LANA-Mediated Recruitment of Host Polycomb Repressive Complexes onto the KSHV Genome during De Novo Infection

One of the hallmarks of the latent phase of Kaposi’s sarcoma-associated herpesvirus (KSHV) infection is the global repression of lytic viral gene expression. Following de novo KSHV infection, the establishment of latency involves the chromatinization of the incoming viral genomes and recruitment of the host Polycomb repressive complexes (PRC1 and PRC2) to the promoters of lytic genes, which is accompanied by the inhibition of lytic genes. However, the mechanism of how PRCs are recruited to the KSHV episome is still unknown. Utilizing a genetic screen of latent genes in the context of KSHV genome, we identified the latency-associated nuclear antigen (LANA) to be responsible for the genome-wide recruitment of PRCs onto the lytic promoters following infection. We found that LANA initially bound to the KSHV genome right after infection and subsequently recruited PRCs onto the viral lytic promoters, thereby repressing lytic gene expression. Furthermore, both the DNA and chromatin binding activities of LANA were required for the binding of LANA to the KSHV promoters, which was necessary for the recruitment of PRC2 to the lytic promoters during de novo KSHV infection. Consequently, the LANA-knockout KSHV could not recruit PRCs to its viral genome upon de novo infection, resulting in aberrant lytic gene expression and dysregulation of expression of host genes involved in cell cycle and proliferation pathways. In this report, we demonstrate that KSHV LANA recruits host PRCs onto the lytic promoters to suppress lytic gene expression following de novo infection.     

Kaposi's sarcoma-associated herpesvirus latent gene vFLIP inhibits viral lytic replication through NF-kappaB-mediated suppression of the AP-1 pathway: a novel mechanism of virus control of latency

Kaposi's sarcoma-associated herpesvirus (KSHV) latency is central to the evasion of host immune surveillances and induction of KSHV-related malignancies. The mechanism of KSHV latency remains unclear. Here, we show that the KSHV latent gene vFLIP promotes viral latency by inhibiting viral lytic replication. vFLIP suppresses the AP-1 pathway, which is essential for KSHV lytic replication, by activating the NF-kappaB pathway. Thus, by manipulating two convergent cellular pathways, vFLIP regulates both cell survival and KSHV lytic replication to promote viral latency. These results also indicate that the effect of the NF-kappaB pathway on KSHV replication is determined by the status of the AP-1 pathway and hence provide a mechanistic explanation for the contradictory role of the NF-kappaB pathway in KSHV replication. Since the NF-kappaB pathway is commonly activated during infection of gammaherpesviruses, these findings might have general implications for the control of gammaherpesviral latency.     

Murine herpesvirus pathogenesis: a model for the analysis of molecular mechanisms of human gamma herpesvirus infections

Murine herpes virus (MHV), a natural pathogen originally isolated from free-living rodents, constitutes the most amenable animal model for human gamma herpesviruses. Based on DNA sequence homology, this virus was classified as Murid Herpesvirus 4 to subfamily Gammaherpesvirinae. Pilot studies in our laboratory, using mice inoculated by the intranasal route, showed that MHV infects macrophages, B lymphocytes, lung alveolar as well as endothelial cells. From the lungs the virus spreads via the bloodstream to spleen and bone marrow and via the lymphatics to the mediastinal lymph nodes. Similarly to other gamma herpesviruses, MHV established life-long latency maintained in host B lymphocytes and macrophages. An IM-like syndrome (per analogy to EBV) may develop during acute MHV infection, in which the atypical T/CD8+ lymphocytes eliminate viral DNA carrying B cells expressing the M2 latency associated protein. During latency, the MHV LANA (a KSHV LANA homologue) maintains the latent viral genome, assuring its copying and partition to new carrier cells in the course of division of the maternal cell. The nonproductive latency is turned onto virus replication by means of Rta protein. The chronic lymphoproliferative syndrome of unclear pathogenesis, which occurs in a certain part of latent MHV carriers, is related to the expression of gamma herpesvirus common latency-associated genes such as v-cyclin and/or to that of a virus-specific (M11/bcl-2) gene. This review attempts to summarize our knowledge concerning the function of MHV genes (either gamma herpesvirus common or MHV specific) related to immune evasion, latency and lymphoproliferation when highlighting the unsolved problems and/or controversial opinions.