STUDIES OF NATURAL SIV-INFECTION IN SOOTY MANGABEYS

这个子项目是利用资源的许多研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 该项目的重点是了解为什么SIV感染的自然宿主，如白眉猴（SM），与HIV感染者形成鲜明对比，尽管病毒血症很高，但对艾滋病不敏感。我们最近发现，与人类和猕猴相比，SM的中央记忆CD 4 + T细胞中CCR 5的表达显著降低，并且这种较低的表达导致对SIV感染的易感性降低。这部作品现已提交出版。此外，作为R 01-AI 66998申办的研究的一部分，我们进行了三项新观察，这些观察结果现已全部发表（见下文）。第一个观察结果是，对自然感染SIV的SM的五年纵向调查的结论促使我们认识到感染与CD 4 + T细胞缓慢但进行性的下降有关，而不增加病毒载量或免疫激活。第二个观察结果是5-7%的天然SIV感染的SM对于CCR 5的第二胞外环中的2bp缺失是纯合的，这导致该分子的废除的表面表达。有趣的是，这些罕见的CCR 5敲除SM感染SIV，尽管水平较低。这些动物不使用CXCR 4产生病毒，而是使用其他SIV共受体，如GPR-1和GPR-15。第三个观察结果是，在自然SIV感染的SM中，自体中和抗体的水平非常低，并且与病毒载量或CD 4 + T细胞损失无关。我们相信这些数据提高了我们对SM中SIV感染的病理生理学的理解。

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. This project focuses on understanding the reasons why natural hosts for SIV infection, such as the sooty mangabeys (SMs), in striking contrast to HIV-infected individuals, are not susceptible to AIDS despite high viremia. We recently showed that CCR5 expression is significantly lower in central memory CD4+ T cells of SMs when compared to humans and macaques, and that this lower expression results in decreased susceptibility to SIV infection. This work is now submitted for publication. In addition, as part of the studies sponsored by R01-AI66998, we have made three novel observation that are all now published (see below). The first observation is that the conclusion of a five-years longitudinal survey of naturally SIV-infected SMs prompted us to realize that the infection is associated with a slow but progressive decline of CD4+ T cells without increasing viral load or immune activation. The second observation is that 5-7% of naturally SIV-infected SMs are homozygous for a 2bp deletion in the second extracellular loop of CCR5 that results in abrogated surface expression of thsi molecule. Interestingly, these rare CCR5 knock-out SMs are infected with SIV albeit at lower levels. These animals do not develop viruses using CXCR4, but other SIV co-receptors such as GPR-1 and GPR-15. The third observation is that, in naturally SIV-infected SMs, the level of autologous neutralizing antibodies is very low, and does not correlate with either viral load or CD4+ T cell loss. We believe that these data improve our understanding of the pathophysiology of SIV infection in SMs.