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预防前预防（PREP）是一种非常有效的生物医学HIV预防 战略。但是，许多因多个问题而受到艾滋病毒收购高风险的人没有收到准备， 包括潜在的药物毒性，依从性和成本。因此，有必要开发额外的安全和 有效的生物医学艾滋病毒预防策略。目前正在开发的主要预防策略包括 通过被动免疫或疫苗接种分别提供或诱导抗病毒中和抗体。 在非人类灵长类动物中已经验证了中和抗体预防HIV感染的效用。 被动转移的抗体可保护非人类灵长类动物免受口服，阴道，直肠和静脉注射 猿猴人类免疫缺陷病毒（SHIV）面临的挑战。抗体提供保护的主要原因是 封锁病毒进入过程，但也可能涉及通过抗体FC消除感染的细胞或病毒体 依赖功能。中和抗体的临床前非人类灵长类动物研究中经常被忽视的问题 避免SHIV挑战的保护是人类艾滋病毒感染是暴露于 含有无细胞和相关病毒的感染性身体液。引发新艾滋病毒的病毒 感染称为传播创始人（TF）病毒。初步数据评估了细胞的体外中和 使用PGT121抗HIV的一组湿aiv的湿婆板板的自由和细胞对细胞传播 中和抗体。对于其中几种病毒，PGT121完全中和无细胞的扩散，但没有 中和细胞间扩散。拟议的研究将评估无细胞和细胞至细胞的明显中和是否明显 细胞病毒扩散会影响中和抗体防止体内病毒暴露后感染的能力。 这项工作将使用TF Shivs之一Shivbg505在恒河猴中执行无细胞或相关的挑战 猕猴注入了PGT121，同种型控制或PGT121的版本，废除/减少FC 依赖功能。中心假设是：（i）PGT121将防止无细胞SHIVBG505后感染 挑战; （ii）PGT121不会防止在与细胞相关的SHIVBG505挑战之后感染；和（iii）FC 依赖功能将有助于无细胞或相关的SHIVBG505挑战的结果。这些 假设将在三个具体目标上进行评估：（i）评估PGT121是否保护猕猴免受 无细胞的Shivbg505挑战； （ii）评估PGT121是否保护恒河猕猴免受细胞的挑战 相关的shivbg505; （iii）确定FC依赖功能对无细胞或无细胞结果的影响 PGT121中与细胞相关的SHIVBG505挑战。生成的数据将有助于 开发基于抗体的艾滋病毒预防工具，通过提供对特征的精致定义 实现保护所需的中和抗体。这项工作将在Yerkes国家灵长类 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 是完全过渡到独立的研究者。