Genotypic and Phenotypic Characterization of Heterosexually Transmitted HIV-1

描述(申请人提供)：这项建议的长期目标是为了更好地了解艾滋病毒-1在异性传播过程中的发病机制。以前的研究在感染后早期检查受试者，但主要是在HIV-1血清转换之后，已经产生了有价值的见解。例如，我们和其他人已经证明，新感染的受试者只会从传播伙伴中传播的一系列病毒变体中获得病毒的子集。此外，病毒结构紧凑且糖基化程度较低的变异体更有利于异性传播。在异性传播过程中选择这些包膜基因的生物学机制尚不清楚。病毒包膜糖蛋白结构预测，糖基化程度较低的短包膜具有更开放的构象，导致与宿主细胞受体的亲和力增强，并可能具有更高的抗体中和敏感度。由于在宿主体液免疫反应中感染后不久可能发生包膜修改，我们建议评估和比较HIV-1血清转换前新感染受者及其传播伙伴的包膜特性。我们将调查受体相互作用和细胞感染效率，从受体和供体的信封。此外，我们将测试通过更好的病毒包膜糖蛋白-宿主细胞受体相互作用来感染宿主细胞的更高效率是否可以赋予传播的适合性。我们的研究旨在检查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入侵的杀微生物剂的努力具有重要意义。公共卫生相关性：我们提案的目的是确定在传播过程中影响特定HIV-1变种选择的生物学机制。我们建议检查一个新的不协调对队列，以独特地解决新传播的病毒和传播伙伴中的大多数变体之间的受体亲和力和融合动力学差异。我们将探索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，用于在HIV-1传播过程中进行选择。

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.