This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Cytomegalovirus (CMV) is an important opportunistic pathogen in AIDS. Although CMV disease manifests in the setting of immunosuppression, the mechanisms underlying impaired CMV-specific T cell immunity in AIDS are not well understood. In this study, we investigated whether loss of CD4+ T cells can impair functionality of CMV-specific CD8+ T cells and lead to CMV reactivation in rhesus macaques. Six SIV-negative CMV-seropositive rhesus macaques were subjected to in vivo CD4+ T cell depletion by administration of the humanized anti-CD4 monoclonal antibody (huOKT4A). CMV viral load and changes in the frequency and functionality of CMV-specific CD8+ T lymphocytes were monitored longitudinally for one year. Greater than 95 percent CD4+ T cell depletion was achieved in 5/6 macaques and was sustained at less than 30 percent of baseline levels for up to one year. CMV reactivation as evidenced by detectable CMV viremia and/or increased CMV DNA load in urine or saliva was observed intermittently in the first four months post CD4 depletion in 5/6 macaques, at time-points with greater than 70 percent peripheral CD4+ T cell depletion and subnormal CMV-specific CD4+ T cell responses. An increase in the frequency of interferon (IFN)-gamma-secreting CMV-specific CD8+ T cells with intact proliferative ability was observed and likely reflected a response to increased antigen load. Thus, CMV reactivation appeared to be related to the loss of a direct effector function of CD4+ T cells rather than to impaired functionality of CMV-specific CD8+ T cells, an observation supported by the presence of Granzyme B+ CMV-specific CD4+ T cells in rhesus macaques. Although the absence of CD4+ T cells did not impair the ability to mount an appropriate CD8+ T cell response to increased virus load, the increase in IFN-g-secreting CMV-specific CD8+ T cells outpaced the increase in perforin-secreting cells. Thus, it appears that the expanded pool of CMV-specific CD8+ T cells in the CD4-depleted macaques were enriched for cells with impaired cytolytic function. In the absence of SIV infection, CD4+ T cells mediate immune control of latent CMV infection by multiple mechanisms. Impairment of CD4+ T helper function in AIDS may contribute to disseminated CMV disease, both through loss of a direct cytotoxic function, as well as by impairing cytotoxicity of CMV-specific CD8+ T cells.
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