Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
National Institute for Communicable Diseases, a division of the National Health Laboratory Service, Johannesburg, South Africa.
Nat Commun. 2024 Aug 22;15(1):7240. doi: 10.1038/s41467-024-51539-8.
Previous studies have linked the evolution of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) genetic variants to persistent infections in people with immunocompromising conditions, but the processes responsible for these observations are incompletely understood. Here we use high-throughput, single-genome amplification and sequencing (HT-SGS) to sequence SARS-CoV-2 spike genes from people with HIV (PWH, n = 22) and people without HIV (PWOH, n = 25). In PWOH and PWH with CD4 T cell counts (i.e., CD4 counts) ≥ 200 cells/μL, we find that most SARS-CoV-2 genomes sampled in each person share one spike sequence. By contrast, in people with advanced HIV infection (i.e., CD4 counts < 200 cells/μL), HT-SGS reveals a median of 46 distinct linked groupings of spike mutations per person. Elevated intra-host spike diversity in people with advanced HIV infection is detected immediately after COVID-19 symptom onset, and early intra-host spike diversity predicts SARS-CoV-2 shedding duration among PWH. Analysis of longitudinal timepoints reveals rapid fluctuations in spike sequence populations, replacement of founder sequences by groups of new haplotypes, and positive selection at functionally important residues. These findings demonstrate remarkable intra-host genetic diversity of SARS-CoV-2 in advanced HIV infection and suggest that adaptive intra-host SARS-CoV-2 evolution in this setting may contribute to the emergence of new variants of concern.
先前的研究将严重急性呼吸综合征冠状病毒 2 型（SARS-CoV-2）遗传变异与免疫功能低下人群的持续性感染联系起来，但这些观察结果的发生过程仍不完全清楚。在这里，我们使用高通量、单基因组扩增和测序（HT-SGS）技术，对 22 名 HIV 感染者（PWH）和 25 名无 HIV 感染者（PWOH）的 SARS-CoV-2 刺突基因进行测序。在 PWOH 和 CD4 计数（即 CD4 计数）≥200 个/μL 的 PWH 中，我们发现每个人体内采样的大多数 SARS-CoV-2 基因组共享一个刺突序列。相比之下，在 HIV 感染晚期的人群中（即 CD4 计数 < 200 个/μL），HT-SGS 显示每个人平均有 46 个不同的刺突突变相关分组。在 HIV 感染晚期人群中，SARS-CoV-2 感染者体内的刺突多样性升高是在 COVID-19 症状出现后立即检测到的，并且早期的体内刺突多样性可预测 HIV 感染者的 SARS-CoV-2 脱落持续时间。对纵向时间点的分析揭示了刺突序列群体的快速波动、由新单倍型群体取代创始人序列以及功能重要残基的正选择。这些发现表明，在 HIV 感染晚期，SARS-CoV-2 存在显著的体内遗传多样性，并表明在这种情况下，适应性的 SARS-CoV-2 体内进化可能有助于新关注变异株的出现。
