Assessing if distinct susceptibility to neutralization of cell-free and cell-to-cell spread impacts antibody conferred protection from SHIV infection

项目总结/摘要 基于抗逆转录病毒治疗的暴露前预防（PrEP）是一种高效的生物医学HIV预防方法 战略然而，许多艾滋病毒感染高风险的人由于多种问题而没有接受PrEP， 包括潜在的药物毒性、依从性和成本。因此，需要开发额外的安全且 有效的生物医学艾滋病毒预防战略。目前正在制定的主要预防战略包括 分别通过被动免疫或疫苗接种提供或诱导抗病毒中和抗体。 中和抗体用于预防HIV感染的效用已在非人灵长类动物中得到验证。 被动转移抗体保护非人灵长类动物免受口服，阴道，直肠和静脉注射 人类免疫缺陷病毒（SHIV）抗体提供的保护主要是由于 阻断病毒进入过程，但也可涉及通过抗体Fc消除感染的细胞或病毒体 依赖函数非人灵长类动物中和抗体临床前研究中一个常被忽视的问题 保护免受SHIV攻击的一个重要原因是人类HIV感染是暴露于 含有无细胞和细胞相关病毒的传染性体液。引发新艾滋病毒的病毒 感染被称为传播的创始者（TF）病毒。初步数据评估体外细胞中和- 使用PGT 121抗HIV抗体，一组具有TF HIV包膜的SHIV的游离和细胞间扩散 中和抗体对于这些病毒中的几种，PGT 121完全中和无细胞扩散，但不 中和细胞间的传播拟议的研究将评估无细胞和细胞间的不同中和作用是否存在 细胞病毒扩散影响中和抗体在体内病毒暴露后预防感染的能力。 这项工作将使用TF SHIV之一SHIVBG 505在恒河猴中进行无细胞或细胞相关的挑战 输注PGT 121、同种型对照或Fc消除/减少的PGT 121形式的猕猴 依赖函数中心假设是：（I）PGT 121将预防无细胞SHIVBG 505后的感染 （II）PGT 121将不能预防细胞相关SHIVBG 505攻击后的感染;和（III）Fc 依赖性功能将有助于无细胞或细胞相关SHIVBG 505攻击的结果。这些 将在三个具体目标上评估假设：（I）评估PGT 121是否保护恒河猴免于 （II）评估PGT 121是否保护恒河猴免受无细胞SHIVBG 505的攻击; 相关SHIVBG 505的影响;和（III）确定Fc依赖性功能对无细胞或 在PGT 121输注的恒河猴中的细胞相关SHIVBG 505攻击。生成的数据将有助于 开发基于抗体的艾滋病毒预防工具，通过提供对 需要中和抗体来实现保护。这项工作将在耶基斯国家灵长类动物中心完成 研究中心是候选人职业发展计划的关键部分。候选人的长期目标 就是完全转变成一名独立调查员

PROJECT SUMMARY/ABSTRACT Antiretroviral therapy-based pre-exposure prophylaxis (PrEP) is a highly effective biomedical HIV prevention strategy. However, many individuals at high risk of HIV acquisition are not receiving PrEP due to multiple issues, including potential drug toxicity, adherence and cost. As such, there is a need to develop additional safe and effective biomedical HIV prevention strategies. Major prevention strategies currently in development include the provision or induction of anti-viral neutralizing antibodies by passive immunization or vaccination, respectively. The utility of neutralizing antibodies for preventing HIV infection has been validated in nonhuman primates. Passively transferred antibodies protect nonhuman primates from oral, vaginal, rectal and intravenous challenges with simian human immunodeficiency virus (SHIV). Antibody conferred protection is primarily due to blockade of the viral entry process but can also involve the elimination of infected cells or virions via antibody Fc dependent functions. An often overlooked issue in preclinical nonhuman primate studies of neutralizing antibody conferred protection from SHIV challenge is that human HIV infections are a consequence of exposure to infectious bodily fluids containing both cell-free and cell-associated virus. The viruses that initiate new HIV infections are termed transmitted founder (TF) viruses. Preliminary data assessed in vitro neutralization of cell- free and cell-to-cell spread of a panel of SHIVs with envelopes from TF HIVs using the PGT121 anti-HIV neutralizing antibody. For several of these viruses, PGT121 fully neutralized cell-free spread but did not neutralize cell-to-cell spread. The proposed research will assess if distinct neutralization of cell-free and cell-to- cell viral spread impacts the ability of a neutralizing antibody to prevent infection following in vivo viral exposure. This work will use one of the TF SHIVs, SHIVBG505, to perform cell-free or cell-associated challenges in rhesus macaques infused with PGT121, an isotype control or a version of PGT121 with abrogated/diminished Fc dependent functions. The central hypotheses are: (I) PGT121 will prevent infection following cell-free SHIVBG505 challenge; (II) PGT121 will not prevent infection following cell-associated SHIVBG505 challenge; and (III) Fc dependent functions will contribute to the outcomes of cell-free or cell-associated SHIVBG505 challenges. These hypotheses will be evaluated across three specific aims: (I) assess if PGT121 protects rhesus macaques from challenge with cell-free SHIVBG505; (II) assess if PGT121 protects rhesus macaques from challenge with cell- associated SHIVBG505; and (III) determine the impact of Fc dependent functions on the outcome of cell-free or cell-associated SHIVBG505 challenges in PGT121 infused rhesus macaques. Generated data will contribute to the development of antibody-based HIV prevention tools, by providing a refined definition of the characteristics of neutralizing antibodies required to achieve protection. This work will be done at the Yerkes National Primate Research Center and is a key piece of the candidate's career development plan. The candidate's long-term goal is to fully transition into an independent investigator.