Evolution of HIV Envelope Following HIV Transmission

HIV包膜糖蛋白被广泛认为是病毒适合性和 传播性。环境病毒如何影响传播还没有仔细定义。在前期工作中，我们 在一个独特的传播对队列中研究了病毒，在这些队列中，源病毒被确认为 进行了系统发育测序，并将这些病毒与在一组非传播性病毒对中发现的病毒进行了比较。 使用伪型病毒和单周期检测，我们发现来自传播疾病的受试者的R5病毒 与来自不使用CCR5的受试者的R5病毒相比，病毒在使用CCR5方面似乎具有更高的效率 传播病毒。CCR5利用率的可变性和病毒成功之间的这种明显联系 传播不能用血浆病毒血症水平来解释。 在这个拟议的项目中，我们将测试HIV有效利用CCR5的能力是一个 强大而独立的预测性或传递性。在具体目标1中，我们将首先尝试确认 使用大型伪型病毒的R5利用效率和传播率之间的关系 感染不同艾滋病毒亚型的传播者和非传播者的数量。到时候我们会的 检查与该相互作用相关的特定病毒相关属性(例如，结合亲和力，融合原性， 适合性/感染性，对中和抗体和包括趋化因子和R5在内的其他抑制剂的敏感性 抑制剂、N-连接糖基化位点的数量和位置或可变环长)。《特定目标2》 我们将确定源合作伙伴中与更多可传播性相关的宿主因素 HIV，重点是CCR5受体。最后，在具体目标3中，我们将调查这些因素的影响 宿主因素对艾滋病毒传播性进化的影响。 这些广泛定义的目标将在xxx传输对和yyy的扩展队列中得到解决 旧金山的非传输线对。为了研究病毒亚型的作用，我们将扩展我们的 到巴西南部工作，那里的C亚型感染率最近急剧上升 在新感染的人中。总共将识别50个传输对和50个非传输对， 预计其中约50%的人携带C亚型病毒。

The HIV envelope glycoprotein is widely believed to be an important determinant of viral fitness and transmissibility. How Env affects transmission has not been carefully defined. In our preliminary work, we studied viruses in a unique cohort of transmission pairs in which the source virus was confirmed with phylogenetic sequencing, and compared these viruses to those found in a cohort of non-transmitting pairs. Using a pseudotyped viruses and a single-cycle assay, we found that R5 viruses from subjects who transmit virus appear to have greater efficiency in using CCR5 compared to R5 viruses from subjects who do not transmit virus. This apparent link between variability in CCR5 utilization efficiency and successful virus transmission was not explained by the level of plasma viremia. In this proposed project we will test the hypothesis that the capacity of HIV to efficiently utilize CCR5 is a strong and independent predictor or transmissibility. In Specific Aim 1, we will first attempt to confirm the association between R5 utilization efficiency and transmissibility using pseudotyped viruses from a large number of transmitting and non-transmitting individuals infected with diverse HIV subtypes. We will then examine the specific virus-related properties related to this interaction (e.g., binding affinity, fusogenicity, fitness/infectivity, sensitivity to neutralizing antibodies and other inhibitors including chemokines and R5 inhibitors, the number and location of N-linked glycosylation sites or variable loop lengths). In Specific Aim 2 we will determine host factors in the source partner which are associated with harboring more transmissible HIV, focusing on the CCR5 receptor. Finally, in Specific Aim 3, we will investigate the influence of these host factors on the evolution of HIV transmissibility. These broadly defined objectiveswill be addressed in an expanded cohort of xxx transmitting pairs and yyy non-transmitting pairs in San Francisco. In order to investigate the role of virus subtype, we will extend our work to southern Brazil, where there has been a recent sharp increase in the prevalence of subtype C among newly infected individuals. A total of 50 transmission and 50 non-transmitting pairs will be identified, of whom approximately 50% are expected to have harbor subtype C virus.