Development of a low inoculum SHIV challenge model

低接种量 SHIV 挑战模型的开发

• 批准号: 6591368
• 负责人: Silvija I Staprans
• 金额: $ 40万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-01 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6591368
• 关键词: AIDS education /prevention; HIV infections; Macaca nemestrina; active immunization; communicable disease transmission; disease /disorder model; dosage; drug screening /evaluation; immunity; interdisciplinary collaboration; model design /development; simian immunodeficiency virus; virus replication

DESCRIPTION (provided by applicant): There is an urgent need to develop effective and implementable strategies to prevent HIV infection. Given the lack of a vaccine, and that half of all infections occur in women, development of an HIV-inhibiting microbicide is a growing priority. Consensus exists that an effective microbicide may be feasible. Simian AIDS models have helped guide the development and prioritization of HIV prevention strategies. However, current models may not provide realistic pre-clinical tests of HIV prevention efficacy. The viral inoculum sizes used to infect macaques exceed those that humans are exposed to, and may lead to underestimation of the efficacy of HIV preventions. The small inocula associated with most human HIV transmission events, combined with the likely stochastic nature of early infection events, may even make HIV transmission particularly susceptible to intervention. This proposal brings together investigators with expertise in the mathematical analysis of HIV transmission events, simian AIDS model development, and AIDS virology and immunology, to develop a challenge model that better recapitulates HIV transmission. The model uses intravaginal inoculation with low doses of a CCR5-utilizing SHIV. Overall hypotheses: 1) Low-dose inocula, applied repeatedly, will achieve experimental SHIV infection with enough reproducibility so that prevention efficacy studies could be performed; power analyses predict that the animal numbers required to demonstrate efficacy are similar to those used in current high-dose challenge models, and 2) A low-dose challenge model will provide a more sensitive, physiologically relevant measure of the efficacy of microbicides, vaccines or other preventions. Efficacy would be demonstrated by showing that an intervention increases the number of challenges required to achieve infection, compared to controls. Specific aims: 1) Define the animal infectious dose 50% (ID50) for SHIV-SF162P inoculation of pig-tailed macaques, and 2) Determine whether repeated challenges with the ID50 result in reproducible infection. If validated, this low dose model could help define relevant correlates of protection, and would be ideal for testing the efficacy of HIV microbicides, vaccines, and pre-exposure prophylaxis strategies. Efficacy measures obtained in the low dose model could be compared to those obtained in 'high virus challenge' models, to see if the low-dose model detects efficacy that is masked by high virus inocula.

描述（由申请人提供）：迫切需要制定有效且可实施的策略来预防艾滋病毒感染。 由于缺乏疫苗，而且一半的感染发生在女性中，开发抑制艾滋病毒的杀菌剂已成为当务之急。人们一致认为有效的杀微生物剂可能是可行的。 猿猴艾滋病模型有助于指导艾滋病毒预防策略的制定和优先排序。然而，当前的模型可能无法提供艾滋病毒预防功效的现实临床前测试。用于感染猕猴的病毒接种量超过了人类接触的病毒接种量，可能导致低估艾滋病毒预防的功效。与大多数人类艾滋病毒传播事件相关的小接种量，加上早期感染事件可能具有的随机性，甚至可能使艾滋病毒传播特别容易受到干预。该提案汇集了在艾滋病毒传播事件数学分析、猿猴艾滋病模型开发以及艾滋病病毒学和免疫学方面具有专业知识的研究人员，以开发一个更好地概括艾滋病毒传播的挑战模型。该模型使用低剂量的利用 CCR5 的 SHIV 进行阴道内接种。总体假设：1）低剂量接种，反复应用，将实现具有足够重复性的实验性SHIV感染，以便进行预防效果研究；功效分析预测，证明功效所需的动物数量与当前高剂量攻击模型中使用的动物数量相似，并且 2) 低剂量攻击模型将为杀菌剂、疫苗或药物的功效提供更灵敏、生理相关的测量方法。其他预防措施。与对照相比，干预措施增加了实现感染所需的挑战数量，从而证明了其有效性。具体目标：1) 定义猪尾猕猴接种 SHIV-SF162P 的动物感染剂量 50% (ID50)，2) 确定 ID50 的重复攻击是否会导致可重复感染。如果得到验证，这种低剂量模型可以帮助定义保护的相关相关性，并且非常适合测试 HIV 杀菌剂、疫苗和暴露前预防策略的功效。可以将低剂量模型中获得的功效测量与“高病毒攻击”模型中获得的功效进行比较，以观察低剂量模型是否检测到被高病毒接种物掩盖的功效。