VIROLOGIC CORRELATES OF HETEROSEXUAL TRANSMISSION

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 该项目的主要目标是：（1）确定在传播过程中是否选择了gp 120内的序列变异;（2）确定病毒变异的选择是否反映了供体生殖液中存在的病毒数量或传播过程的生物限制;和（3）确定HIV在早期感染后在两个伴侣中重叠感染的频率、动力学、病毒学和免疫学分支。 这些研究的结果增强了我们对异性传播过程的理解，并产生了对设计和测试全球有效的候选疫苗至关重要的新信息。我们正在分析HIV-1病毒种群，在卢旺达和赞比亚的不和谐夫妇的独特队列中，在传播事件发生后立即从捐赠者和接受者中分离出来。 这些研究提供了一个独特的机会，调查异性传播的病毒学决定因素，以及频率和影响的艾滋病毒重叠感染的样本，从大型，特征良好的不一致的夫妇队列，代表两个主要分支（A和C）的艾滋病毒-1。最近的研究证实，在传播过程中发生了严重的遗传瓶颈，大多数血清转化伴侣被其配偶的单一遗传变异感染，尽管炎症性生殖器感染可以增加建立感染的变异数量。新传播的病毒表现出对高水平的CCR 5和CD 4的依赖性，并以低效率感染巨噬细胞。 尽管在男性和女性的生殖道中存在病毒变体的区室化，但在配偶中建立感染的病毒似乎与这些富集的人群不同  与粘膜表面发生的传播瓶颈一致。最后，在22对夫妇中的5对中检测到重复感染，其中感染发生在婚姻之外，并且每个伴侣的病毒在遗传上不同。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The major goals of this project have been to (1) determine whether sequence variants within gp120 are selected during transmission; (2) determine whether the selection of viral variants reflects the population of virus present in the genital fluids of the donor or a biological restriction of the transmission process; and (3) determine the frequency, kinetics, and the virologic and immunologic ramifications of HIV superinfection in both partners following early infection. The results of these studies are enhancing our understanding of the heterosexual transmission process and yield novel information that is critical to the design and testing of globally effective vaccine candidates. We are analyzing HIV-1 virus populations, isolated from both the donor and recipient immediately following a transmission event, in unique cohorts of discordant couples in Rwanda and Zambia. These studies have provided a unique opportunity to investigate both the virologic determinants of heterosexual transmission as well as the frequency and implications of HIV superinfection using samples from large, well-characterized discordant couple cohorts that represent two predominant clades (A and C) of HIV-1. Recent studies confirm that a severe genetic bottleneck occurs during transmission with a majority of seroconverting partners being infected by a single genetic variant from their spouse, although inflammatory genital infections can increase the number of variants establishing infection. Newly transmitted viruses exhibit a dependence on high levels of both CCR5 and CD4 for entry, and infect macrophages with low efficiency. Despite compartmentalization of virus variants in the genital tract of both men and women, the viruses that establish infection in the spouse appear to be distinct from these enriched populations  consistent with the bottleneck to transmission occurring at the mucosal surface. Finally, superinfection was detected in 5 of 22 couples where infection occurred outside the marriage and the viruses in each partner are genetically different.