Division of Infectious Diseases, Department of Medicine, Stanford University, Stanford, CA 94305, USA.
Institute for Genomics and Evolutionary Medicine, Temple University, Philadelphia, PA 19122, USA.
Viruses. 2023 Apr 18;15(4):992. doi: 10.3390/v15040992.
With the approval of the HIV-1 capsid inhibitor, lenacapavir, capsid sequencing will be required for managing lenacapavir-experienced individuals with detectable viremia. Successful sequence interpretation will require examining new capsid sequences in the context of previously published sequence data.
We analyzed published HIV-1 group M capsid sequences from 21,012 capsid-inhibitor naïve individuals to characterize amino acid variability at each position and influence of subtype and cytotoxic T lymphocyte (CTL) selection pressure. We determined the distributions of usual mutations, defined as amino acid differences from the group M consensus, with a prevalence ≥ 0.1%. Co-evolving mutations were identified using a phylogenetically-informed Bayesian graphical model method.
162 (70.1%) positions had no usual mutations (45.9%) or only conservative usual mutations with a positive BLOSUM62 score (24.2%). Variability correlated independently with subtype-specific amino acid occurrence (Spearman rho = 0.83; < 1 × 10) and the number of times positions were reported to contain an HLA-associated polymorphism, an indicator of CTL pressure (rho = 0.43; = 0.0002).
Knowing the distribution of usual capsid mutations is essential for sequence quality control. Comparing capsid sequences from lenacapavir-treated and lenacapavir-naïve individuals will enable the identification of additional mutations potentially associated with lenacapavir therapy.
随着 HIV-1 衣壳抑制剂 lenacapavir 的批准，需要对有可检测病毒血症的 lenacapavir 经验个体进行衣壳测序，以进行管理。成功的序列解释需要在先前发表的序列数据的背景下检查新的衣壳序列。
我们分析了来自 21012 名衣壳抑制剂初治个体的已发表的 HIV-1 组 M 衣壳序列，以描述每个位置的氨基酸变异性以及亚型和细胞毒性 T 淋巴细胞 (CTL) 选择压力的影响。我们确定了通常突变的分布，定义为与组 M 共识氨基酸差异的频率≥0.1%。使用基于系统发育的贝叶斯图形模型方法确定共进化突变。
162 个（70.1%）位置没有通常的突变（45.9%）或只有带正 BLOSUM62 评分的保守通常突变（24.2%）。变异性与亚型特异性氨基酸出现（Spearman rho = 0.83；<1×10）和报告包含 HLA 相关多态性的位置次数独立相关，这是 CTL 压力的指标（rho = 0.43；<0.0002）。
了解通常衣壳突变的分布对于序列质量控制至关重要。比较 lenacapavir 治疗和 lenacapavir 初治个体的衣壳序列，将能够识别可能与 lenacapavir 治疗相关的其他突变。
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