TRANSMISSION & PATHOGENESIS OF X4 & R5 SHIVS

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。 我们之前报道了静脉接种R5猴-人类免疫缺陷病毒SF162P3N(SIV(SF162P3N))的恒河猴共受体开关。然而，R5到X4病毒的进化是否发生在黏膜感染的动物中，以及这种转换发生在哪个解剖部位，没有得到解决。在此，我们报告了直肠内感染SHV(SF162P3N)的猕猴的辅受体偏好的变化。这种转变发生在病毒复制水平高、抗病毒抗体反应不可检测以及gp120包膜蛋白V3环中所需序列发生变化的感染动物中。X4病毒的出现与外周CD4(+)T细胞计数加速下降有关，但发生在CD4(+)T细胞丧失之前而不是之后。因此，直肠内感染的动物的条件、基因类型要求和辅受体转换模式与静脉感染的猕猴的情况非常一致。它们也与人类上报道的重叠，暗示了两个宿主中共同的受体切换机制。此外，在一只感染的动物身上发现了两条独立的从R5到X4的进化途径，导致了在开关动力学和组织定位上不同的双嗜性和X4病毒。早期以双向转换事件为主，病毒在多个组织部位建立感染。相反，向X4病毒的转变发生得较晚，主要在周围淋巴结内启动和扩展。这些发现有助于将R5Shiv(SF162P3N)感染猕猴作为研究HIV-1共受体开关的机制基础、动力学和位置的模型。

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. We previously reported coreceptor switch in rhesus macaques inoculated intravenously with R5 simian-human immunodeficiency virus SF162P3N (SHIV(SF162P3N)). Whether R5-to-X4 virus evolution occurs in mucosally infected animals and in which anatomic site the switch occurs, however, were not addressed. We herein report a change in coreceptor preference in macaques infected intrarectally with SHIV(SF162P3N). The switch occurred in infected animals with high levels of virus replication and undetectable antiviral antibody response and required sequence changes in the V3 loop of the gp120 envelope protein. X4 virus emergence was associated with an accelerated drop in peripheral CD4(+) T-cell count but followed rather than preceded the onset of CD4(+) T-cell loss. The conditions, genotypic requirements, and patterns of coreceptor switch in intrarectally infected animals were thus remarkably consistent with those found in macaques infected intravenously. They also overlapped with those reported for humans, suggestive of a common mechanism for coreceptor switch in the two hosts. Furthermore, two independent R5-to-X4 evolutionary pathways were identified in one infected animal, giving rise to dual-tropic and X4 viruses which differed in switch kinetics and tissue localization. The dual-tropic switch event predominated early, and the virus established infection in multiple tissues sites. In contrast, the switch to X4 virus occurred later, initiating and expanding mainly in peripheral lymph nodes. These findings help define R5 SHIV(SF162P3N) infection of rhesus macaques as a model to study the mechanistic basis, dynamics, and sites of HIV-1 coreceptor switch.