INTERACTIONS BETWEEN CMV AND SIV IN RHESUS MACAQUES

Harvard Medical School, Boston MA

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Abstract

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. 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. To determine whether loss of CD4-positive T cells can impair functionality of CMV-specific CD8-positive T cells and lead to CMV reactivation in rhesus macaques, six SIV-negative CMV-seropositive rhesus macaques were subjected to in vivo CD4-positive 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-positive T lymphocytes were monitored longitudinally for 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-positive T cell depletion and subnormal CMV-specific CD4-positive T cell responses. An increase in the frequency of interferon (IFN)-gamma-secreting CMV-specific CD8-positive T cells with intact proliferative ability was observed and likely reflected a response to increased antigen load. However, the increase in IFN-gamma-secreting CMV-specific CD8-positive T cells was not matched with a commensurate increase in perforin-secreting ability suggesting that the expanded pool of CMV-specific CD8-positive T cells in the CD4-depleted macaques had impaired cytolytic function. Thus, immune control of persistent CMV infection is mediated by both CD4-positive and CD8-positive T lymphocytes.