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

描述（由申请人提供）：候选人是马里兰州医学院人类病毒学研究所（IHV）的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人员，专门从事HIV感染的体液免疫领域。本建议书旨在为候选人提供实现这一目标的适当工具和环境。IHV建立在临床医生和实验室研究人员之间形成强大合作氛围的前提下，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（疫苗部门）和临床研究部门的研究人员的指导，沿着以免疫学为重点的职业发展计划，候选人将获得坚实的基础，在此基础上建立独立的学术医学职业生涯。候选人的短期目标概括在研究建议中，如下所示。HIV-1的疫苗接种工作受到生物学现实的阻碍，即人类一旦感染HIV-1就永远无法完全清除;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，约有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复制控制在最低水平。我们最近描述了这样一组HIV-1感染者，天然病毒抑制剂（NVS）。NVS和类似的队列（精英控制者）代表了对HIV-1天然免疫的最佳可用模型。到目前为止，大部分研究重点都放在血浆中的循环抗体上。然而，正如我们将要证明的那样，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应答的档案记录。该建议的具体假设是有效的体液免疫（记忆B细胞频率和来自记忆B细胞抗体的中和）与NVS中观察到的HIV-1病毒抑制相关（但不是HIV对照）。我们建议对记忆B细胞（它保存了所有产生的抗体）而不是NVS（HIV感染者，他们不用药物就能控制病毒）中的循环池（通常检测的）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.