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

评估对无细胞和细胞间传播中和的不同敏感性是否会影响抗体赋予免受 SHIV 感染的保护

• 批准号: 10404668
• 负责人: Matthew Sidney Parsons
• 金额: $ 21.31万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-15 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10404668
• 关键词: AIDS prevention; Address; Adherence; Animals; Antibodies; Binding; Blocking Antibodies; Cell model; Cells; Characteristics; Clinical Trials; Contracts; Cytoprotection; Data; Development; Development Plans; Dose; Drug toxicity; Exposure to; Fc Receptor; Glycoproteins; Goals; HIV; HIV Infections; Human; IgG1; In Vitro; Individual; Infection; Infection prevention; Intravenous; Liquid substance; Macaca; Macaca mulatta; Mediating; Modeling; Monitor; Mucous Membrane; Mutate; Mutation; Oral; Outcome; Passive Immunization; Passive Transfer of Immunity; Pathway interactions; Persons; Phagocytosis; Physiological; Plasma; Predisposition; Prevention approach; Prevention strategy; Primates; Process; Prophylactic treatment; Research; Research Personnel; Risk; Satellite Viruses; Vaccination; Vagina; Variant; Viral; Viremia; Virion; Virus; Virus Diseases; Work; antibody-dependent cell cytotoxicity; antiretroviral therapy; base; career development; cost; design; high risk; in vitro Assay; in vivo; mutant; neutralizing antibody; nonhuman primate; passive antibodies; pre-clinical; pre-exposure prophylaxis; prevent; rectal; seroconversion; side effect; simian human immunodeficiency virus; tool; transmission process; viral DNA; viral RNA

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.

项目摘要/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预防HIV 策略。然而，由于多个问题，许多感染艾滋病毒的高风险个人没有接受PrEP， 包括潜在的药物毒性、依从性和成本。因此，有必要开发更多的安全和 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接种疫苗提供或诱导抗病毒中和抗体。 中和抗体在预防HIV感染方面的效用已经在非人类灵长类动物中得到验证。 被动转移的抗体保护非人灵长类动物免受口腔、阴道、直肠和静脉注射的伤害 与猴人类免疫缺陷病毒(SIV)的挑战。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清除受感染的细胞或病毒粒子 依赖函数。临床前非人类灵长类中和抗体研究中一个经常被忽视的问题 对新城疫病毒挑战的保护是人类感染艾滋病毒是接触 含有无细胞病毒和细胞相关病毒的感染性体液。引发新艾滋病毒的病毒 感染被称为传播型方正(TF)病毒。细胞体外中和评估的初步数据- 使用PGT121抗HIV病毒的TFHIV信封的SHIV面板的游离和细胞间传播 中和抗体。对于其中几种病毒，PGT121完全中和了无细胞传播，但没有 中和细胞间的传播。这项拟议的研究将评估是否有明显的中和无细胞和细胞到细胞- 细胞病毒传播影响中和抗体预防体内病毒暴露后感染的能力。 这项工作将使用一种转移因子SHIVBG505，在恒河猴中执行无细胞或细胞相关的挑战 注射了PGT121的猕猴、同型对照或具有去除/减少Fc的PGT121版本 依赖函数。中心假设是：(I)PGT121将防止无细胞SHIVBG505后的感染 (Ii)PGT121不能预防细胞相关SHIVBG505挑战后的感染；及(Iii)Fc 依赖功能将有助于无细胞或与细胞相关的SHIVBG505挑战的结果。这些 假说将通过三个具体目标进行评估：(I)评估PGT121是否保护恒河猴免受 用无细胞SHIVBG505挑战；(Ii)评估PGT121是否保护恒河猴免受细胞挑战- 相关的SHIVBG505；和(Iii)确定FC依赖功能对无细胞或 细胞相关SHIVBG505在PGT121输注猕猴中的挑战。生成的数据将有助于 开发以抗体为基础的艾滋病毒预防工具，对艾滋病毒的特征进行完善的定义 获得保护所需的中和抗体。这项工作将在耶尔克斯国家灵长类动物完成 研究中心，是应聘者职业发展计划的关键部分。候选人的长期目标 就是完全转型为独立调查员。