Characterization of the Relationship between KSHV and Host Immune Response

All viruses must evade detection by the host immune response to establish productive infection. Kaposi's sarcoma-associated herpesvirus (KSHV) employs numerous sophisticated mechanisms that enable it to remain undetected. The coordinated innate and adaptive immune responses suppress KSHV infection and keep the virus in a latent, symbiotic relationship with the host. However, loss of immune suppression leads to uncontrolled viral replication, and increased potential for KSHV-associated malignancy. We have uncovered novel mechanisms KSHV utilizes to tip the balance of immune control and viral persistence in its favor. Once infection has ensued, KSHV persists in a latent state within a cell. Using latently infected cells, KSHV reactivation from latency was shown to occur in response to activation of toll-like receptors (TLR) 7 and 8. TLRs sense pathogens and induce an inflammatory state to eliminate the threat. These results suggest that KSHV senses its environment in response to activation of innate immune receptors such as TLRs to initiate viral replication as means of survival. KSHV encodes Orf63, a late lytic protein localized to the tegument of the virion. A role for Orf63 in immune modulation was found in blocking NLRP1 and NLRP3 inflamamsomes, two members of the NLR family of innate immune sensors and key cellular antipathogen molecules. Bioinformatics analyses revealed that Orf63 mimics the nucleotide binding and leucine-rich repeat domains of NLRP1, which Orf63 uses to block NLRP1 function. Inhibition of Orf63 expression during primary infection in human monocytes and reactivation in latently infected cells resulted in increased cytokine secretion and decreased viral fitness. Hence, viral pathogenesis may be strongly affected by NLRs in the absence of Orf63. Proper antiviral adaptive immune responses are dependent on expression of cell surface costimulatory molecules on antigen presenting cells. In latently infected monocytes, we found that KSHV suppresses expression of costimulatory molecules. Moreover, expression and secretion of several proinflammatory cytokines is downregulated in latently infected monocytes compared to uninfected control cells. These data suggest that in the latent state KSHV reduces its immunological signature and the potential for detection by cells of the adaptive immune response to facilitate persistent infection