MOLECULAR ANALYSIS & MODELING OF HIV-1 TRANSMISSION, CONTAINMENT AND ESCAPE

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。 在这项研究中，我们解决了全球健康倡议的重大挑战#6：了解哪些免疫反应提供保护性免疫（针对HIV-1）。 在过去的一年里，我们证实，与在赞比亚夫妇中观察到的主要是单系传播的艾滋病毒（C亚型占主导地位）相似，在卢旺达，A亚型占主导地位的传播也主要是单系传播（90%的总比率）。相比之下，多个遗传变异被传播给3/7的受试者，他们被非配偶感染。这种多价传播在统计学上与可能扰乱生殖器粘膜的炎症性生殖器感染的存在有关。为了表征免疫应答，我们从C亚型患者中分离出一种B细胞杂交瘤，其产生高度株特异性中和单克隆抗体（Mab）。虽然来源于感染后4年收集的血细胞，但Mab 6.4C仅中和在急性感染期间和感染后2个月分离的携带自体Env的病毒，表明Env中随后的突变诱导的逃逸。 我们现在正在扩增和测序来自40名卢旺达捐赠者及其新感染伙伴的近全长病毒基因组，以检查随着时间的推移发生的病毒遗传变化，这些变化解释了从中和抗体和细胞毒性CD 8 + T细胞反应中逃逸的原因。

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. In this study we address the Grand Challenge #6 of the Global Health Initiative: Learn which immunological responses provide protective immunity (against HIV-1). This past year we confirmed that, similar to primarily monophyletic transmission of HIV observed in Zambian couples where subtype C predominates, transmission in Rwanda where subtype A prevails is also largely monophyletic (90% overall rate). In contrast, multiple genetic variants were transmitted to 3/7 of subjects who were infected by a non-spouse. This multivalent transmission was statistically linked with the presence of inflammatory genital infections that might perturb the genital mucosa. In order to characterize immune response we isolated a B-cell hybridoma from a subtype C patient that produced a highly strain-specific neutralizing monoclonal antibody (Mab). Although derived from blood cells collected 4 years post infection, Mab 6.4C only neutralized viruses harboring autologous Env isolated during acute infection and for 2 months post infection, suggesting subsequent mutation-induced escape in Envs. We are now amplifying and sequencing near-full-length viral genomes from 40 Rwandan donors and their newly infected partners to examine genetic changes in virus that occur over time that explain escape from both neutralizing antibodies and from cytotoxic CD8+ T cell responses.