The circulating and memory B-antibody responses in HIV-infected patients

简介（由申请人提供）：该候选人是马里兰大学医学院人类病毒学研究所（IHV）医学和传染病助理教授。候选人的长期目标是成为一名独立的临床研究者，专门研究HIV感染的体液免疫领域。该建议的目的是为候选人提供适当的工具和环境来实现这一目标。IHV建立的前提是在临床医生和实验室研究人员之间建立强有力的合作氛围，以促进将基础科学发现转化为临床相关应用。通过来自IHV基础科学（疫苗部）和临床研究部门的研究人员的指导，以及以免疫学为重点的职业发展计划，候选人将获得在学术医学领域建立独立职业的坚实基础。候选人的短期目标包含在研究计划中，如下所示。人类一旦感染HIV-1就永远无法完全清除，这一生物学现实阻碍了针对HIV-1的疫苗研制工作；因此，发现体液保护的免疫相关性已被证明是困难的。然而，在艾滋病毒感染人群中，大约1%的人可以在不使用抗逆转录病毒药物的情况下有效地将病毒的复制控制在最低水平。我们最近描述了这样一组HIV-1感染个体，自然病毒抑制者（NVS）。NVS和类似的队列（精英控制者）代表了对HIV-1自然免疫的最佳可用模型。到目前为止，大部分的研究重点都放在血浆中的循环抗体上。然而，正如我们将证明的那样，标准化血浆中和可能无法提供这些个体的准确综合图像。相比之下，记忆B细胞提供了宿主一生中体液反应的档案记录。该提议的具体假设是，有效的体液免疫（记忆B细胞频率和源自记忆B细胞抗体的中和）与NVS（但与hiv对照组无关）中观察到的HIV-1病毒抑制相关。我们建议对记忆B细胞进行详细的抗体分析（存档所有抗体），而不是对NVS（不使用药物控制病毒的hiv感染者）中的循环池（通常测试的）进行详细的抗体分析，将揭示记忆B细胞抗体与NVS之间的关联。如果这是正确的，那么NVS将成为设计HIV疫苗抗体部分的抗体控制模型。

DESCRIPTION (provided by applicant): The candidate is an Assistant Professor of Medicine and Infectious Diseases at the Institute of Human Virology (IHV) at the University of Maryland School of Medicine. The candidate's long-term goal is to become an independent clinical investigator specializing in the field of humoral immunity in HIV infection. The purpose of this proposal is to provide the candidate with the appropriate tools and environment to reach this goal. The IHV was built on the premise of bringing a strong collaborative atmosphere between clinicians and laboratory researchers to promote translating basic scientific discoveries into clinically relevant applications. Through the mentorship of researchers from both the basic science (Vaccine Division) and clinical research divisions of the IHV, along with a career development program focused on Immunology, the candidate will receive a solid foundation upon which to build an independent career in academic medicine. The candidate's short-term goals are encapsulated in the research proposal, which is presented below. Vaccine efforts for HIV-1 have been hampered by the biological reality that humans can never completely clear HIV-1 once infected; consequently, finding immune correlates of humoral protection have proven to be difficult. However, within the HIV-infected population, about 1% can effectively control the replication of the virus to minimal levels without antiretrovirals. We have recently described such a cohort of HIV-1 infected individuals, Natural Viral Suppressors (NVS). The NVS and similar cohorts (Elite Controllers) represent the best available model of natural immunity to HIV-1. Much of the research focus until now has been placed on circulating antibodies in the plasma. However, as we will demonstrate, standardized plasma neutralization may not provide an accurate composite picture in these individuals. By contrast, memory B cells provide an archival record of humoral responses for the lifetime of the host. The specific hypothesis of this proposal is that effective humoral immunity (memory B cell frequency and neutralization derived from memory B cell antibodies), correlates with the HIV-1 viral suppression seen in the NVS (but not HIV-controls). We propose that detailed antibody analysis of memory B cells (which archive every antibody ever made) rather than the circulating pool (what is normally tested) in the NVS (HIV-infected persons who control the virus without medication) will reveal an association between memory B cell antibodies and being NVS. If this is correct, then NVS will be a model of antibody control for designing the antibody part of an HIV vaccine.