Nab evolution in humans and RMs

总结 项目2将测试这样一个假设，即尽管它们的复杂性和曲折性，B的体细胞进化 细胞对bNAb活性的影响是决定性的。也就是说，bNAb的产生将遵循共同的和可再现的生物学特性。 克隆进化的途径，其在响应SHIV感染时是可再现的，其中嵌合病毒携带 来自原发或传播/创始HIV-1毒株的Envs。这个问题对所有艾滋病毒的潜在效用至关重要- 1谱系设计疫苗策略：如果bNAb应答是体细胞进化的独特事件，那么谱系 基于单个罕见人类受试者的反应设计疫苗不太可能普遍适用。 相反，如果在人类个体和RM中bNAb活性的克隆进化遵循一个共同的进化过程， 由连续抗原暴露引导的轨迹，引导克隆进化的谱系设计疫苗将被 对许多疫苗接种者有效。项目2包括三个具体目标。在目标1和2中，我们建议 为了表征相同感染的RM中的生发中心（GC）和记忆B细胞（BCRs）反应， 项目1，分子克隆的SHIV-CH 848（或其他靶向SHIV的V3-聚糖）或SHIV-CAP 256（或其他靶向SHIV的V3-聚糖） V1 V2靶向SHIV）。这些研究的主要目的是确定NAb和bNAb是否 不同远交系RM的反应以SHIV Env特异性方式基本相似。合作 利用核心B和C，我们将确定NA B的特异性、亲合力、中和能力和体细胞遗传学 和由SHIV感染引起的bNA B B细胞。相似的B细胞反应，根据特异性和V（D）J定义 选择，将证明决定性因素控制NA B和bNA B B细胞的体细胞进化 由SHIV感染引起。在目的3中，我们建议跟踪SHIV感染RM的B细胞应答， 接种疫苗项目3如果任何疫苗都不能赋予完全和完全的抵抗力， 感染，目标3将使我们能够表征疫苗对克隆选择，亲和力成熟， SHIV感染引起的NAb和bNAb B细胞克隆频率的变化。这些信息将 允许项目3“调整”疫苗策略以获得最大效果。 1

Summary Project 2 will test the hypothesis that despite their complexity and tortuous nature, the somatic evolution of B cells to bNAb activity is deterministic. That is, generation of bNAbs will follow a common and reproducible pathway(s) of clonal evolution that is reproducible in response to SHIV infections with chimeric viruses bearing Envs from primary or transmitted/founder HIV-1 strains. This question is crucial to the potential utility of all HIV- 1 lineage design vaccine strategies: if bNAb responses are unique accidents of somatic evolution, lineage design vaccines based on the response of a single, rare human subject are unlikely to be generally applicable. In contrast, if clonal evolution to bNAb activity in individual humans and in RMs follows a shared evolutionary trajectory guided by serial antigen exposure, lineage design vaccines that guide clonal evolution will be potentially effective in many vaccinees. Project 2 comprises three Specific Aims. In Aims 1 and 2, we propose to characterize the germinal center (GC) and memory B-cell (Bmem) responses in RMs identically infected in Project 1 with molecularly cloned SHIV-CH848 (or other V3-glycan targeting SHIV) or SHIV-CAP256 (or other V1V2 targeting SHIV). The principal goal of these studies is to determine whether the NAb and bNAb responses of different outbred RMs are substantially similar in a SHIV Env-specific manner. In collaboration with Cores B and C, we will define the specificity, avidity, neutralization capacity, and somatic genetics of NAb and bNAb B cells elicited by SHIV infection. Similar B-cell responses, as defined by specificity and V(D)J selection, will demonstrate that deterministic factors control the somatic evolution of NAb and bNAb B cells elicited by SHIV infection. In Aim 3, we propose to follow the B cell responses of SHIV infected RMs that have been vaccinated by Project 3. In the event that any vaccine does not confer full and complete resistance to infection, Aim 3 will allow us to characterize the vaccine's effects on clonal selection, affinity maturation, and changes in the frequencies of NAb and bNAb B-cell clones elicited by SHIV infection. This information will allow Project 3 to “tune” vaccine strategies for maximal effect. 1