Viral Interferon Regulatory Factors Are Critical for Delay of the Host Immune Response against Rhesus Macaque Rhadinovirus Infection

Abstract

Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) is a gamma-2 gammaherpesvirus that was identified in 1994 to be the cause of AIDS-related KS (11), one of the most common malignancies within human immunodeficiency virus (HIV)-infected individuals. KSHV establishes a persistent infection within B cells (2,14) and is also associated with the malignant B cell disorders, multicentric Castleman's disease (MCD), and primary effusion lymphoma (PEL) (9, 48). Patients who develop MCD and PEL often have a poor outcome, especially if these B cell disorders develop before the introduction of highly active antiretroviral therapy (HAART) (7). Moreover, recent studies have documented an increase in KS within individuals on long-term therapy, despite maintenance of low HIV loads and high CD4 T cell numbers (31). These findings now suggest that the development of KSHV-associated diseases is dependent on other unidentified factors and not simply just immune suppression.Studying host-pathogen interactions during de novo KSHV infection and disease pathogenesis has been hindered by the scarcity of animal models that recapitulate the human disease (10, 16, 42). Rhesus macaque (RM) rhadinovirus (RRV) is a closely related gammaherpesvirus (1, 13, 15, 46) that naturally infects RMs and establishes latency within B cells (4). Moreover, RRV infection of RMs induces an acute hyperproliferation of B cells (17, 54) that often develops into diseases that resemble non-Hodgkin's lymphoma and MCD in immune-compromised animals (37). The striking similarities between KSHV-and RRV-associated pathologies (4,17,37,54), along with the nearly colinear genomic organization (1, 46), make RRV infection of RMs an ideal model for studying KSHV disease. Moreover, recent generation and characterization of a bacterial artificial chromosome (BAC) clone of RRV isolate 17577 (wild-type BAC-derived [WT BAC ] RRV 17577 ) (17) allow specific genes to be targeted for deletion to effectively address their roles during infection.KSHV and RRV encode a number of viral homologues of cellular genes involved in immune signaling, apoptosis, and cellular growth and differentiation. Accordingly, these viral homologues play critical roles in subverting the immune response (3). In particular, KSHV and RRV both encode a cluster of viral interferon ( (5, 6, 18-20, 24, 29, 52, 55). Furthermore, KSHV vIRF-1 displayed tumorigenic potential in NIH 3T3 cells and nude mice (20), and KSHV vIRF-1, -3, and -4 independently disrupt p53 function, inhibiting p53-induced apoptosis and/or cell cycle control (28,34,43,47). Additional antiapoptotic functions have also been attributed to KSHV vIRF-1 and vIRF-3. For example, KSHV vIRF-1 binds and sequesters the proapoptotic protein Bim, reducing levels of apoptosis (12), and RNA interference knockdown of KSHV vIRF-3 results in increased activity of effector caspases in KSHV-infected PEL cells (53). Collectively, these data illustrate the functional breadth and diversity of pathways/cellular functions that are targeted by the vIRFs, but these da...

Distinct Roles of Kaposi's Sarcoma-Associated Herpesvirus-Encoded Viral Interferon Regulatory Factors in Inflammatory Response and Cancer

“…KSHV and rhesus macaque rhadinovirus (RRV), the two highly related gammaherpesviruses, are the only viruses known to (146). Collectively, these findings demonstrate that both KSHV and RRV vIRFs have a broad impact on herpesvirus pathogenesis and host immune responses.…”

A Rhesus Rhadinovirus Viral Interferon (IFN) Regulatory Factor Is Virion Associated and Inhibits the Early IFN Antiviral Response

“…Virus particles with gold particles are indicated by the white arrowhead, and virus particles with no gold particles are indicated by black arrowheads. nificant differences in the antiviral state early during infection (33,34). The RRV vIRFs were found to be responsible for a decrease in gene expression and IFN production, as well as decreased nuclear accumulation of pIRF3 during de novo infection with RRV.…”

“…In addition, type I IFNs have dramatic effects on natural killer (NK) cells (49,50) and CD4 ϩ and CD8 ϩ T cells (51,52), as well as dendritic cells (DCs) (53)(54)(55)(56). In fact, it was previously shown that complete deletion of all 8 RRV vIRFs initiates an earlier T cell response (34), and therefore, it could be postulated that the IFN-␤ inhibition mediated by virion-associated R6 contributes to the delayed T cell response observed in WT RRV infection. It would be particularly interesting to create an R6 deletion mutant of RRV and to determine the phenotype of this virus and the ensuing immune response.…”

“…Infection of rhesus macaques with vIRF-ko RRV resulted in lower viral loads and increased levels of plasma IFN-␣. Interestingly, although persistence was established in the absence of the RRV vIRFs, decreased levels of persistent virus were detected in B cells, along with decreased development of B cell hyperplasia (34). The decrease in B cell hyperplasia, however, could be due to smaller amounts of circulating virus within these animals.…”

“…Recent studies have tested whether the RRV vIRFs are capable of antagonizing the function of cellular IRFs and IRF-mediated induction of IFN (33,34). This was achieved via the construction of a recombinant RRV lacking all 8 vIRF open reading frames (ORFs) (vIRF-ko RRV) (33), the backbone of which is derived from a bacterial artificial chromosome (BAC) clone of wild-type (WT) RRV 17757 (WT BAC RRV) (35).…”