VIROLOGIC CORRELATES OF HETEROSEXUAL TRANSMISSION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 该项目的主要目标是：(1)确定在传播过程中是否选择了gp120内的序列变异；(2)确定病毒变异的选择是否反映了捐赠者生殖液中存在的病毒种群或传播过程的生物限制；(3)确定早期感染后HIV重叠感染在双方中的频率、动力学以及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。我们正在分析卢旺达和赞比亚独特的不和谐夫妇队列中的HIV-1病毒种群，这些病毒是在一次传播事件发生后立即从捐赠者和接受者身上分离出来的。 这些研究提供了一个独特的机会，利用代表艾滋病毒-1的两个主要分支(A和C)的大型、特征良好的不和谐夫妇队列样本，研究异性传播的病毒学决定因素以及艾滋病毒重叠感染的频率和影响。最近的研究证实，在传播过程中出现了严重的遗传瓶颈，大多数血清转换伴侣被来自其配偶的单一基因变体感染，尽管炎症性生殖器感染会增加建立感染的变体的数量。新传播的病毒表现出对CCR5和CD4的高水平进入的依赖，并以低效率感染巨噬细胞。 尽管男性和女性生殖道中的病毒变种被区分开来，但在配偶中确定感染的病毒似乎与这些丰富的种群截然不同，这些病毒与发生在粘膜表面的传播瓶颈相一致。最后，在22对夫妇中有5对被检测到双重感染，这些夫妇的感染发生在婚姻之外，每个伴侣的病毒在遗传上是不同的。

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.