PDF(Pubmed)
Abstract：
Combinational antiretroviral therapy (cART) is the most effective tool to prevent and control HIV-1 infection without an effective vaccine. However, HIV-1 drug resistance mutations (DRMs) and naturally occurring polymorphisms (NOPs) can abrogate cART efficacy. Here, we aimed to characterize the HIV-1 pol mutation landscape in Cameroon, where highly diverse HIV clades circulate, and identify novel treatment-associated mutations that can potentially affect cART efficacy. More than 8,000 functional Cameroonian HIV-1 pol sequences from 1987 to 2020 were studied for DRMs and NOPs. Site-specific amino acid frequencies and quaternary structural features were determined and compared between periods before (≤2003) and after (2004-2020) regional implementation of cART. cART usage in Cameroon induced deep mutation imprints in reverse transcriptase (RT) and to a lower extent in protease (PR) and integrase (IN), according to their relative usage. In the predominant circulating recombinant form (CRF) 02_AG (CRF02_AG), 27 canonical DRMs and 29 NOPs significantly increased or decreased in RT during cART scale-up, whereas in IN, no DRM and only seven NOPs significantly changed. The profound genomic imprints and higher prevalence of DRMs in RT compared to PR and IN mirror the dominant use of reverse transcriptase inhibitors (RTIs) in sub-Saharan Africa and the predominantly integrase strand transfer inhibitor (InSTI)-naïve study population. Our results support the potential of InSTIs for antiretroviral treatment in Cameroon; however, close surveillance of IN mutations will be required to identify emerging resistance patterns, as observed in RT and PR. Population-wide genomic analyses help reveal the presence of selective pressures and viral adaptation processes to guide strategies to bypass resistance and reinstate effective treatment.
摘要：
联合抗逆转录病毒疗法（cART）是在没有有效疫苗的情况下预防和控制HIV-1感染的最有效工具。然而,HIV-1耐药突变（DRMs）和自然发生的多态性（NOPs）可以消除cART功效。这里,我们旨在描述喀麦隆的HIV-1pol突变情况，高度多样化的艾滋病毒分支在那里传播，并鉴定可能影响cART疗效的新型治疗相关突变。从1987年到2020年，研究了8,000多个功能性喀麦隆HIV-1pol序列的DRM和NOP。确定并比较了cART区域实施之前（≤2003年）和之后（2004-2020年）的特定位置氨基酸频率和四级结构特征。cART在喀麦隆的使用诱导了逆转录酶（RT）和蛋白酶（PR）和整合酶（IN）的深度突变印记，根据他们的相对用法。在主要的循环重组形式（CRF）02_AG（CRF02_AG）中，在cART放大期间，RT中有27个规范的DRM和29个NOP显着增加或减少，而在IN,没有DRM，只有七个NOP发生了重大变化。与PR和IN相比，RT中DRM的深刻基因组印记和更高的患病率反映了逆转录酶抑制剂（RTIs）在撒哈拉以南非洲和主要是整合酶链转移抑制剂（InSTI）-幼稚研究人群中的主要使用。我们的结果支持InSTIs在喀麦隆抗逆转录病毒治疗的潜力；然而，需要密切监测IN突变，以识别新出现的耐药模式，如在RT和PR中观察到的。全人群基因组分析有助于揭示选择性压力和病毒适应过程的存在，以指导绕过耐药性和恢复有效治疗的策略。
