Susceptibility of HIV-1 Subtypes B′, CRF07_BC and CRF01_AE that Are Predominantly Circulating in China to HIV-1 Entry Inhibitors

Xiaoling Yu,Lin Yuan,Lin Yuan,Yiming Shao,Yiming Shao,Shuwen Liu,Shibo Jiang,Shibo Jiang,Shibo Jiang,Yang Huang,Yang Huang,Weisi Xu,Liying Ma,Liying Ma,Zhiming Fang,Zhiming Fang,Robert Geraghty

doi:10.1371/journal.pone.0017605

Abstract

BackgroundThe B′, CRF07_BC and CRF01_AE are the predominant HIV-1 subtypes in China. It is essential to determine their baseline susceptibility to HIV entry inhibitors before these drugs are used in China.Methodology/Principal FindingsThe baseline susceptibility of 14 representative HIV-1 isolates (5 CRF07_BC, 4 CRF01_AE, and 5 B′), most of which were R5 viruses, obtained from drug-naïve patients to HIV entry inhibitors, including two fusion inhibitors (enfuvirtide and C34), two CCR5 antagonists (maraviroc and TAK779) and one CXCR4 antagonist (AMD3100), were determined by virus inhibition assay. The sequences of their env genes were amplified and analyzed. These isolates possessed similar susceptibility to C34, but they exhibited different sensitivity to enfuvirtide, maraviroc or TAK779. CRF07_BC isolates, which carried polymorphisms of A578T and V583I in the N-terminal heptad repeat and E630Q, E662A, K665S, A667K and S668N in the C-terminal heptad repeat of gp41, were about 5-fold less sensitive than B′ and CRF01_AE isolates to enfuvirtide. Subtype B′ isolates with a unique polymorphism site of F317W in V3 loop, were about 4- to 5-fold more sensitive than CRF07_BC and CRF01_AE isolates to maraviroc and TAK779. AMD3100 at the concentration as high as 5 µM exhibited no significant inhibitory activity against any of the isolates tested.ConclusionOur results suggest that there are significant differences in baseline susceptibility to HIV entry inhibitors among the predominant HIV-1 subtypes in China and the differences may partly result from the naturally occurring polymorphisms in these subtypes. This study provides useful information for rational design of optimal therapeutic regimens for HIV-1-infected patients in China.

Highlights

The human immunodeficiency virus type 1 (HIV-1) can be classified to three major groups, M, O and N
The HIV-1 entry inhibitors can be classified into three groups, including i) attachment inhibitors (e.g., NBD556 and BMS378806) that block the interaction between the HIV-1 envelope glycoprotein (Env) surface subunit gp120 and CD4 receptor by targeting to the CD4-binding site on gp120; ii) co-receptor antagonists, which block the interaction ligand between gp120 and CCR5 (e.g., UK427857 and TAK779) or CXCR4 (e.g., AMD3100); and iii) HIV1 fusion inhibitors [9,10]
The present study aims to test the baseline susceptibility of the predominant HIV-1 subtypes circulating in China to HIV entry inhibitors and characterize the genotype polymorphisms in these subtypes

Summary

Introduction

The human immunodeficiency virus type 1 (HIV-1) can be classified to three major groups, M (major), O (outlier) and N (nonM non-O or new). The M group, which has caused the vast majority of HIV-1 infections worldwide, can be further divided into several subtypes, including A–D, F–H, J and K, as well as several circulating and unique recombinant forms (CRFs and URFs) [1,2]. The greatest genetic diversity of HIV-1 subtypes has been found in China. HIV-1 subtype B9 ( known as Thai B), CRF07_BC (BC) and CRF01_AE (AE) are the predominant circulating viruses in China [3,4]. HIV-1 infection is established after viral entry into the target cell [5]. The B9, CRF07_BC and CRF01_AE are the predominant HIV-1 subtypes in China.

Methods

Results

Discussion

Conclusion