Evolution of HIV Envelope Following HIV Transmission

HIV包膜糖蛋白被广泛认为是病毒适应性的重要决定因素， 可传递性Env如何影响传播尚未仔细定义。在前期工作中，我们 研究了一个独特的传播对队列中的病毒，其中源病毒被确认为 系统发育测序，并将这些病毒与非传播对队列中发现的病毒进行比较。 使用假型病毒和单循环试验，我们发现来自传播病毒的受试者的R5病毒 与来自不使用CCR 5的受试者的R5病毒相比， 传播病毒CCR 5利用效率的可变性与成功的病毒感染之间的明显联系 血浆病毒血症水平不能解释传播。 在这个提议的项目中，我们将测试艾滋病毒有效利用CCR 5的能力是一个假设。 强而独立的预测或传递性。在具体目标1中，我们将首先尝试确认 R5利用效率和使用来自大规模的假型病毒的传播性之间的关联 感染不同艾滋病毒亚型的传播和非传播个体的数量。然后我们将 检查与这种相互作用相关的特定病毒相关特性（例如，结合亲和力，融合性， 适应性/感染性，对中和抗体和其他抑制剂（包括趋化因子和R5）的敏感性 抑制剂，N-连接的糖基化位点的数量和位置或可变环长度）。具体目标2 我们将确定来源伙伴中的宿主因素，这些因素与携带更多的可传播性有关。 HIV，重点是CCR 5受体。最后，在具体目标3中，我们将研究这些因素的影响。 宿主因素对HIV传播性的影响。 这些广泛定义的目标将在xxx传播对和yyy的扩展队列中得到解决 在旧金山弗朗西斯科的非传输对。为了研究病毒亚型的作用，我们将扩展我们的 我在巴西南部工作，那里最近C亚型的流行率急剧上升 在新感染者中。总共将确定50对传输和50对非传输， 其中大约50%的人预计携带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.