University of Washington, Seattle, Washington, United States of America.
Seattle Children's Research Institute, Seattle, Washington, United States of America.
PLoS Med. 2018 Mar 27;15(3):e1002537. doi: 10.1371/journal.pmed.1002537. eCollection 2018 Mar.
Transmission of human immunodeficiency virus type 1 (HIV-1) drug resistance mutations, particularly that of minority drug-resistant variants, remains poorly understood. Population-based studies suggest that drug-resistant HIV-1 is less transmissible than drug-susceptible viruses. We compared HIV-1 drug-resistant genotypes among partner-pairs in order to assess the likelihood of transmission of drug resistance mutations and investigate the role of minority variants in HIV transmission.
From 1992-2010, 340 persons with primary HIV-1 infection and their partners were enrolled into observational research studies at the University of Washington Primary Infection Clinic (UWPIC). Out of 50 partner-pairs enrolled, 36 (72%) transmission relationships were confirmed by phylogenetic distance analysis of HIV-1 envelope (env) sequences, and 31 partner-pairs enrolled after 1995 met criteria for this study. Drug resistance mutations in the region of the HIV-1 polymerase gene (pol) that encodes protease and reverse transcriptase were assessed by 454-pyrosequencing. In 25 partner-pairs where the transmission direction could be determined, 12 (48%) transmitters had 1-4 drug resistance mutations (23 total) detected in their HIV-1 populations at a median frequency of 6.0% (IQR 1.5%-98.7%, range 1.0%-99.6%). Of 10 major mutations detected in five transmitters at a frequency >95%, 100% (95% CI 69.2%-100%) were detected in recipients. All of these transmitters were antiretroviral (ARV)-naïve at the time of specimen collection. Fourteen mutations (eight major mutations and six accessory mutations) were detected in nine transmitters at low frequencies (1.0%-11.8%); four of these transmitters had previously received ARV therapy. Two (14% [95% CI 1.8%-42.8%]) G73S accessory mutations were detected in both transmitter and recipient. This number is not significantly different from the number expected based on the observed frequencies of drug-resistant viruses in transmitting partners. Limitations of this study include the small sample size and uncertainties in determining the timing of virus transmission and mutation history.
Drug-resistant majority variants appeared to be commonly transmitted by ARV-naïve participants in our analysis and may contribute significantly to transmitted drug resistance on a population level. When present at low frequency, no major mutation was observed to be shared between partner-pairs; identification of accessory mutations shared within a pair could be due to transmission, laboratory artifact, or apolipoprotein B mRNA-editing enzyme, catalytic polypeptides (APOBECs), and warrants further study.
人类免疫缺陷病毒 1 型（HIV-1）耐药突变的传播，特别是少数耐药变异体的传播，仍知之甚少。基于人群的研究表明，耐药性 HIV-1 的传染性低于敏感性病毒。我们比较了伴侣对中 HIV-1 耐药基因型，以评估耐药突变传播的可能性，并研究少数变异体在 HIV 传播中的作用。
1992 年至 2010 年，340 名初次感染 HIV-1 的患者及其伴侣在华盛顿大学初次感染诊所（UWPIC）参加了观察性研究。在 50 对伴侣中，有 36 对（72%）通过 HIV-1 包膜（env）序列的系统进化距离分析确认了传播关系，1995 年后有 31 对符合本研究标准。通过 454 焦磷酸测序评估了 HIV-1 聚合酶基因（pol）中编码蛋白酶和逆转录酶的区域的耐药突变。在可确定传播方向的 25 对伴侣中，12 对（48%）传播者的 HIV-1 群体中检测到 1-4 种耐药突变（共 23 种），中位频率为 6.0%（IQR 1.5%-98.7%，范围 1.0%-99.6%）。在 5 个传播者中检测到频率 >95%的 10 个主要突变中，100%（95%CI 69.2%-100%）在接受者中被检测到。所有这些传播者在采集标本时均未接受过抗逆转录病毒（ARV）治疗。在 9 个传播者中，有 14 种突变（8 种主要突变和 6 种辅助突变）以低频率（1.0%-11.8%）检测到；其中 4 个传播者以前接受过 ARV 治疗。两个（14%[95%CI 1.8%-42.8%]）G73S 辅助突变在传播者和接受者中均被检测到。这一数字与根据传播伙伴中耐药病毒的观察频率预测的数量没有显著差异。本研究的局限性包括样本量小，以及确定病毒传播和突变史时间的不确定性。
在我们的分析中，似乎 ARV-初治参与者普遍传播耐药性优势变异体，并且可能对人群耐药传播产生重大影响。当以低频率存在时，未观察到主要突变在伴侣之间共享；在一对中发现共享的辅助突变可能是由于传播、实验室假象或载脂蛋白 B mRNA 编辑酶、催化多肽（APOBECs）引起的，需要进一步研究。
