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. During the initial funding period, we have identified 8 monkeys that are long-term nonprogressors (LTNP); they harbor a multiply deleted simian immunodeficiency virus (SIV), in which the axis of Rev and the Rev-Responsive Element (RRE) had been replaced with the constitutive transport element (CTE) of simian retrovirus type D (SRV/D). CTE was inserted in lieu of nef into SIVmac239 backbone. The resulting Rev-independent nef-deleted SIV, termed Rev-ind nef SIV, critically depends on an intact CTE for viral RNA export into the cytoplasm. Even monkeys infected as neonates have tightly controlled this virus, although this age group is uniquely sensitive to pathogenic effects of viruses that are nonvirulent in adults. As such, Rev-ind nef SIV has passed a stringent safety test. The new goal is to dissect the host-virus dynamics of this non-pathogenic interaction and to evaluate the efficacy of Rev-ind nef SIV to protect the LTNP and monkeys infected for much shorter time periods with this virus against low-dose mucosal challenges with pathogenic SIV.
The Specific Aims are to: 1. Examine the host-virus dynamics in rhesus macaques of Indian origin during acute infection with Rev-ind nef SIV and wt SIVmac239 nef+, during early chronic infection and finally in the LTNP cohort. 2. Assess the efficacy of Rev-ind nef SIV against wild-type, pathogenic SIVmac251. We will challenge rhesus monkeys with multiple, low-dose inocula of SIVmac251 to more closely mimic the mucosal HIV transmission in humans. 3. Assess the efficacy of Rev-ind nef SIV against heterologous virus challenge with SIVsmE660, again using multiple low-dose intrarectal virus challenges. 4. Elucidate the mechanisms of host control over Rev-ind nef SIV by selective depletion of CD8+ lymphocytes or B cells with cytotoxic monoclonal antibodies. These studies will deepen our understanding of the interaction between rhesus monkey hosts, which are susceptible to lentiviral pathogenesis, and Rev-ind nef SIV, an apathogenic virus, even in neonates.
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