HIV disease is characterized by impairment of two key bone marrow (BM) functions: multilineage hemapoiesis and T cell homeostasis. Abnormal hemapoiesis leads to failure of diverse lineages (WBCs, RBCs, platelets, thymic progenitors), while compromised T cell homeostasis contributes to progressive CD4+ T cell loss. It is difficult to study HIV-induced BM suppression in humans, and there are no systematic analyses of the precise stages of hemapoiesis and T cell homeostasis that are altered. Direct HIV infection of BM cells does not appear to play a major role in suppression, pointing to indirect mechanisms of damage. These pathogenic mechanisms can be studied in SIV-infected non-human primates, in particular by comparing the divergent responses of natural and non-natural hosts to SIV infection, and by experimental manipulation to test hypotheses about disease mechanisms. Our studies of SIV-infected sooty mangabeys (SMs), the natural reservoir host from which HIV-2 arose, demonstrate that SMs avoid CD4+ T cell loss and BM suppression despite high viremia. In contrast, SIV infection of the non-natural rhesus macaque (RM) host, recapitulates the BM suppression and lymphopenia seen in human AIDS. In RMs, the chronic immune activation that accompanies an active, yet ineffective immune response correlates with lymphopenia and immune dysfunction. We believe that these inflammatory processes lead to both increased bystander death of uninfected lymphocytes, as well as active suppression of BM regenerative capabilities. In contrast, SMs mount limited cellular immune responses to SIV infection, sparing them of the chronic immune activation and its associated pathogenic bystander effects. In our studies, we also observed that the BM is a site of significant T cell proliferation in healthy, uninfected animals, suggesting a previously unappreciated role for the BM in the homeostasis of T cells. We have developed a comparative infection model, in which SMs and RMs can be infected with the same SIV strain, enabling study of the divergent host responses that lead to BM suppression in RMs, but not in SMs. We will use this model to: 1) Identify the stages of hemapoiesis and T cell homeostasis suppressed by pathogenic SIV infection, 2) Identify candidate pathogenic mechanisms of BM suppression, and 3) Probe putative BM-suppressive pathways by specific interventions. Understanding HIV-induced BM suppression will be key for effective hematologic and immune reconstitution strategies.
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