This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Our work has provided compelling evidence that the onset of immune deficiency in pathogenic SIVmac239 infection of rhesus macaques (RM) is intimately linked with patterns of CD4+ memory T cell dynamics, and reflects a complex interplay of direct viral cytopathogenicity, and the indirect effects of persistent immune activation on CD4+ memory T cell proliferation, differentiation and survival. Our data have strongly implicated a decline in effector site, CD4+ effector memory (TEM) populations below a crucial threshold as a major proximate mechanism of overt immunodeficiency, but significantly, have also demonstrated that in CCR5-tropic SIV infection, even massive viral-mediated destruction of CD4+ TEM is rarely, if ever, sufficient for functional failure of this population. Instead, our data indicate that this failure is determined in large part by the ability of CD4+ central memory T cells (TCM) to produce new TEM, which in turn depends on the maintenance of the CD4+ TCM population itself. In chronic SIV infection, we found that a slow decline of the number and often, proliferative activity of CD4+ TCM underlies CD4+ TEM population failure, and """"""""sets the clock"""""""" for the onset of overt disease. Recent work has focused on the mechanisms responsible for CD4+ TCM homeostatic failure, in particular the role of IL-7 and IL-15 in maintaining CD4+ TCM homeostasis and the relative contribution of recruitment of new TCM from the na?ve compartment vs. regeneration of pre-existent TCM in the maintenance of the CD4+ TCM compartment during progressive SIV infection. By mAb-mediated depletion of CD4+ T cell in thymectomized monkeys, we have created """"""""CD4 naiveless"""""""" RM after memory cells regenerate in the absence of a thymus. Importantly, the lack of a na?ve CD4+ T cell compartment has little measureable effect on the maintenance of CD4+ memory T cells after SIV infection, suggesting that maintenance of this population depends predominantly on the regeneration of pre-existent memory cells as opposed to na?ve cell recruitment. Other work in this project has looked at B cell dynamics in SIV infection and mechanisms by which CD8+ T cells affect SIV replications and pathogenesis.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Primate Research Center Grants (P51)
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Special Emphasis Panel (ZRR1-CM-8 (01))
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Oregon Health and Science University
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