HIV-1 蛋白酶、Gag 和 gp41 基线替换与基于 PI 的方案的病毒学应答相关。

HIV-1 protease, Gag and gp41 baseline substitutions associated with virological response to a PI-based regimen.

机构信息

IAME, UMR 1137, INSERM, Université Paris Diderot, Sorbonne Paris Cité, AP-HP, Laboratoire de Virologie, Hôpital Bichat, AP-HP, Paris, France.

Sorbonne Université, INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), AP-HP, Hôpital Pitié-Salpêtrière, Laboratoire de Virologie, F-75013 Paris, France.

出版信息

J Antimicrob Chemother. 2019 Jun 1;74(6):1679-1692. doi: 10.1093/jac/dkz043.

DOI:10.1093/jac/dkz043

PMID:30768160

Abstract

OBJECTIVES

To assess, at ART initiation, the impact of baseline substitutions in protease, Gag and gp41 regions on the virological response to a first-line PI-based regimen.

PATIENTS AND METHODS

One hundred and fifty-four HIV-infected ART-naive patients initiating a PI-based regimen including darunavir (n = 129) or atazanavir (n = 25) were assessed, including 36 experiencing virological failure (VF). Whole pol, gag and gp41 genes were sequenced at ART baseline by ultra-deep sequencing (UDS) using Illumina® technology. Supervised data-mining analyses were performed to identify mutations associated with virological response. Structural analyses were performed to assess the impact of mutations on protease conformation.

RESULTS

UDS was successful in 127, 138 and 134 samples for protease, Gag and gp41, respectively (31% subtype B and 38% CRF02_AG). Overall, T4A and S37T mutations in protease were identified as being associated with VF (P = 0.02 and P = 0.005, respectively). Among CRF02_AG sequences, I72M and E21D mutations were associated with VF (P = 0.03 for both). They all induced some conformational changes of some protease side-chain residues located near mutated residues. In Gag, mutations associated with VF were G62D, N315H and Y441S (P = 0.005, P = 0.007 and P = 0.0003, respectively). All were localized outside Gag cleavage sites (G62D, matrix; N315H, capsid; and Y441S, p1). In gp41, the I270T mutation, localized in the cytoplasmic tail, was associated with VF (P = 0.003), and the I4L mutation, in the fusion peptide, was associated with virological success (P = 0.004).

CONCLUSIONS

In this study, new baseline substitutions in Gag, protease and g41, potentially impacting PI-based regimen outcome, were evidenced. Phenotypic analyses are required to confirm their role in the PI-resistance mechanism.

摘要

目的

在开始接受抗逆转录病毒治疗（ART）时，评估蛋白酶、 gag 和 gp41 区的基线替换对基于蛋白酶抑制剂（PI）的一线方案的病毒学反应的影响。

方法

对 154 名开始接受包括达芦那韦（n ⁇ ⁇ 129）或阿扎那韦（n ⁇ ⁇ 25）的基于 PI 的方案的 HIV 感染的、未经 ART 治疗的患者进行评估，其中 36 名患者发生了病毒学失败（VF）。采用 Illumina®技术的超深度测序（UDS）在 ART 基线时对完整 pol、 gag 和 gp41 基因进行测序。进行监督数据分析，以确定与病毒学反应相关的突变。进行结构分析，以评估突变对蛋白酶构象的影响。

结果

蛋白酶、 gag 和 gp41 分别有 127、138 和 134 个样本的 UDS 成功（31%为亚型 B，38%为 CRF02_AG）。总体而言，蛋白酶中的 T4A 和 S37T 突变被确定与 VF 相关（P ⁇ ⁇ 0.02 和 P ⁇ ⁇ 0.005，分别）。在 CRF02_AG 序列中，I72M 和 E21D 突变也与 VF 相关（两者均 P ⁇ ⁇ 0.03）。它们都诱导了一些位于突变残基附近的蛋白酶侧链残基的构象变化。在 gag 中，与 VF 相关的突变是 G62D、N315H 和 Y441S（P ⁇ ⁇ 0.005、P ⁇ ⁇ 0.007 和 P ⁇ ⁇ 0.0003，分别）。所有这些突变都位于 gag 切割位点之外（G62D，基质；N315H，衣壳；和 Y441S，p1）。在 gp41 中，位于细胞质尾巴中的 I270T 突变与 VF 相关（P ⁇ ⁇ 0.003），位于融合肽中的 I4L 突变与病毒学成功相关（P ⁇ ⁇ 0.004）。