Contribution of the gp120 V3 loop to envelope glycoprotein trimer stability in primate immunodeficiency viruses

Dane Bowder,Haley Hollingsead,Kate Durst,Duoyi Hu,Wenzhong Wei,Joshua Wiggins,Halima Medjahed,Andrés Finzi,Joseph Sodroski,Shi-Hua Xiang

doi:10.1016/j.virol.2018.06.005

Abstract

The V3 loop of the human immunodeficiency virus type 1 (HIV-1) gp120 exterior envelope glycoprotein (Env) becomes exposed after CD4 binding and contacts the coreceptor to mediate viral entry. Prior to CD4 engagement, a hydrophobic patch located at the tip of the V3 loop stabilizes the non-covalent association of gp120 with the Env trimer of HIV-1 subtype B strains. Here, we show that this conserved hydrophobic patch (amino acid residues 307, 309 and 317) contributes to gp120-trimer association in HIV-1 subtype C, HIV-2 and SIV. Changes that reduced the hydrophobicity of these V3 residues resulted in increased gp120 shedding and decreased Env-mediated cell-cell fusion and virus entry in the different primate immunodeficiency viruses tested. Thus, the hydrophobic patch is an evolutionarily conserved element in the tip of the gp120 V3 loop that plays an essential role in maintaining the stability of the pre-triggered Env trimer in diverse primate immunodeficiency viruses.

Highlights

IntroductionThe third variable (V3) loop of the gp120 envelope glycoprotein (Env) on the surface of human immunodeficiency virus type 1 (HIV-1) becomes exposed after the virus binds CD4, the initial receptor; the V3 loop plays an important role in contacting the coreceptor CCR5 or CXCR4 to mediate viral entry (Cashin et al, 2013; Foda et al, 2001; Hartley et al, 2005; Hongjaisee et al, 2017; Huang et al, 2005; Jiang et al, 2010; Moore and Nara, 1991)
In some human immunodeficiency virus type 1 (HIV-1) strains, a single glycine residue insertion in the V3 loop can be lethal to the virus, a phenomenon that was first observed in primary HIV-1 subtype B viruses (Xiang et al, 2010)
Mutagenesis studies have implicated the V3 base and tip in contacting the CCR5 or CXCR4 coreceptors: the V3 base contributes to the interaction with the sulfated Nterminus of the coreceptor, whereas the V3 tip interacts with extracellular loop 2 (ECL2) of the coreceptor (Abayev et al, 2015; Arimont et al, 2017; Huang et al, 2007; Kufareva, 2016)

Summary

Introduction

The third variable (V3) loop of the gp120 envelope glycoprotein (Env) on the surface of human immunodeficiency virus type 1 (HIV-1) becomes exposed after the virus binds CD4, the initial receptor; the V3 loop plays an important role in contacting the coreceptor CCR5 or CXCR4 to mediate viral entry (Cashin et al, 2013; Foda et al, 2001; Hartley et al, 2005; Hongjaisee et al, 2017; Huang et al, 2005; Jiang et al, 2010; Moore and Nara, 1991). In available structural models of the HIV-1 Env trimer (Julien et al, 2013a; Lee et al, 2016; Lyumkis et al, 2013; Pancera et al, 2014), the V3 loop is located at the apex of the trimer along with the gp120 V1 and V2 variable regions. This apical location potentially allows the V3 loop to participate in interprotomer contacts that contribute to Env trimer stability. Substitution of hydrophobic residues near the V3 hydrophobic patch raised the melting temperature of soluble gp140 SOSIP.664 Env trimers (de Taeye et al, 2018, 2015)

Methods

Results

Conclusion