A COMPARISON OF PATHOLOGICAL CORRELATES OF ATTENUATED VARIANTS OF SIVMAC239

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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 key feature of SIV and HIV infection is the rapid and near complete depletion of mucosal CD4+ T lymphocytes, however, this depletion also occurs in nonpathogenic infections of natural hosts, suggesting that it is a common feature of primate lentiviral infections. Here we evaluate pathological correlates produced by two variants of highly pathogenic SIVmac239, ¿nef and ¿GY, in rhesus macaques. Compared to SIVmac239, ¿nef has a deleted nef gene, critical for virulence in vivo; ¿GY has Gly-Tyr deletion from a conserved trafficking motif, Yxx¿, in the envelope cytoplasmic tail. Acute peak viremia of ¿GY was 1 week later, but comparable to, SIVmac239 (1.1 x 10^7 vs. 1.3 x 10^7) and higher than ¿nef (3.2 x 10^5). Acute infection with ¿GY and ¿nef spared gut CD4+ T lymphocytes, compared to pathogenic SIV, despite high plasma viral loads. Compared to SIVmac239, the gut immune effector sites were infected by ¿GY, however, the infection was less diffuse and rapidly shifted to immune inductive sites. Confocal microscopy identified ¿GY- infected cells as CD3+ T lymphocytes; ¿GY was not observed in macrophages or in the brain, indicating a less diverse target cell population and tissue distribution than for SIVmac239. Over time, the ¿GY-infected animals with the highest viral loads exhibited a slow decline in gut and blood CD4+ T lymphocytes, and in these animals, sequencing identified two recurring mutations in the envelope cytoplasmic tail, either S727P (a previously identified compensatory mutation) or the generation of new Yxx¿ motifs. In all envelope clones the Gly-Tyr deletion remained intact despite a high mutation rate. Interestingly, the S727P mutation also developed in the ¿nef-infected animal with the highest viral load. Our results show ¿GY and ¿nef have a reduced ability to deplete mucosal CD4+ T lymphocytes, suggesting a common defect in entering and/or replicating at this site.