Genotypic and Phenotypic Characterization of Heterosexually Transmitted HIV-1

描述（由申请人提供）：本提案的长期目标是更好地了解HIV-1在异性传播过程中的发病机制。先前的研究在感染后早期检查受试者，但主要是在HIV-1血清转换后，已经产生了有价值的见解。例如，我们和其他人已经表明，新感染的受试者只从传播伙伴中传播的病毒变体阵列中获得一个病毒子集。此外，具有紧凑和较少糖基化变体的病毒有利于异性传播。在异性性传播过程中选择这些包膜基因型的生物学机制仍不清楚。病毒包膜糖蛋白结构将预测短的和较少糖基化的包膜将具有更多的开放构象，导致对宿主细胞受体的亲和力增强，并且可能具有更大的抗体中和敏感性。由于信封修改后不久，可以发生在感染后的主机体液免疫反应的设置，我们建议评估和比较信封属性从新感染的收件人采样前HIV-1血清转换和他们的传播伙伴。我们将研究受体相互作用和细胞感染效率的信封从受体和供体。此外，我们将测试是否通过更好的病毒包膜糖蛋白-宿主细胞受体相互作用感染宿主细胞的更高效率可以赋予传播的适应性。我们的研究旨在研究在异性传播过程中为病毒提供优势的潜在生物学机制。我们的研究可能对旨在使用受体和融合抑制剂来防止病毒进入的杀微生物剂的努力具有重要意义。公共卫生相关性：我们的建议的目的是确定在传播过程中影响特定HIV-1变异体选择的生物学机制。我们建议检查一个新的队列的不一致的夫妇，以独特的地址受体亲和力和融合动力学之间的差异，新传播的病毒和大多数变异的传输合作伙伴。我们将探讨观察到的这些表型特性差异的生物学相关性，以开发潜在的生物学模型，用于HIV-1传播过程中的选择。

DESCRIPTION (provided by applicant): The long term objectives of this proposal are to provide a better understanding of the pathogenesis of HIV-1 during heterosexual transmission. Previous studies examining subjects early after infection, but primarily after HIV-1 seroconversion, have yielded valuable insights. For instance, we and other have shown that newly infected subjects only acquire a subset of viruses from the array of viral variants circulating in the transmitting partner. In addition, viruses with compact and less glycosylated variants are favored for heterosexual transmission. The biological mechanism for the selection of these envelope genotypes during heterosexual transmission remains undefined. The viral envelope glycoprotein structure would predict that short and less glycosylated envelopes would have more open conformations leading to an enhanced affinity for host cell receptors and possibly greater antibody neutralization sensitivity. Because envelope modifications can occur soon after infection in the setting of the host humoral immune response, we propose to evaluate and compare envelope properties from newly infected recipients sampled prior to HIV-1 seroconversion and their transmitting partner. We will investigate receptor interactions and cell infection efficiencies of the envelopes from recipients and donors. In addition, we will test whether greater efficiency in infecting host cells through better viral envelope glycoprotein-host cell receptor interactions could confer fitness for transmission. Our studies aim to examine potential biological mechanisms that provide an advantage for viruses during heterosexual transmission. Our studies could have significant implications for microbicides efforts aimed at using receptor and fusion inhibitors to prevent viral entry. PUBLIC HEALTH RELEVANCE: The aim of our proposal is to define the biological mechanisms that influence the selection of specific HIV-1 variants during transmission. We propose to examine a novel cohort of discordant couples to uniquely address receptor affinity and fusion kinetics differences among newly transmitted viruses and the majority of variants in the transmitting partner. We will explore the biological relevance of observed differences in these phenotypic properties to develop potential biological models for selection during HIV-1 transmission.