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. The scientific focus of this pilot proposal is the role of CD4+ memory T cell depletion in SIV pathogenesis. We seek to refine experimental approaches that will specifically determine whether CD4+ memory T cell depletion is required for the onset of symptomatic immunodeficiency, and if so, whether prevention of this depletion (e.g., keeping mucosal CD4+ memory cell numbers above the threshold mentioned above) prevents overt pathogenesis in effect, inducing an AIDS-susceptible RM to resemble an AIDS-resistant AGM or SM. Our ultimate objective is to use gene delivery approaches to provide AIDS-susceptible RM with a population of virus-resistant CD4+ memory T cells, either pre-SIV challenge or at various times post-challenge. These cells will be obtained by transfection of large numbers of CD4+ T cells (derived from thoracic duct canulation) with lentiviral vectors encoding what is essentially a resistance factor for SIV infection (see below). These transfected CD4+ T cells will be re-infused back into the host animal either immediately before or after pathogenic SIV challenge in sufficient numbers to maintain mucosal CD4+ memory T cells above the aforementioned 3-4% threshold. Note that transfected cells would always be a relatively minor population in vivo, and thus, we do expect that SIV dynamics will be significantly affected by this intervention. Controls will consist of monkeys re-infused with cells transfected with control vectors (e.g., lacking the resistance factor). We expect that provision of such viral resistant CD4+ memory T cells prior to SIV challenge or at various times post-infection will prevent and/or partially correct mucosal CD4+ T cell depletion (compared to appropriate controls), but given that viral targets will still (at least initially) be plentiful, will not substantially alter viral dynamics. However, if severe mucosal CD4+ T cell depletion has a key role in pathogenesis, we would expect that at any given level of viral replication, the RM with the protected CD4+ T cells would demonstrate slower disease progression than controls.
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