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极大的推广。虽然这种广泛的抗逆转录病毒疗法的分布大大降低了与艾滋病毒/艾滋病相关的死亡率，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%的人在开始治疗的12个月内经历了病毒学失败。其中53%到90%的病毒具有临床上重要的HIV-1耐药性突变。因此，抗逆转录病毒耐药性是全球控制艾滋病毒-1的主要威胁之一。由于非核苷类逆转录酶抑制剂(NNRTI)的广泛使用，在撒哈拉以南非洲地区，NNRTI耐药性显著增加，并传播了NNRTI耐药性。尽管在未接受治疗的�患者和有经验的艾滋病毒感染者中，耐NNRTI变异体的出现频率不断上升，但下一代二芳基嘧啶类NNRTIs-达匹韦林(TMC120)、依特拉韦林(ETV)和利培韦林(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艾滋病毒-1感染。事实上，许多撒哈拉以南非洲国家已经有机会获得教育电视，这种电视已被批准用于治疗有艺术经验的个人的艾滋病毒感染。RIL是与恩曲他滨和替诺福韦共同开发的，正在等待批准，作为撒哈拉以南非洲的一线ART方案。一种长效RIL制剂也在开发中，作为暴露前预防性制剂，用于资源有限的环境。最后，ASPIRE研究目前正在评估TMC120是否可以安全地预防HIV-1感染，如果TMC120通过每月更换一次硅胶环在阴道内持续释放。大多数关于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，有越来越多的证据表明耐药亚型存在差异。因此，本项目的主要目标是研究RIL、ETV和TMC120在非B亚型病毒中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.