National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, Jilin, China.
Department of Medicine, Duke Human Vaccine Institute, Duke University Medical Center, 303 Research Dr., 244 Sands Building, DUMC 102359, Durham, NC, 27710, USA.
Retrovirology. 2017 Oct 10;14(1):46. doi: 10.1186/s12977-017-0371-4.
Mutations rapidly accumulate in the HIV-1 genome after infection. Some of those mutations are selected by host immune responses and often cause viral fitness losses. This study is to investigate whether strongly selected mutations that are not associated with immune responses result in fitness losses.
Strongly selected mutations were identified by analyzing 5'-half HIV-1 genome (gag/pol) sequences from longitudinal samples of subject CH0131. The K43R mutation in the gag gene was first detected at day 91 post screening and was fixed in the viral population at day 273 while the synonymous N323tc mutation was first detected at day 177 and fixed at day 670. No conventional or cryptic T cell responses were detected against either mutation sites by ELISpot analysis. However, when fitness costs of both mutations were measured by introducing each mutation into their cognate transmitted/founder (T/F) viral genome, the K43R mutation caused a significant fitness loss while the N323tc mutation had little impact on viral fitness.
The rapid fixation, the lack of detectable immune responses and the significant fitness cost of the K43R mutation suggests that it was strongly selected by host factors other than T cell responses and neutralizing antibodies.
HIV-1 基因组在感染后迅速积累突变。其中一些突变被宿主免疫反应选择，通常会导致病毒适应性降低。本研究旨在探讨是否存在与免疫反应无关的强选择突变导致适应性降低。
通过分析纵向样本中 CH0131 受试者的 5'-半 HIV-1 基因组（gag/pol）序列，鉴定出强选择突变。 gag 基因中的 K43R 突变于筛查后第 91 天首次检测到，并在第 273 天固定在病毒群体中，而同义 N323tc 突变于第 177 天首次检测到，并于第 670 天固定。ELISpot 分析未检测到针对任一突变位点的常规或隐匿性 T 细胞反应。然而，当通过将每个突变引入其同源传播/原始（T/F）病毒基因组来测量这两种突变的适应性成本时，K43R 突变导致显著的适应性降低，而 N323tc 突变对病毒适应性几乎没有影响。
K43R 突变的快速固定、缺乏可检测的免疫反应以及显著的适应性成本表明，它是由宿主因素而不是 T 细胞反应和中和抗体选择的。
