Kaposi's sarcoma associated herpesvirus (KSHV) or human herpesvirus 8 (HHV8) is a major etiological agent for multiple severe malignancies in immune-compromised patients. KSHV establishes lifetime persistence in the infected individuals and displays two distinct life cycles, generally a prolonged passive latent, and a short productive or lytic cycle. During latent phase, the viral episome is tethered to the host chromosome and replicates once during every cell division. Latency-associated nuclear antigen (LANA) is a predominant multifunctional nuclear protein expressed during latency, which plays a central role in episome tethering, replication and perpetual segregation of the episomes during cell division. LANA binds cooperatively to LANA binding sites (LBS) within the terminal repeat (TR) region of the viral episome as well as to the cellular nucleosomal proteins to tether viral episome to the host chromosome. LANA has been shown to modulate multiple cellular signaling pathways and recruits various cellular proteins such as chromatin modifying enzymes, replication factors, transcription factors, and cellular mitotic framework to maintain a successful latent infection. Although, many other regions within the KSHV genome can initiate replication, KSHV TR is important for latent DNA replication and possible segregation of the replicated episomes. Binding of LANA to LBS favors the recruitment of various replication factors to initiate LANA dependent DNA replication. In this review, we discuss the molecular mechanisms relevant to KSHV genome replication, segregation, and maintenance of latency.

Human herpesvirus 8 (HHV-8), also known as Kaposi’s sarcoma-associated herpesvirus (KSHV), is a malignant human oncovirus belonging to the gamma herpesvirus family. HHV-8 is closely linked to the pathogenesis of Kaposi’s sarcoma (KS) and two other B-cell lymphoproliferative diseases: primary effusion lymphoma (PEL) and a plasmablastic variant of multicentric Castleman’s disease (MCD). KS is an invasive tumor of endothelial cells most commonly found in untreated HIV-AIDS or immuno-compromised individuals. KS tumors are highly vascularized and have abnormal, excessive neo-angiogenesis, inflammation, and proliferation of infected endothelial cells. KSHV directly induces angiogenesis in an autocrine and paracrine fashion through a complex interplay of various viral and cellular pro-angiogenic and inflammatory factors. KS is believed to originate due to a combination of KSHV’s efficient strategies for evading host immune systems and several pro-angiogenic and pro-inflammatory stimuli. In addition, KSHV infection of endothelial cells produces a wide array of viral oncoproteins with transforming capabilities that regulate multiple host-signaling pathways involved in the activation of angiogenesis. It is likely that the cellular-signaling pathways of angiogenesis and lymph-angiogenesis modulate the rate of tumorigenesis induction by KSHV. This review summarizes the current knowledge on regulating KSHV-mediated angiogenesis by integrating the findings reported thus far on the roles of host and viral genes in oncogenesis, recent developments in cell-culture/animal-model systems, and various anti-angiogenic therapies for treating KSHV-related lymphoproliferative disorders.

Kaposi’s sarcoma-associated herpesvirus or Human herpesvirus-8 (KSHV/HHV-8), an oncogenic human herpesvirus and the leading cause of cancer in HIV-infected individuals, is a major public health concern with recurring reports of epidemics on a global level. The early detection of KSHV virus and subsequent activation of the antiviral immune response by the host’s immune system are crucial to prevent KSHV infection. The host’s immune system is an evolutionary conserved system that provides the most important line of defense against invading microbial pathogens, including viruses. Viruses are initially detected by the cells of the host innate immune system, which evoke concerted antiviral responses via the secretion of interferons (IFNs) and inflammatory cytokines/chemokines for elimination of the invaders. Type I IFN and cytokine gene expression are regulated by multiple intracellular signaling pathways that are activated by germline-encoded host sensors, i.e., pattern recognition receptors (PRRs) that recognize a conserved set of ligands, known as ‘pathogen-associated molecular patterns (PAMPs)’. On the contrary, persistent and dysregulated signaling of PRRs promotes numerous tumor-causing inflammatory events in various human cancers. Being an integral component of the mammalian innate immune response and due to their constitutive activation in tumor cells, targeting PRRs appears to be an effective strategy for tumor prevention and/or treatment. Cellular PRRs are known to respond to KSHV infection, and KSHV has been shown to be armed with an array of strategies to selectively inhibit cellular PRR-based immune sensing to its benefit. In particular, KSHV has acquired specific immunomodulatory genes to effectively subvert PRR responses during the early stages of primary infection, lytic reactivation and latency, for a successful establishment of a life-long persistent infection. The current review aims to comprehensively summarize the latest advances in our knowledge of role of PRRs in KSHV infections.

HIV-1 replication is a tightly controlled mechanism which demands the interplay of host as well as viral factors. Both gp120 (envelope glycoprotein) and Nef (regulatory protein) have been correlated with the development of AIDS disease in independent studies. In this context, the ability of HIV-1 to utilize immature dentritic cells for transfer of virus is pivotal for early pathogenesis. The presence of C-type lectins on dendritic cells (DCs) like DC-SIGN, are crucial in inducing antiviral immunity to HIV-1. Both gp120 and Nef induce the release of cytokines leading to multiple effects of viral pathogenesis. Our study elucidated for the first time the cross-talk of the signaling mechanism of these two viral proteins in immature monocyte derived dentritic cells (immDCs). Further, gp120 was found to downregulate the IL-6 release by Nef, depending on the interaction with DC-SIGN. A cascade of signaling followed thereafter, including the activation of SOCS-3, to mediate the diminishing effect of gp120. Our results also revealed that the anti-apoptotic signals emanated from Nef was put to halt by gp120 through inhibition of Nef induced STAT3. Thus our results implicate that the signaling generated by gp120 and Nef, undergoes a switch-over mechanism that significantly contributes to the pathogenesis of HIV-1 and widens our view towards the approach on battling the viral infection.

We have implemented the latest technology of a multiregion hybridization assay (MHAbce, version 2) for the molecular characterization of HIV-1 among injecting drug users (IDUs) of Manipur, India. This study provides a more detailed analysis on the basis of probes designed from eight different genomic regions of HIV-1, to achieve a clear picture of HIV-1 genomic diversity in Manipur. Out of 30 samples, 15 were found to be of subtype C, 1 of subtype B, 5 with dual-probe reactivity, 8 with multigenomic recombination pattern and 1 sample showed both dual-probe reactivity and multigenomic variations. In contrast, the heteroduplex mobility assay (HMA) with respect to gag and env genes revealed 21 samples to be of subtype C (gag C/env C), 3 samples of subtype B (gag B/env B) and 6 samples of B/C recombinants (gag C/env B). MHAbce illustrates the occurrence of inter- and intragenomic variants and dual infection in an IDU population from India. It also indicates the possibility of the presence of new circulating recombinant forms of HIV-1 strains, which might have been difficult to trace by HMA alone.