Identification of novel molecular determinants of co-receptor usage in HIV-1 subtype F V3 envelope sequences

Maximiliano Distefano,María Florencia Fernández,Esteban Lanzarotti,Paula Aulicino,Andrea Mangano,Marcelo Martí

doi:10.1038/s41598-020-69408-x

Abstract

HIV-1 determinants of coreceptor usage within the gp120 V3 loop have been broadly studied over the past years. This information has led to the development of state-of the-art bioinformatic tools that are useful to predict co-receptor usage based on the V3 loop sequence mainly of subtypes B, C and A. However, these methods show a poor performance for subtype F V3 loops, which are found in an increasing number of HIV-1 strains worldwide. In the present work we investigated determinants of viral tropisms in the understudied subtype F by looking at genotypic and structural information of coreceptor:V3 loop interactions in a novel group of 40 subtype F V3 loops obtained from HIV-1 strains phenotypically characterized either as syncytium inducing or non-syncytium inducing by the MT-2 assay. We provide novel information about estimated interactions energies between a set of V3 loops with known tropism in subtype F, that allowed us to improve predictions of the coreceptor usage for this subtype. Understanding genetic and structural features underlying HIV coreceptor usage across different subtypes is relevant for the rational design of preventive and therapeutic strategies aimed at limiting the HIV-1 epidemic worldwide.

Highlights

Human immunodeficiency virus type 1 (HIV-1) determinants of coreceptor usage within the gp[120] V3 loop have been broadly studied over the past years
Determinants of HIV-1 coreceptor usage have been widely studied in subtype B viruses
By using HIV-1 V3 loop V3 structures defined by Tamammis et al[18,19], we modelled for the first time a set of V3 loop subtype F sequences obtained from syncytium inducing (SI) (X4-using) and non-syncytium inducing (NSI) (R5-using) viruses

Summary

Introduction

HIV-1 determinants of coreceptor usage within the gp[120] V3 loop have been broadly studied over the past years This information has led to the development of state-of the-art bioinformatic tools that are useful to predict co-receptor usage based on the V3 loop sequence mainly of subtypes B, C and A. These methods show a poor performance for subtype F V3 loops, which are found in an increasing number of HIV-1 strains worldwide. Determinants that govern coreceptor usage have been mapped to the envelope gene, especially to the variable regions, and in particular the gp[120] V3 loop This has led to the development of multiple rules and algorithms that allow prediction of coreceptor usage based on V3 sequence information. Improved predictions for several non-B subtypes were obtained by using subtype-specific training sets for the development of the GTT tools

Methods

Results

Conclusion