Novel mechanisms of HIV resistance to RTIs

描述（由申请人提供）：在过去的十年中，抗逆转录病毒疗法（ART）在全球范围内得到了巨大的推广。尽管抗逆转录病毒疗法的广泛分布大大降低了艾滋病毒/艾滋病相关死亡率，但目前的数据表明，在撒哈拉以南非洲接受一线抗逆转录病毒疗法的人中，高达24%的人在开始治疗后12个月内出现病毒学失败。其中53%至90%的病毒具有临床重要的HIV-1耐药性突变。因此，抗逆转录病毒药物耐药性是全球控制HIV-1的主要威胁之一。由于非核苷类逆转录酶（RT）抑制剂（NNRTI）的广泛使用，在撒哈拉以南非洲地区，NNRTI耐药性和传播的NNRTI耐药性显著增加。尽管ART初治和经历过HIV感染的个体中存在的NNRTI耐药变体频率不断上升，但下一代二芳基嘧啶（DAPY）NNRTI-达匹韦林（TMC 120），依曲韦林（ETV）和利匹韦林（RIL） 预计将越来越多地用于在资源有限的情况下治疗和预防HIV-1感染。事实上，许多撒哈拉以南非洲国家已经可以使用ETV，该药物已被批准用于治疗有抗逆转录病毒治疗经验的人的艾滋病毒感染。与恩曲他滨和替诺福韦共同配制的RIL正在等待批准作为撒哈拉以南非洲的一线ART方案。长效RIL制剂也在开发中，作为用于资源有限环境的暴露前预防剂。最后，ASPIRE研究目前正在评估TMC 120是否可以安全地预防HIV-1感染，当从每月更换一次的硅胶环中持续释放时。大多数对HIV-1耐药性的研究都集中在B亚型病毒上，但全球90%的感染是由非B亚型病毒株引起的。重要的是，越来越多的证据表明耐药性的亚型差异。因此，本项目的主要目标是研究非B亚型病毒中RIL、ETV和TMC 120的耐药和交叉耐药途径。

DESCRIPTION (provided by applicant): The past decade has seen an enormous global scale-up of antiretroviral therapy (ART). Although this widespread distribution of ART has dramatically reduced HIV/AIDs-related mortality, current data suggests that up to 24% of individuals receiving 1st-line ART in sub-Saharan Africa experience virologic failure within 12 months of initiation of therapy. Between 53 to 90% of these have viruses with clinically important HIV-1 drug resistance mutations. As such, antiretroviral drug resistance is one of the main threats to the global control of HIV-1. Due to the extensive use of nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs), there has been a significant increase in NNRTI drug resistance, and transmitted NNRTI drug resistance, in regions of sub-Saharan Africa. Despite the escalating frequency of NNRTI-resistant variants present in ART-na�ve and - experienced HIV-infected individuals, the next-generation diarylpyrimidine (DAPY) NNRTIs - dapivirine (TMC120), etravirine (ETV) and rilpivirine (RIL) are expected to be increasingly used for the treatment and prevention of HIV-1 infection in resource-limited settings. Indeed, many sub-Saharan Africa countries already have access to ETV, which has been approved for the treatment of HIV-infection in ART-experienced individuals. RIL, which has been co-formulated with emtricitabine and tenofovir, is pending approval as a 1st- line ART regimen in sub-Saharan Africa. A long-acting RIL formulation is also in development as a pre- exposure prophylaxis agent for use in resource-limited settings. Finally, the ASPIRE study is currently assessing whether TMC120 can safely prevent HIV-1 infection when continuously released in the vagina from a silicone ring replaced once a month. The majority of research into HIV-1 drug resistance has focused on subtype B viruses, yet non-subtype B strains are responsible for 90% of global infections. Importantly, there is increasing evidence of subtype differences in drug resistance. As such, the primary goals of this project are to study the resistance and cross-resistance pathways for RIL, ETV and TMC120 in non-subtype B viruses.