目前尚无有效艾滋病疫苗的主要原因之一是不能在人或动物体内诱导广谱中和抗体。由于HIV-1不能感染除人之外的其他动物，SHIV感染恒河猴成为唯一用来评价以诱导中和抗体为目的疫苗保护力的动物模型。但由于很少在短期SHIV感染恒河猴体内检测到针对HIV-1的广谱中和活性，并且也未能从恒河猴体内分离到这类单克隆抗体，对恒河猴能否产生针对HIV-1的广谱中和抗体及其特性和机制尚不清楚。我们在前期工作中跟踪研究了感染SHIV长达6年的恒河猴，这是目前已报道感染时间最长的恒河猴，并在它们体内检测到针对HIV-1的广谱中和活性，且发现与人广谱中和抗体具有相似的表位。在本课题中将综合运用单细胞分选、中和抗体表达和鉴定及病毒单基因组测序等技术系统地研究恒河猴感染SHIV体内广谱中和抗体产生和进化机制以及与人体产生广谱中和抗体的相关性，从而为更好地应用恒河猴模型来诱导抗HIV-1广谱中和抗体提供理论和实验依据。

One of the main challenges for the unsuccessful HIV-1 vaccine is the failure to elicit broadly neutralizing antibodies (bnAbs) in animals or humans. Since HIV-1 does not infect animals other than humans, the only animal model to evaluate protection efficacy of a bnAb-based vaccine is the non-human primate (NHP) model by challenging monkeys with simian-human immunodeficiency virus (SHIV), in which the env gene in the SIV genome is replaced by the env gene from HIV-1. In previous limited studies, broad neutralization activity against HIV-1 has only been detected in a few SHIV-infected NHPs. Up to date, no monoclonal bnAbs have been isolated from SHIV-infected NHPs. We have followed SHIV-infected monkeys for up to 6 years, which is the longest follow-up cohort of SHIV-infected monkeys in the world. We have detected broad neutralization activity in those monkeys. Importantly, we found that these nAbs targeted similar epitopes as those identified in humans. We will comprehensively analyze bnAbs in those monkeys by using technologies (single epitope specific B cell sorting, expression and characterization of bnAbs, and single genome amplification of viral genomes, etc.) to systematically investigate the bnAb maturation process and mechanisms of bnAb induction in SHIV-infected monkeys. More importantly, the comparison between development of bnAbs in NHPs and humans will provide unprecedented insight into the factors that are important for development of bnAbs in NHPs. The knowledge learned from this study will be critical for better use of the SHIV-NHP model to elicit bnAbs and to evaluate their ability to prevent infection since the SHIV-NHP model is the only one that can be used to study bnAbs to HIV-1 and evaluation of efficacy of HIV-1 Env-based vaccines.