herpes simplex virus 1 (HSV-1)-infected cells, cement the contribution of host STAT3 to persistence of herpesviruses and simultaneously reveal an important lead to devise strategies to improve lytic-phasedirected therapies for herpesviruses. IMPORTANCELytic activation of the cancer-causing Kaposi's sarcoma-associated herpesvirus (KSHV) is vital to its life cycle and causation of disease. Like other herpesviruses, however, a substantial fraction of latently infected cells are resistant to lytic-phase-inducing stimuli. Investigating the molecular basis for this refractory state is essential for understanding how the virus persists and how it causes disease and to guide efforts to improve treatment of KSHV-mediated diseases. We found that, like two other herpesviruses, EBV and HSV-1, KSHV exploits the cellular transcription factor STAT3 to regulate the susceptibility of latently infected cells to lytic triggers. These findings highlight a common STAT3-centered strategy used by herpesviruses to maintain persistence in their hosts while also revealing a key molecule to pursue while devising methods to improve herpesvirus lytic-phase-directed therapies.T he oncogenic human gammaherpesvirus human herpesvirus 8 (HHV-8), widely known as Kaposi's sarcoma-associated herpesvirus (KSHV), is the etiologic agent of three human malignancies: Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD) (1, 2). Like other herpesviruses, KSHV exhi...

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“…An Mta mutant with a lesion in a putative A/T hook domain is altered in DNA binding and debilitated in transactivation. We propose that one molecular mechanism of Mtamediated transactivation is a direct effect on transcription by direct and indirect promoter association.Reactivation of Kaposi's-sarcoma associated herpesvirus (KSHV) (also known as human herpesvirus 8) from latency is a crucial step in Kaposi's sarcoma development (7,11,27,43,65,76,81,87,104). It is likely that reactivation of KSHV contributes to Kaposi's sarcoma development by facilitating dissemination of the virus from its B-cell reservoir and permitting the expression of lytic cycle genes with direct roles in cancer progression.…”

mentioning

confidence: 99%

Promoter- and Cell-Specific Transcriptional Transactivation by the Kaposi's Sarcoma-Associated Herpesvirus ORF57/Mta Protein

Palmeri

Spadavecchia

Carroll

et al. 2007

J Virol

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The Kaposi's sarcoma-associated herpesvirus (KSHV) Mta protein, encoded by open reading frame 57, is a transactivator of gene expression that is essential for productive viral replication. Previous studies have suggested both transcriptional and posttranscriptional roles for Mta, but little is known regarding Mta's transcriptional function. In this study, we demonstrate that Mta cooperates with the KSHV lytic switch protein, Rta, to reactivate KSHV from latency, but Mta has little effect on reactivation when expressed alone. We demonstrate that the Mta and Rta proteins are expressed with similar but distinct kinetics during KSHV reactivation. In single-cell analyses, Mta expression coincides tightly with progression to full viral reactivation. We demonstrate with promoter reporter assays that while Rta activates transcription in all cell lines tested, Mta's ability to transactivate promoters, either alone or synergistically with Rta, is cell and promoter specific. In particular, Mta robustly transactivates the nut-1/PAN promoter independently of Rta in 293 and Akata-31 cells. Using nuclear run-on assays, we demonstrate that Mta stimulates transcriptional initiation in 293 cells. Rta and Mta physically interact in infected cell extracts, and this interaction requires the intact leucine repeat and central region of Rta in vitro. We demonstrate that Mta also binds to the nut-1/PAN promoter DNA in vitro and in infected cells. An Mta mutant with a lesion in a putative A/T hook domain is altered in DNA binding and debilitated in transactivation. We propose that one molecular mechanism of Mtamediated transactivation is a direct effect on transcription by direct and indirect promoter association.Reactivation of Kaposi's-sarcoma associated herpesvirus (KSHV) (also known as human herpesvirus 8) from latency is a crucial step in Kaposi's sarcoma development (7,11,27,43,65,76,81,87,104). It is likely that reactivation of KSHV contributes to Kaposi's sarcoma development by facilitating dissemination of the virus from its B-cell reservoir and permitting the expression of lytic cycle genes with direct roles in cancer progression. Most of the candidate pathogenic genes of KSHV (encoding proteins with growth-deregulatory and immunomodulatory functions) are expressed in the delayed early class of the lytic gene expression program (8,14,17,25,26,28,30,41,46,49,75,86,94). Therefore, a complete understanding of KSHV pathogenesis demands elucidation of the mechanisms that regulate viral reactivation and progression through the lytic cycle.The members of the Herpesviridae all encode multiple lytic cycle transactivators that cooperate to promote viral replication. For herpes simplex virus type 1 (HSV-1) infection, the two essential transactivating proteins are called infected cell protein 4 (ICP4) and ICP27. ICP4 is a transcriptional transactivator necessary for activation of early and late genes (80, 103). ICP27 is a posttranscriptional and transcriptional activator that stimulates the switch from early-to late-gene expression (66,67,...

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Human Herpesvirus 8 DNA in the Skin and Blood of Patients with Mediterranean Kaposi’s Sarcoma: Clinical Correlations

Cited by 33 publications

References 34 publications

Molecular Genetics of Kaposi's Sarcoma-Associated Herpesvirus (Human Herpesvirus 8) Epidemiology and Pathogenesis

Molecular Genetics of Kaposi's Sarcoma-Associated Herpesvirus (Human Herpesvirus 8) Epidemiology and Pathogenesis

STAT3 Regulates Lytic Activation of Kaposi's Sarcoma-Associated Herpesvirus

Promoter- and Cell-Specific Transcriptional Transactivation by the Kaposi's Sarcoma-Associated Herpesvirus ORF57/Mta Protein

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