Chaillon Antoine, Nakazawa Masato, Wertheim Joel O, Little Susan J, Smith Davey M, Mehta Sanjay R, Gianella Sara
Department of Medicine, University of California-San Diego, La Jolla, California, USA
Department of Medicine, University of California-San Diego, La Jolla, California, USA.
J Virol. 2017 Oct 13;91(21). doi: 10.1128/JVI.00769-17. Print 2017 Nov 1.
During primary HIV infection, the presence of minority drug resistance mutations (DRM) may be a consequence of sexual transmission, mutations, or technical errors in identification. Baseline blood samples were collected from 24 HIV-infected antiretroviral-naive, genetically and epidemiologically linked source and recipient partners shortly after the recipient's estimated date of infection. An additional 32 longitudinal samples were available from 11 recipients. Deep sequencing of HIV reverse transcriptase (RT) was performed (Roche/454), and the sequences were screened for nucleoside and nonnucleoside RT inhibitor DRM. The likelihood of sexual transmission and persistence of DRM was assessed using Bayesian-based statistical modeling. While the majority of DRM (>20%) were consistently transmitted from source to recipient, the probability of detecting a minority DRM in the recipient was not increased when the same minority DRM was detected in the source (Bayes factor [BF] = 6.37). Longitudinal analyses revealed an exponential decay of DRM (BF = 0.05) while genetic diversity increased. Our analysis revealed no substantial evidence for sexual transmission of minority DRM (BF = 0.02). The presence of minority DRM during early infection, followed by a rapid decay, is consistent with the "mutation-selection balance" hypothesis, in which deleterious mutations are more efficiently purged later during HIV infection when the larger effective population size allows more efficient selection. Future studies using more recent sequencing technologies that are less prone to single-base errors should confirm these results by applying a similar Bayesian framework in other clinical settings. The advent of sensitive sequencing platforms has led to an increased identification of minority drug resistance mutations (DRM), including among antiretroviral therapy-naive HIV-infected individuals. While transmission of DRM may impact future therapy options for newly infected individuals, the clinical significance of the detection of minority DRM remains controversial. In the present study, we applied deep-sequencing techniques within a Bayesian hierarchical framework to a cohort of 24 transmission pairs to investigate whether minority DRM detected shortly after transmission were the consequence of (i) sexual transmission from the source, (ii) emergence shortly after infection followed by viral selection and evolution, or (iii) technical errors/limitations of deep-sequencing methods. We found no clear evidence to support the sexual transmission of minority resistant variants, and our results suggested that minor resistant variants may emerge shortly after transmission, when the small effective population size limits efficient purge by natural selection.
在原发性HIV感染期间，少数耐药性突变（DRM）的存在可能是性传播、突变或鉴定过程中的技术错误所致。在估计感染日期后不久，从24对基因和流行病学相关的HIV感染初治抗逆转录病毒治疗的源伴侣和接受者伴侣中采集基线血样。另外还从11名接受者处获得了32份纵向样本。对HIV逆转录酶（RT）进行了深度测序（罗氏/454），并对序列进行了核苷和非核苷RT抑制剂DRM筛查。使用基于贝叶斯的统计模型评估DRM的性传播可能性和持续性。虽然大多数DRM（>20%）从源持续传播到接受者，但当在源中检测到相同的少数DRM时，在接受者中检测到少数DRM的概率并未增加（贝叶斯因子[BF]=6.37）。纵向分析显示DRM呈指数衰减（BF=0.05），而遗传多样性增加。我们的分析没有发现支持少数DRM性传播的实质性证据（BF=0.02）。早期感染期间少数DRM的存在，随后迅速衰减，与“突变-选择平衡”假说一致，即在HIV感染后期，当较大的有效种群规模允许更有效的选择时，有害突变会更有效地被清除。未来使用更不易出现单碱基错误的最新测序技术的研究，应通过在其他临床环境中应用类似的贝叶斯框架来证实这些结果。敏感测序平台的出现导致了少数耐药性突变（DRM）的识别增加，包括在初治抗逆转录病毒治疗的HIV感染个体中。虽然DRM的传播可能会影响新感染个体未来的治疗选择，但检测到少数DRM的临床意义仍存在争议。在本研究中，我们在贝叶斯层次框架内将深度测序技术应用于24对传播对的队列，以研究传播后不久检测到的少数DRM是否是以下原因导致的：（i）来自源的性传播；（ii）感染后不久出现，随后是病毒选择和进化；或（iii）深度测序方法的技术错误/局限性。我们没有发现明确的证据支持少数耐药变异的性传播，我们的结果表明，少数耐药变异可能在传播后不久出现，此时较小的有效种群规模限制了自然选择的有效清除。
