VIROLOGIC CORRELATES OF HETEROSEXUAL TRANSMISSION

这个子项目是许多利用 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来调查异性传播的病毒学决定因素，使用来自代表HIV-1两个主要分支（A和C）的大型、特征良好的不一致夫妇队列的样本。最近的研究表明，与供体来源的准种相比，建立感染的进化枝C而不是进化枝A病毒编码更紧凑的Env蛋白。 病毒传播主要是单系的，但炎症性生殖器感染往往与多个准种的传播，这表明一个完整的粘膜代表了一个强大的感染屏障。从两个合作伙伴中分离的Env显示出对CD 4和CCR 5受体的强烈需求，但增强感染的细胞与低受体/辅助受体水平不发生与更紧凑的Env的假设。系统发育分析表明，传播的病毒并不对应于供体生殖道中更丰富的准种，而是代表次要种。 最后，在15对非连锁（婚外传播）夫妇中的3对中检测到重复感染，这表明通过重组进行更快速的病毒进化的机会。

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 the virologic determinants of heterosexual transmission using samples from large, well-characterized discordant couple cohorts that represent two predominant clades (A and C) of HIV-1. Recent studies show clade C but not clade A viruses, which establish infection, encode a more compact Env protein compared to donor derived quasispecies. The viral transmission is primarily monophyletic, but inflammatory genital infections are often associated with the transmission of multiple quasispecies, suggesting an intact mucosa represents a strong barrier to infection. Env isolated from both partners showed strong requirements for both CD4 and CCR5 receptors, but enhanced infection of cells with low receptor/coreceptor levels does not occur with more compact Envs as hypothesized. Phylogenetic analysis shows transmitted viruses do not correspond to more abundant quasispecies in donor genital tracks, but instead represent minor species. Finally, superinfection was detected in 3 of 15 unlinked (transmission outside marriage) couples suggesting an opportunity for more rapid viral evolution through recombination.