IMMUNOPATHOGENESIS OF CLADE C SHIV-1157IPD3N4 IN M NEMESTRINA

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 为了进一步了解宿主-病原体相互作用的多样性及其如何在灵长类慢病毒感染的发病机制中的作用，我们研究了CCR5嗜性分支C SHIV1157ipd3N4在猪尾猕猴直肠内感染的后遗症。我们去年首次报道，在感染SHV病毒后，辫尾猕猴的多个粘膜部位的CD4+T细胞迅速而大量地丧失。感染后2-3周，CD28-CD95+效应记忆细胞和CD28-CCR5+T细胞严重耗竭，这与SHIV1157ipd3N4的R5趋向性一致。在超过感染急性期的三只动物中，两只显示持续48周的血浆病毒血症，其余一只将血浆病毒载量控制在基线水平(102拷贝/毫升)。在感染24周后，两种持续感染病毒的动物都产生了交叉分支中和抗体。然而，两只动物都出现了与猿猴艾滋病一致的临床症状，并被安乐死。我们目前正在研究这些动物中病毒序列的进化，以更好地了解病毒基因组的变化，这些变化可能会使猪尾猕猴更适合持续感染。

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. To gain further insight on the diversity of host-pathogen interactions and how they contribute to pathogenesis of primate lentivirus infection, we examined the sequelae of intrarectal infection with a CCR5-tropic clade C SHIV1157ipd3N4 in pigtailed macaques. We reported last year for the first time a rapid and substantial loss of CD4+ T cells at multiple mucosal sites in pigtailed macaques following SHIV infection. By 2-3 wks post-infection, profound depletion of CD4+CCR5+ T cells cells and CD28-CD95+ effector memory cells were observed, consistent with the R5-tropism of SHIV1157ipd3N4. Two of the three animals that were studied beyond the acute phase of infection showed persistent plasma viremia for 48 wks, while the remaining one controlled its plasma viral load at baseline (102 copies/ml). Cross-clade neutralizing antibodies developed in both persistently viremic animals starting at 24 weeks after infection. However, both animals developed clinical signs consistent with simian AIDS and were euthanized. We are currently studying the evolution of viral sequences in these animals to gain a better insight on changes in the viral genome that may confer greater fitness for persistent infection in pig-tailed macaques.