Kaposi sarcoma associated herpesvirus gene function

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) is an opportunistic pathogen causing Kaposi's sarcoma. It is capable of establishing latent infection, which can be reactivated to engage lytic infection for progeny production. KSHV contains a ˜165 kilobase DNA genome predicted to encode at least 90 open reading frames (ORFs). In this report, we generated 91 KSHV mutants, each characterized by the disruption of a single viral ORF. The growth of these mutants in cultured cells was examined to systematically investigate the necessity of each ORF for viral latency, reactivation, and lytic replication. Salient aspects are (a) 44 ORFs are essential for viral lytic replication in cultured cells and 47 are nonessential; (b) KSHV reactivation can be positively or negatively regulated by specific viral ORFs; and (c) ORFs identified to regulate viral reactivation encode functions modulating both innate and adaptive immune responses. The intersection of viral immunomodulatory genes controlling reactivation suggests that KSHV engages in a concerted effort to communicate and respond to the host immune system for reactivation and replication using a viral sensory network. Our results imply a novel mechanism in which reactivation of KSHV is actively controlled by the virus in response to its surrounding environment, leading to the opportunistic nature of viral diseases that are strongly correlated to the host's immune status and conditions.

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