Kearney Mary F, Spindler Jonathan, Shao Wei, Yu Sloane, Anderson Elizabeth M, O'Shea Angeline, Rehm Catherine, Poethke Carry, Kovacs Nicholas, Mellors John W, Coffin John M, Maldarelli Frank
HIV-1 Drug Resistance Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America.
Advanced Biomedical Computing Center, SAIC, Frederick, Maryland, United States of America.
PLoS Pathog. 2014 Mar 20;10(3):e1004010. doi: 10.1371/journal.ppat.1004010. eCollection 2014 Mar.
A better understanding of changes in HIV-1 population genetics with combination antiretroviral therapy (cART) is critical for designing eradication strategies. We therefore analyzed HIV-1 genetic variation and divergence in patients' plasma before cART, during suppression on cART, and after viral rebound. Single-genome sequences of plasma HIV-1 RNA were obtained from HIV-1 infected patients prior to cART (N = 14), during suppression on cART (N = 14) and/or after viral rebound following interruption of cART (N = 5). Intra-patient population diversity was measured by average pairwise difference (APD). Population structure was assessed by phylogenetic analyses and a test for panmixia. Measurements of intra-population diversity revealed no significant loss of overall genetic variation in patients treated for up to 15 years with cART. A test for panmixia, however, showed significant changes in population structure in 2/10 patients after short-term cART (<1 year) and in 7/10 patients after long-term cART (1-15 years). The changes consisted of diverse sets of viral variants prior to cART shifting to populations containing one or more genetically uniform subpopulations during cART. Despite these significant changes in population structure, rebound virus after long-term cART had little divergence from pretherapy virus, implicating long-lived cells infected before cART as the source for rebound virus. The appearance of genetically uniform virus populations and the lack of divergence after prolonged cART and cART interruption provide strong evidence that HIV-1 persists in long-lived cells infected before cART was initiated, that some of these infected cells may be capable of proliferation, and that on-going cycles of viral replication are not evident.
更好地理解联合抗逆转录病毒疗法（cART）下HIV-1群体遗传学的变化对于设计根除策略至关重要。因此，我们分析了HIV-1感染患者在接受cART之前、cART治疗期间病毒被抑制时以及病毒反弹后的血浆中的HIV-1基因变异和分化情况。从HIV-1感染患者中获取了血浆HIV-1 RNA的单基因组序列，这些患者分别处于接受cART之前（N = 14）、cART治疗期间病毒被抑制时（N = 14）和/或cART中断后病毒反弹时（N = 5）。通过平均成对差异（APD）来测量患者体内的群体多样性。通过系统发育分析和随机交配检验来评估群体结构。群体内多样性的测量结果显示，接受cART治疗长达15年的患者总体基因变异没有显著损失。然而，随机交配检验显示，短期cART（<1年）后，10名患者中有2名的群体结构发生了显著变化；长期cART（1 - 15年）后，10名患者中有7名的群体结构发生了显著变化。这些变化包括cART之前的各种病毒变体转变为cART期间包含一个或多个基因均一亚群的群体。尽管群体结构发生了这些显著变化，但长期cART后的反弹病毒与治疗前病毒的差异很小，这表明cART之前感染的长寿细胞是反弹病毒的来源。长期cART及cART中断后基因均一病毒群体的出现以及缺乏差异，有力地证明了HIV-1在cART开始之前感染的长寿细胞中持续存在，其中一些感染细胞可能具有增殖能力，并且病毒复制的持续循环并不明显。
