HIV-1 亚型 C 的 Nef 介导的 SERINC5 下调显著促进了 Nef 的整体活性。

HIV-1 subtype C Nef-mediated SERINC5 down-regulation significantly contributes to overall Nef activity.

机构信息

HIV Pathogenesis Programme, The Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, 4001, South Africa.

Chantal BIYA International Reference Centre for Research on HIV/AIDS Prevention and Management (CIRCB), P.O. Box 3077, Yaoundé, Cameroon.

出版信息

Retrovirology. 2023 Mar 31;20(1):3. doi: 10.1186/s12977-023-00618-7.

DOI:10.1186/s12977-023-00618-7

PMID:37004071

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10067162/

Abstract

BACKGROUND

Nef performs multiple cellular activities that enhance HIV-1 pathogenesis. The role of Nef-mediated down-regulation of the host restriction factor SERINC5 in HIV-1 pathogenesis is not well-defined. We aimed to investigate if SERINC5 down-regulation activity contributes to HIV-1 subtype C disease progression, to assess the relative contribution of this activity to overall Nef function, and to identify amino acids required for optimal activity. We measured the SERINC5 down-regulation activity of 106 subtype C Nef clones, isolated from individuals in early infection, for which the Nef activities of CD4 and HLA-I down-regulation as well as alteration of TCR signalling were previously measured. The relationship between SERINC5 down-regulation and markers of disease progression, and the relative contribution of SERINC5 down-regulation to a Nef fitness model-derived E value (a proxy for overall Nef fitness in vivo), were assessed.

RESULTS

No overall relationship was found between SERINC5 down-regulation and viral load set point (p = 0.28) or rate of CD4 T cell decline (p = 0.45). CD4 down-regulation (p = 0.02) and SERINC5 down-regulation (p = 0.003) were significant determinants of E values in univariate analyses, with the greatest relative contribution for SERINC5 down-regulation, and only SERINC5 down-regulation remained significant in the multivariate analysis (p = 0.003). Using a codon-by-codon analysis, several amino acids were significantly associated with increased (10I, 11V, 38D, 51T, 65D, 101V, 188H and, 191H) or decreased (10K, 38E, 65E, 135F, 173T, 176T and, 191R) SERINC5 down-regulation activity. Site-directed mutagenesis experiments of selected mutants confirmed a substantial reduction in SERINC5 down-regulation activity associated with the mutation 173T, while mutations 10K, 135F, and 176T were associated with more modest reductions in activity that were not statistically significant.

CONCLUSIONS

These results suggest that SERINC5 down-regulation is a significant contributor to overall Nef function and identify potential genetic determinants of this Nef function that may have relevance for vaccines or therapeutics.

摘要

背景

Nef 具有多种增强 HIV-1 发病机制的细胞活性。Nef 介导的宿主限制因子 SERINC5 下调在 HIV-1 发病机制中的作用尚不清楚。我们旨在研究 SERINC5 下调活性是否有助于 HIV-1 亚型 C 的疾病进展，评估该活性对整体 Nef 功能的相对贡献，并确定最佳活性所需的氨基酸。我们测量了从早期感染个体中分离的 106 个 HIV-1 亚型 C Nef 克隆的 SERINC5 下调活性，先前已测量了这些克隆的 CD4 和 HLA-I 下调以及 TCR 信号改变的 Nef 活性。评估了 SERINC5 下调与疾病进展标志物之间的关系，以及 SERINC5 下调相对于 Nef 适应度模型衍生的 E 值（体内整体 Nef 适应度的代理）的相对贡献。

结果

SERINC5 下调与病毒载量设定点（p=0.28）或 CD4 T 细胞下降率（p=0.45）之间没有总体关系。CD4 下调（p=0.02）和 SERINC5 下调（p=0.003）是单变量分析中 E 值的显著决定因素，SERINC5 下调的相对贡献最大，并且仅 SERINC5 下调在多变量分析中仍然显著（p=0.003）。使用密码子对密码子分析，发现几个氨基酸与增加的 SERINC5 下调活性（10I、11V、38D、51T、65D、101V、188H 和 191H）或减少的 SERINC5 下调活性（10K、38E、65E、135F、173T、176T 和 191R）显著相关。选定突变体的定点诱变实验证实与突变 173T 相关的 SERINC5 下调活性大幅降低，而突变 10K、135F 和 176T 与活性降低相关，但降低幅度不大且无统计学意义。