PATHOGENESIS OF AN ATTENUATED SIVMAC239 IN RHESUS AND PIGTAIL MACAQUES

点击翻译按钮获取中文摘要

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. Differences in SIV pathogenesis have been noted between rhesus (RhM) and pigtail (PTM) macaques with PTMs progressing more rapidly to AIDS. We previously reported that SIVmac239 containing a Gly-Tyr deletion (designated GY) in a conserved trafficking motif in the Env cytoplasmic tail was attenuated in RhM. In more recent studies to identify pathological correlates of attenuation we observed in 6 RhM that GY acute peak viremia was later (3 wks vs. 2 wks) and slightly lower than for SIVmac239 (0.5 log) with viral set points that were considerably reduced (~2 logs). Despite robust replication in organized lymphoid tissues, GY infection in lamina propria was transient with little if any infection or CD4 depletion seen from day 28 to 1 year. In PTMs GY showed a rapid (10-14 day) and high (1.8x10^6-1.6x10^7 copies/RNA) acute peak, but remarkably, in all 5 animals viral set points declined to undetectable levels with animals maintaining normal numbers of peripheral CD4 cells for e3 years. In two animals, GY reappeared after CD8 depletion, and both were protected from an i.v. SIVmac239 challenge. Notably, although all 5 were infectable by heterologous SIVmacE660, and in three E660 was controlled to d10^2 copies/ml for 3- 5 years. In follow-up studies at TNPRC, 4 PTMs have been infected with GY to determine pathological correlates of control. Preliminary results at 4 weeks indicate that peak viremia in PTM again appears earlier (2 wks) than for RhM with a more rapid decline in plasma viremia. Follow-up studies to determine the distribution of GY infection in gut and peripheral lymphoid tissues are in progress. Why PTM, a more susceptible species for pathogenic SIVmac infection exhibits better control of GY than RhM will be of great interest in determining viral and host interactions that are relevant to virologic control and disease.