TRANSMISSION & PATHOGENESIS OF X4 & R5 SHIVS

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。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 与最初的R5病毒相比，过渡中间体的适合性劣势被认为是阻止辅受体切换的原因之一，这解释了X4病毒出现得较晚。利用人类免疫缺陷病毒1型(HIV-1)共受体切换的猿猴模型，我们在本研究中证明，在感染R5猿猴/人类免疫缺陷病毒(SHIV)(SF162P3N)的猕猴中，存在类似的辅助受体切换的分子进化途径。在感染动物中，多种途径的扩展或转换为CXCR4的途径并存，过渡中间体在辅助受体使用效率上的适宜性影响它们在感染病毒种群中的生长和表现。双嗜性和X4病毒出现在不同的疾病阶段，但它们的进入效率低于共存的R5毒株，这可能解释了为什么它们没有胜过R5病毒。在两只感染了辅受体开关的猕猴中也进行了类似的观察，提供了体内证据，表明适应性缺陷是X4出现和扩展的障碍。

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. Fitness disadvantage of the transitional intermediates compared to the initial R5 viruses has been suggested to constitute one of the blockades to coreceptor switching, explaining the late appearance of X4 viruses. Using a simian model for human immunodeficiency virus type 1 (HIV-1) coreceptor switching, we demonstrate in this study that similar molecular evolutionary pathways to coreceptor switch occur in more than one R5 simian/human immunodeficiency virus (SHIV)(SF162P3N)-infected macaque. In infected animals where multiple pathways for expansion or switch to CXCR4 coexist, fitness of the transitional intermediates in coreceptor usage efficiency influences their outgrowth and representation in the infecting virus population. Dualtropic and X4 viruses appear at different disease stages, but they have lower entry efficiency than the coexisting R5 strains, which may explain why they do not outcompete the R5 viruses. Similar observations were made in two infected macaques with coreceptor switch, providing in vivo evidence that fitness disadvantage is an obstacle to X4 emergence and expansion.