Faculty of Health Sciences, Simon Fraser University, Burnaby, Canada.
HIV Pathogenesis Programme, The Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa.
PLoS Pathog. 2020 Sep 14;16(9):e1008813. doi: 10.1371/journal.ppat.1008813. eCollection 2020 Sep.
HIV Nef counteracts cellular host restriction factors SERINC3 and SERINC5, but our understanding of how naturally occurring global Nef sequence diversity impacts these activities is limited. Here, we quantify SERINC3 and SERINC5 internalization function for 339 Nef clones, representing the major pandemic HIV-1 group M subtypes A, B, C and D. We describe distinct subtype-associated hierarchies for Nef-mediated internalization of SERINC5, for which subtype B clones display the highest activities on average, and of SERINC3, for which subtype B clones display the lowest activities on average. We further identify Nef polymorphisms that modulate its ability to counteract SERINC proteins, including substitutions in the N-terminal domain that selectively impair SERINC3 internalization. Our findings demonstrate that the SERINC antagonism activities of HIV Nef differ markedly among major viral subtypes and between individual isolates within a subtype, suggesting that variation in these functions may contribute to global differences in viral pathogenesis.
HIV Nef 拮抗细胞宿主限制因子 SERINC3 和 SERINC5，但我们对天然存在的全球 Nef 序列多样性如何影响这些活性的理解有限。在这里，我们定量了 339 个 Nef 克隆的 SERINC3 和 SERINC5 内化功能，这些克隆代表了主要的大流行 HIV-1 组 M 亚型 A、B、C 和 D。我们描述了 Nef 介导的 SERINC5 内化的不同亚型相关层次结构，其中 B 亚型克隆的平均活性最高，以及 SERINC3 的内化，其中 B 亚型克隆的平均活性最低。我们进一步确定了调节其拮抗 SERINC 蛋白能力的 Nef 多态性，包括选择性损害 SERINC3 内化的 N 端结构域中的取代。我们的研究结果表明，HIV Nef 的 SERINC 拮抗活性在主要病毒亚型之间以及同一亚型内的不同分离株之间存在显著差异，这表明这些功能的变异可能导致病毒发病机制的全球差异。
