Visualization of in vivo HIV-1 vaginal transmission in the presence and absence of PrEP

 描述（由申请方提供）：在缺乏有效疫苗的情况下，在人类免疫缺陷病毒1型（HIV-1）暴露前给予抗逆转录病毒药物（暴露前预防或PrEP）可能是保护高危HIV阴性个体免受感染的可靠方法。每日口服替诺福韦和FTC（Truvada）目前已被批准用于高风险个体的PrEP，但迄今为止在人体临床试验中的成功有限，主要是由于依从性问题。 阿匹韦林（RPV）是最近批准用于HIV-1抗逆转录病毒治疗（ART）的逆转录酶抑制剂。在RPV治疗失败的患者中检测到的耐药突变主要对RPV产生低水平耐药，RPV对其他药物选择的大多数突变体具有活性。RPV已被配制成可注射的长效纳米颗粒（RPV-LA），用作由医疗保健提供者管理的长效PrEP。在PrEP过程中RPV耐药变异体的耐药性或传播的发展以前没有得到解决，特别是它们对随后的ART的影响。最近描述了一个病例，一名妇女在RPV-LA治疗期间感染HIV-1，随后在亚治疗血浆RPV浓度的存在下发展出RPV耐药病毒。我们建议使用一种新的动物模型，在存在和不存在治疗浓度和亚治疗浓度的RPV-LA PrEP或Truvada的情况下，研究野生型（WT）HIV-1和耐药变体的阴道传播，该模型还将使我们能够实时研究女性生殖道中感染和传播的动态。 使用创新的新报告病毒系统和充分表征的人源化小鼠模型，我们假设对RPV和Truvada（E138 K/M184 I）均耐药的流行HIV-1突变体将在不存在药物和存在Truvada PrEP的情况下传播，但在存在治疗性RPV-LA浓度的情况下，将导致生殖道中局部CD 4+靶细胞的流产感染。然而，耐药HIV-1的传播或发展将导致随后的ART期间更快的病毒学失败。

 DESCRIPTION (provided by applicant): In the absence of an effective vaccine, administration of antiretroviral drugs prior to human immunodeficiency virus type 1 (HIV-1) exposure (pre-exposure prophylaxis or PrEP) may be a reliable method to protect high-risk HIV-negative individuals from infection. Daily oral tenofovir and FTC (Truvada) is currently approved for use as PrEP in high-risk individuals but has had limited success in human clinical trials to date, mainly due to adherence issues. Rilpivirine (RPV) is the most recent reverse transcriptase inhibitor approved for antiretroviral therapy (ART) for HIV-1. Drug-resistant mutations detected in patients failing RPV-containing regimens conferred mainly low-level resistance to RPV and RPV is active against most mutants selected by other drugs. RPV has been formulated into injectable long-acting nanoparticles (RPV-LA) for use as long-lasting PrEP to be administered by healthcare providers. Development of resistance or transmission of RPV-resistant variants during PrEP has not been previously addressed, particularly their impact on subsequent ART. A case has recently been described of a woman who became HIV-1-infected during RPV-LA treatment and subsequently developed RPV-resistant virus in the presence of sub-therapeutic plasma RPV concentration. We propose to investigate vaginal transmission of wild-type (WT) HIV-1 and drug-resistant variants in the presence and absence of therapeutic and subtherapeutic concentrations of RPV-LA PrEP or Truvada, using a novel animal model that will also allow us to investigate the dynamics of infection and dissemination in the female genital tract in real-time. Using an innovative new reporter virus system and a well-characterized humanized mouse model, we hypothesize that a prevalent HIV-1 mutant resistant to both RPV and Truvada (E138K/M184I) will be transmitted in the absence of drug and in the presence of Truvada PrEP, but will lead to an abortive infection of local CD4+ target cells in the genital trac in the presence of therapeutic RPV-LA concentrations. However, transmission or development of drug-resistant HIV-1 will lead to faster virologic failure during subsequent ART.