We observed that, similar to gp34, which is able to block all of the activating human FRs, i.e., FcRI (CD64), FcRIIa (CD32a), and FcRIIIA (CD16), Rh05 reduced the activation of homologous rhesus FcRs. by expressing viral FcRs (vFcRs). Human cytomegalovirus (HCMV) encodes four distinct vFcRs that differ with respect to their IgG subtype specificity and their impact on antibody-mediated immune functionin vitro. The impact of vFcRs on HCMV pathogenesis and immunomodulationin vivois not known. The closest evolutionary animal model of HCMV is rhesus CMV (RhCMV) infection of rhesus macaques. To enable the characterization of vFcR function in this model, we studied IgG binding by RhCMV. We show that lysates of RhCMV-infected cells contain an IgG-binding protein of 30 kDa encoded by the geneRh05that is a predicted type I glycoprotein belonging to theRL11gene family. Upon deletion ofRh05, IgG-Fc binding by RhCMV strain 68-1 is lost, whereas ectopic expression of Rh05 results in IgG binding to transfected cells consistent with Rh05 being a vFcR. Using a set of reporter cell lines stably expressing human and rhesus FcRs, we further demonstrate thatRh05antagonizes host FcR activation. Compared toRh05-intact RhCMV, RhCMVRh05 showed an increased activation of host FcR upon exposure of Destruxin B infected cells to IgG from RhCMV-seropositive animals, suggesting that Rh05 protects infected cells from opsonization and IgG-dependent activation of host FcRs. However, antagonizing host FcR activation by Rh05 was not required for the establishment and maintenance of infection of RhCMV, even in a seropositive host, as shown by the induction of T cell responses to heterologous antigens expressed by RhCMV lacking the gene region encoding Rh05. In contrast to viral evasion of natural killer cells or T cell recognition, the evasion of antibody-mediated effects does not seem to be absolutely required for infection or reinfection. The identification of the first vFcR that efficiently antagonizes host FcR activation in the RhCMV genome will thus permit more detailed studies of this immunomodulatory mechanism in promoting viral dissemination in the presence of natural or vaccine-induced humoral immunity. IMPORTANCERhesus cytomegalovirus (RhCMV) offers a unique model for studying human cytomegalovirus (HCMV) pathogenesis and vaccine development. RhCMV infection of nonhuman primates greatly broadened the understanding of mechanisms by which CMVs evade or reprogram T cell and natural killer cell responsesin vivo. However, the role of humoral immunity and viral modulation of anti-CMV antibodies has not been studied in this model. There is evidence fromin vitrostudies that HCMVs can evade humoral immunity. By gene mapping and with the help of a novel cell-based reporter assay system we characterized the first RhCMV encoded IgG-Fc binding glycoprotein as a potent antagonist of rhesus FcR activation. We further demonstrate that, unlike evasion of T cell immunity, this viral Fc receptor is not required to overcome anti-CMV immunity to establish secondary infections. These findings enable more detailed studies of thein vivoconsequences of CMV evasion from IgG responses in nonhuman primate models. == INTRODUCTION == As prototypical members of the -subgroup of the herpesvirus family, cytomegaloviruses (CMVs) establish lifelong infection characterized by viral latency and reactivation. Human and animal CMVs share sophisticated mechanisms to evade a multitude of antiviral host immune responses, including both Destruxin B innate and adaptive arms of the immune system (1,2). With respect to cell-mediated immunity, it has been shown that human cytomegalovirus (HCMV) can efficiently evade direct recognition of infected target cells by natural killer (NK) cells, as well as T lymphocytes, using a large repertoire of viral gene products that interfere with antigen presentation, surface receptor transport, or innate receptor signaling (3,4). Complementing viral evasion of cell-mediated immune responses are strategies for evasion of humoral immunity, such as counteracting IgG-mediated antiviral immunity. Ribosomal profiling identified more than 750 translational products that include many potentially antigenic proteins during the sequential immediate-early (IE), early (E), and late (L) phases of gene expression (5). Despite exposure of these potential viral antigens to the hosts immune system, human and animal CMVs maintain lifelong chronic infections with occasional reactivation. Moreover, CMVs Destruxin B are able to reinfect CMV-immune hosts despite the presence of CMV-specific humoral and cellular immune responses (6,7). Potentially due to viral immune evasion capabilities, anti-HCMV IgG preparations such as intravenous hyperimmune immunoglobulin (IVIG) or monoclonal antibodies (MAbs) displayed only limited, if any, efficacy in various clinical settings (813). In nonhuman primate (NHP) models, prevention of fetal transmission only occurred when IVIG was concentrated from plasma of Rabbit polyclonal to GST donors that were preselected for high neutralization activity, whereas IVIG from nonselected plasma was only partially protective, suggesting.