Viral Oncology Program, Developmental Center for AIDS Research, and Department of Microbiology & Immunology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, 1,550 NW 10th Avenue, 109 Papanicolau Building, Miami, Florida 33136, USA.
Kaposi's sarcoma (KS) is the most common cancer in HIV-infected untreated individuals. Kaposi's sarcoma-associated herpesvirus (KSHV; also known as human herpesvirus 8 (HHV8)) is the infectious cause of this neoplasm. In this Review we describe the epidemiology of KS and KSHV, and the insights into the remarkable mechanisms through which KSHV can induce KS that have been gained in the past 16 years. KSHV latent transcripts, such as latency-associated nuclear antigen (LANA), viral cyclin, viral FLIP and viral-encoded microRNAs, drive cell proliferation and prevent apoptosis, whereas KSHV lytic proteins, such as viral G protein-coupled receptor, K1 and virally encoded cytokines (viral interleukin-6 and viral chemokines) further contribute to the unique angioproliferative and inflammatory KS lesions through a mechanism called paracrine neoplasia.
"Like other herpesvirus, KSHV has latent and lytic replication life cycle, which is tightly regulated by its own genes. One of which, the latency-associated nuclear antigen (LANA) encoded by ORF73, is the dominant molecule essential for establishment and maintenance of KSHV latent infection and pathogenesis   . LANA is a multifunctional protein involved in regulation of cellular and viral gene transcription, DNA replication, and tethering the viral episomal DNA to the host chromosomes during mitosis . "
[Show abstract][Hide abstract] ABSTRACT: The Kaposi's sarcoma-associated herpesvirus (KSHV)-encoded latent nuclear antigen LANA plays an essential role in viral episome maintenance. LANA also contributes to DNA replication and tumorigenesis during latency. Recent studies suggested that LANA was involved in regulation of SUMOylation which results in chromatin silencing. To examine the pleiotropic effects of LANA protein on host cell gene expression, we utilized MS analysis to identify cellular proteins associated with the SUMO-Interacting Motif of LANA (LANA(SIM) ). In addition to the 6 bands identified as substantially associated with LANA(SIM) , 151 proteins were positively identified by MS/MS analysis. Compared with previous proteomic analysis of the N- and C- truncated mutants of LANA (LANA(NC) ), our results revealed that a complex of specific proteins with relatively high SUMOylation and SIM motifs are associated with LANA(SIM) . Intriguingly, consistent with our previous report that identified KAP1 as a key component, the in-vitro SUMO-2 modified isoform has a substantially higher affinity with LANA(SIM) than the SUMO-1 modified isoform. Moreover, via cluster and pathway analysis, we proposed a hypothetical model for the LANA(SIM) regulatory circuit involving aberrant SUMOylation of cell cycle (particular mitotic), DNA unwinding and replication, and pre-mRNA/mRNA processing-related proteins. This study provides a SUMOylated and non-SUMOylated proteome profile of LANA(SIM) -associated complex, and facilitates our understanding that viral-mediated gene regulation through SUMOylation is important for KSHV persistence and pathogenesis. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: It has now been over twenty years since a novel herpesviral genome was identified in Kaposi's sarcoma biopsies. Since then, the cumulative research effort by molecular biologists, virologists, clinicians, and epidemiologists alike has led to the extensive characterization of this tumor virus, Kaposi's sarcoma-associated herpesvirus (KSHV; also known as human herpesvirus 8 (HHV-8)), and its associated diseases. Here we review the current knowledge of KSHV biology and pathogenesis, with a particular emphasis on new and exciting advances in the field of epigenetics. We also discuss the development and practicality of various cell culture and animal model systems to study KSHV replication and pathogenesis.
", also known as Kaposi's sarcoma associated herpesvirus (KSHV), belongs to the Herpesviridae family, subfamily Gamma-herpesvirinae, genus Rhadinovirus . HHV8 is etiologically associated to all the clinical forms of Kaposi's sarcoma (KS), and is correlated to other disorders developing in immunosuppressed subjects [Schulz, 2000; Mesri et al., 2010], where it results highly tumorigenic [Wen and Damania , 2010]. Its prevalence varies geographically, and some studies have reported an increasing presence of HHV8 infection in the general population and in particular in some countries, such as Southern Italy, Sicily, Sardinia, and the Po river valley. "
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