This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Although cytomegalovirus (CMV) is an important opportunistic pathogen in AIDS, the mechanism of CMV reactivation following HIV or SIV-induced immunosuppression is not well understood. Previously we have shown that the onset of CMV reactivation in SIV-infected rhesus macaques was preceded by a decline in the frequency of CMV-specific CD4+ and CD8+ T cells. In order to investigate the role of CD4+ T lymphocytes in immune control of latent CMV infection, we investigated the effect of in vivo CD4+ T lymphocyte depletion on CMV reactivation and maintenance of CMV-specific CD8+ T lymphocyte responses in naturally CMV-seropositive rhesus macaques. The humanized monoclonal antibody cdr-OKT4A-huIgG1 was administered to four SIV-negative CMV-seropositive rhesus macaques. Following administration of the anti-CD4 antibody, more than 95% of peripheral blood CD4+ T lymphocytes were depleted in all four macaques. Recovery of peripheral CD4+ T lymphocytes was observed only after 20-41 days. CMV-specific CD4+ T lymphocyte responses were undetectable or markedly reduced during the period of CD4+ T lymphocyte depletion. Recovering peripheral CD4+ T lymphocytes were enriched for CMV-specific T cells. In contrast to CMV-specific CD4+ T cells, the frequency of CMV-specific CD8+ T lymphocytes did not decline during the period of CD4+ T lymphocyte depletion. Instead, a moderate increase in frequency was observed after the onset of CMV reactivation and was likely related to increased CMV antigen load. Transient CMV reactivation as evidenced by increased levels of CMV DNA in plasma, urine or buccal secretions was observed in all four animals. These data highlight the importance of CD4+ T lymphocytes in immune control of natural CMV infection and suggest that loss of CD4+ T lymphocyte help may be an important mechanism underlying the occurrence of disseminated CMV disease in AIDS.
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