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. This study focuses on the identification of the defects in the hematopietic and immunological function of the bone marrow during pathogenic and non-pathogenic Simian Immunodeficiency Virus (SIV) infections of rhesus macaques and sooty mangabeys, respectively. These studies allowed us to determine how these defects are involved in causing the overall collapse of the immune system function that is associated with progression to AIDS in HIV-infected individuals. To this end, we are conducting a series of experimental studies in rhesus macaques and sooty mangabeys that have shown that: (i) high levels of mature T-cell proliferation, involving both naive and memory cells, are present in bone marrow-derived cells from uninfected animals;(ii) in SIV-infected SMs, but not RMs, the level of proliferation of bone marrow-based CD4+ T cells is higher than that of circulating CD4+ T cells;and (iii) limited bone marrow-based CD4+ T-cell proliferation in SIV-infected SMs with low CD4+ T-cell counts (suggesting a regenerative failure in these animals). Collectively, these results confirm that the bone marrow is involved in maintaining T-cell homeostasis in primates and suggest a role for bone marrow-based CD4+ T-cell proliferation in determining the benign nature of natural SIV infection of mangabeys. We are hopeful this study will provide information useful to the treatment of bone marrow deficit of HIV-infected humans.
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