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. A cohort of 8 monkeys infected as neonates or adults with a live attenuated simian immunodeficiency virus (SIV) 9 years ago represents long-term non-progressors (LTNP). These monkeys harbor a multiply-deleted SIV, in which Rev and the Rev-Responsive Element (RRE) were replaced with the constitutive transport element (CTE) of simian retrovirus type D. The resulting Rev-independent nef-deleted SIV, termed Rev-ind nef?SIV, depends on CTE for viral RNA export into the cytoplasm. Even monkeys infected as neonates had no signs of immune dysfunction and had persistent humoral and cellular SIV-specific immunity. We completed multiple low-dose intrarectal challenges with pathogenic SIV;we are evaluating the degree of protection provided by Rev-ind nef?SIV. LTNPs received a high-dose intravenous Rev-ind nef?SIV boost;in parallel, 4 na?ve controls were inoculated which became a chronically-infected cohort. No LTNPs had measurable viremia post-boost. We tested the time interval between infection with live attenuated virus and challenge with pathogenic virus;time intervals studied included challenge of LTNP with a 7+-year history in chronic infection with the live attenuated virus. Challenge was performed with a heterologous SIV strain that was clearly distinct form the vaccine strain. We are currently analyzing gene expression data collected from this cohort of monkeys in order to understand the interaction between live attenuated virus and the host. A new parameter of the host genetic background, a gene called TRIM5a, is being analyzed. We are probing for any correlation between the degree of protection and parameters of innate and adaptive immunity.
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