Molecular Evolution of HIV-1 CRF01_AE Env in Thai Patients

BackgroundThe envelope glycoproteins (Env), gp120 and gp41, are the most variable proteins of human immunodeficiency virus type 1 (HIV-1), and are the major targets of humoral immune responses against HIV-1. A circulating recombinant form of HIV-1, CRF01_AE, is prevalent throughout Southeast Asia; however, only limited information regarding the immunological characteristics of CRF01_AE Env is currently available. In this study, we attempted to examine the evolutionary pattern of CRF01_AE Env under the selection pressure of host immune responses. Methodology/Principal FindingsPeripheral blood samples were collected periodically over 3 years from 15 HIV-1-infected individuals residing in northern Thailand, and amplified env genes from the samples were subjected to computational analysis. The V5 region of gp120 showed highest variability in several samples over 3 years, whereas the V1/V2 and/or V4 regions of gp120 also showed high variability in many samples. In addition, the N-terminal part of the C3 region of gp120 showed highest amino acid diversity among the conserved regions of gp120. Chronological changes in the numbers of amino acid residues in gp120 variable regions and potential N-linked glycosylation (PNLG) sites are involved in increasing the variability of Env gp120. Furthermore, the C3 region contained several amino acid residues potentially under positive selection, and APOBEC3 family protein-mediated G to A mutations were frequently detected in such residues. Conclusions/SignificanceSeveral factors, including amino acid substitutions particularly in gp120 C3 and V5 regions as well as changes in the number of PNLG sites and in the length of gp120 variable regions, were revealed to be involved in the molecular evolution of CRF01_AE Env. In addition, a similar tendency was observed between CRF01_AE and subtype C Env with regard to the amino acid variation of gp120 V3 and C3 regions. These results may provide important information for understanding the immunological characteristics of CRF01_AE Env.

研究背景：包膜糖蛋白（Env）gp120与gp41是1型人类免疫缺陷病毒（HIV-1）中变异性最强的蛋白，亦是针对HIV-1的体液免疫应答的主要靶标。HIV-1循环重组型CRF01_AE在东南亚地区广泛流行，但目前关于CRF01_AE Env的免疫学特征的相关研究信息仍较为匮乏。本研究旨在探究宿主免疫应答选择压力下CRF01_AE Env的进化模式。
方法与结果：研究人员从泰国北部15名HIV-1感染者身上定期采集外周血样本，随访时长达3年，并对样本中扩增得到的env基因开展生物信息学分析。在3年随访周期内的多份样本中，gp120的V5区变异性最高；同时gp120的V1/V2区及/或V4区在多数样本中也呈现出较高变异性。此外，在gp120的保守区域中，gp120 C3区的N末端片段的氨基酸多样性最为显著。gp120可变区氨基酸残基数量与潜在N-糖基化（PNLG）位点的时序性变化，可导致Env gp120的变异性升高。进一步研究发现，C3区存在若干可能处于正向选择压力下的氨基酸残基，且APOBEC3家族蛋白介导的G→A突变在这些残基位点中频繁出现。
结论与意义：本研究揭示，若干因素参与了CRF01_AE Env的分子进化过程，其中包括gp120 C3区与V5区的氨基酸替换、PNLG位点数量变化，以及gp120可变区长度改变。此外，在gp120 V3区与C3区的氨基酸变异模式上，CRF01_AE与HIV-1 C亚型Env呈现出相似的趋势。本研究结果可为阐明CRF01_AE Env的免疫学特征提供重要参考依据。