Modulation of Immune System by Kaposi’s Sarcoma-Associated Herpesvirus: Lessons from Viral Evasion Strategies

Kaposi’s sarcoma-associated herpesvirus (KSHV), a member of the herpesvirus family, has evolved to establish a long-term, latent infection of cells such that while they carry the viral genome gene expression is highly restricted. Latency is a state of cryptic viral infection associated with genomic persistence in their host and this hallmark of KSHV infection leads to several clinical–epidemiological diseases such as KS, a plasmablastic variant of multicentric Castleman’s disease, and primary effusion lymphoma upon immune suppression of infected hosts. In order to sustain efficient life-long persistency as well as their life cycle, KSHV dedicates a large portion of its genome to encode immunomodulatory proteins that antagonize its host’s immune system. In this review, we will describe our current knowledge of the immune evasion strategies employed by KSHV at distinct stages of its viral life cycle to control the host’s immune system

The Latency-Associated Nuclear Antigen Interacts with MeCP2 and Nucleosomes through Separate Domains▿

Kaposi's sarcoma-associated herpesvirus (KSHV)-infected cells express the latency-associated nuclear antigen (LANA) involved in the regulation of host and viral gene expression and maintenance of the KSHV latent episome. Performance of these diverse functions involves a 7-amino-acid chromatin-binding motif (CBM) situated at the amino terminus of LANA that is capable of binding directly to nucleosomes. LANA interacts with additional chromatin components, including methyl-CpG-binding protein 2 (MeCP2). Here, we show that the carboxy-terminal DNA-binding/dimerization domain of LANA provides the principal interaction with MeCP2 but that this association is modulated by the CBM. Both domains are required for LANA to colocalize with MeCP2 at chromocenters, regions of extensive pericentric heterochromatin that can be imaged by fluorescence microscopy. Within MeCP2, the methyl-CpG-binding domain (MBD) is the primary determinant for chromatin localization and acts together with the adjacent repression domains (the transcription repression domain [TRD] and the corepressor-interacting domain [CRID]) to redirect LANA to chromocenters. MeCP2 facilitates repression by LANA bound to the KSHV terminal repeats, a function that requires the MeCP2 C terminus in addition to the MBD and CRID/TRD. LANA and MeCP2 can also cooperate to stimulate transcription of the human E2F1 promoter, which lacks a LANA DNA-binding sequence, but this function requires both the N and C termini of LANA. The ability of LANA to establish multivalent interactions with histones and chromatin-binding proteins such as MeCP2 would enable LANA to direct regulatory complexes to specific chromosomal sites and thereby achieve stable reprogramming of cellular gene expression in latently infected cells