Kaposi sarcoma-associated herpesvirus (KSHV): Molecular biology and oncogenesis

Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
Cancer letters (Impact Factor: 5.62). 09/2009; 289(2):140-50. DOI: 10.1016/j.canlet.2009.07.004
Source: PubMed


Kaposi sarcoma-associated herpesvirus (KSHV) is a double-stranded DNA herpesvirus belonging to the gamma-herpesvirinae subfamily. KSHV has been associated with the development of three neoplastic diseases: Kaposi sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman disease (MCD). In this review, we discuss the three KSHV-associated malignancies, KSHV genome, latent and lytic aspects of the viral lifecycle, putative viral oncogenes, as well as therapeutic regimens used for the treatment of KS, PEL, and MCD.

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    • "Indirect mechanisms are mainly triggered by an inflammatory milieu with production of mutagenic molecules or immunosuppression with loss of the cancer immune surveillance mechanisms [8]. The former mode of transformation implies that the infectious agent acts from within the cell and thus, after the cancer clonal expansion, it is carried in all tumor cells, as it has been documented for tumor herpes viruses [9] [10]; while indirectly acting infectious carcinogenic agents do not necessarily infect the cell forming the tumor. The Delayed infection hypothesis by Greaves proposes that exposure to infectious agents very early in life protects from ALL as it modulates maturation of the immune system. "
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    ABSTRACT: Acute lymphoblastic leukemia (ALL) is the most common cancer in childhood worldwide and Mexico has reported one of the highest incidence rates. An infectious etiology has been suggested and supported by epidemiological evidences; however, the identity of the involved agent(s) is not known. We considered that early transmitted lymphotropic herpes viruses were good candidates, since transforming mechanisms have been described for them and some are already associated with human cancers. In this study we interrogated the direct role of EBV, HCMV, HHV6, and HHV7 human herpes viruses in childhood ALL. Viral genomes were screened in 70 bone marrow samples from ALL patients through standard and a more sensitive nested PCR. Positive samples were detected only by nested PCR indicating a low level of infection. Our result argues that viral genomes were not present in all leukemic cells, and, hence, infection most likely was not part of the initial genetic lesions leading to ALL. The high statistical power of the study suggested that these agents are not involved in the genesis of ALL in Mexican children. Additional analysis showed that detected infections or coinfections were not associated with prognosis.
    BioMed Research International 09/2014; 2014:548097. DOI:10.1155/2014/548097 · 2.71 Impact Factor
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    • "KSHV, also known as human herpesvirus type 8, is a γ-herpesvirus associated with Kaposi’s sarcoma (KS), primary effusion lymphomas (PEL) and multicentric Castlemen’s disease [31]. It is one of the seven recognized human cancer viruses [32]. "
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    ABSTRACT: SUMOylation, as part of the epigenetic regulation of transcription, has been intensively studied in lower eukaryotes that contain only a single SUMO protein; however, the functions of SUMOylation during mammalian epigenetic transcriptional regulation are largely uncharacterized. Mammals express three major SUMO paralogues: SUMO-1, SUMO-2, and SUMO-3 (normally referred to as SUMO-1 and SUMO-2/3). Herpesviruses, including Kaposi's sarcoma associated herpesvirus (KSHV), seem to have evolved mechanisms that directly or indirectly modulate the SUMO machinery in order to evade host immune surveillance, thus advancing their survival. Interestingly, KSHV encodes a SUMO E3 ligase, K-bZIP, with specificity toward SUMO-2/3 and is an excellent model for investigating the global functional differences between SUMO paralogues. We investigated the effect of experimental herpesvirus reactivation in a KSHV infected B lymphoma cell line on genomic SUMO-1 and SUMO-2/3 binding profiles together with the potential role of chromatin SUMOylation in transcription regulation. This was carried out via high-throughput sequencing analysis. Interestingly, chromatin immunoprecipitation sequencing (ChIP-seq) experiments showed that KSHV reactivation is accompanied by a significant increase in SUMO-2/3 modification around promoter regions, but SUMO-1 enrichment was absent. Expression profiling revealed that the SUMO-2/3 targeted genes are primarily highly transcribed genes that show no expression changes during viral reactivation. Gene ontology analysis further showed that these genes are involved in cellular immune responses and cytokine signaling. High-throughput annotation of SUMO occupancy of transcription factor binding sites (TFBS) pinpointed the presence of three master regulators of immune responses, IRF-1, IRF-2, and IRF-7, as potential SUMO-2/3 targeted transcriptional factors after KSHV reactivation. Our study is the first to identify differential genome-wide SUMO modifications between SUMO paralogues during herpesvirus reactivation. Our findings indicate that SUMO-2/3 modification near protein-coding gene promoters occurs in order to maintain host immune-related gene unaltered during viral reactivation.
    BMC Genomics 11/2013; 14(1):824. DOI:10.1186/1471-2164-14-824 · 3.99 Impact Factor
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    • "HHV8 was found in various tumors and lymphoproliferative diseases [8], and the incidence of HHV8-related tumors, even in populations with high HHV8 seroprevalence suggests the need for cofactors [20]. A number of HHV8 genes are known to have effects in cell proliferation and transformation [8], and accumulating data point to the importance of lytic replication for the development of HHV8-associated neoplastic pathologies, as indicated by recent clinical studies [21]. "
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    ABSTRACT: The etiology of primary cutaneous anaplastic large-cell CD30+ lymphoma is largely unknown, and although an infectious involvement has been suspected, the implication of infectious agents in its pathogenesis is still unclear. We report the case of a HIV-negative patient referred to our hospital with a rapidly enlarging skin tumor on her upper eyelid. Surgical excision was performed and histological analysis evidenced a primary cutaneous anaplastic large-cell lymphoma. Due to the ocular localization and to the prominent angiogenic component of the lesion, molecular analyses for the detection of Chlamydophila pneumoniae and HHV8 were performed, revealing the presence of a infection by both pathogens in surgical biopsy and in peripheral blood mononuclear cells. These findings suggest for the first time a possible association of C. pneumoniae and/or HHV8 infection, or both together, with primary cutaneous anaplastic large-cell lymphoma in non-immunocompromised and HIV-negative subjects. This potential pathogenic association, if confirmed, could provide potential indications for future therapy.
    Infectious Agents and Cancer 10/2013; 8(1):41. DOI:10.1186/1750-9378-8-41 · 2.36 Impact Factor
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