Differential evolution of a CXCR4-using HIV-1 strain in CCR5wt/wt and CCR5∆32/∆32 hosts revealed by longitudinal deep sequencing and phylogenetic reconstruction.

Anh Q Le,Jeremy Taylor,Winnie Dong,Kanna Hayashi,Art F Y Poon,Ryan Danroth,M.-J Milloy,Conan Woods,Rosemary Mccloskey,Zabrina L Brumme

doi:10.1038/srep17607

Anh Q Le, Jeremy Taylor + Show 8 more

Open Access

https://doi.org/10.1038/srep17607

Copy DOI

Abstract

Rare individuals homozygous for a naturally-occurring 32 base pair deletion in the CCR5 gene (CCR5∆32/∆32) are resistant to infection by CCR5-using (“R5”) HIV-1 strains but remain susceptible to less common CXCR4-using (“X4”) strains. The evolutionary dynamics of X4 infections however, remain incompletely understood. We identified two individuals, one CCR5wt/wt and one CCR5∆32/∆32, within the Vancouver Injection Drug Users Study who were infected with a genetically similar X4 HIV-1 strain. While early-stage plasma viral loads were comparable in the two individuals (~4.5–5 log10 HIV-1 RNA copies/ml), CD4 counts in the CCR5wt/wt individual reached a nadir of <20 CD4 cells/mm3 within 17 months but remained >250 cells/mm3 in the CCR5∆32/∆32 individual. Ancestral phylogenetic reconstructions using longitudinal envelope-V3 deep sequences suggested that both individuals were infected by a single transmitted/founder (T/F) X4 virus that differed at only one V3 site (codon 24). While substantial within-host HIV-1 V3 diversification was observed in plasma and PBMC in both individuals, the CCR5wt/wt individual’s HIV-1 population gradually reverted from 100% X4 to ~60% R5 over ~4 years whereas the CCR5∆32/∆32 individual’s remained consistently X4. Our observations illuminate early dynamics of X4 HIV-1 infections and underscore the influence of CCR5 genotype on HIV-1 V3 evolution.

Highlights

Entry of human immunodeficiency virus type-1 (HIV-1) into target cells occurs via binding of the viral envelope protein gp[120] to the host CD4 receptor[1] followed by binding to chemokine coreceptors CCR5 or CXCR4 on the host cell surface[2,3]
Acknowledging the possibility that the two individuals could represent a transmission pair, we investigated the frequency of the CCR5∆32/∆32 individual’s T/F virus sequence in the CCR5wt/wt individual’s plasma and peripheral blood mononuclear cells (PBMC) (Fig. 5a,b)
We performed longitudinal HIV-1 env-V3 deep sequencing and ancestral phylogenetic reconstruction to study infection and subsequent diversification of a highly genetically similar X4 HIV-1 strain in CCR5wt/wt and CCR5∆32/∆32 hosts

Summary

Introduction

Entry of human immunodeficiency virus type-1 (HIV-1) into target cells occurs via binding of the viral envelope protein gp[120] to the host CD4 receptor[1] followed by binding to chemokine coreceptors CCR5 or CXCR4 on the host cell surface[2,3]. Acquisition of X4 HIV-1 variants at transmission is less common: recent studies estimate that X4/dual tropic strains comprise between 3–23% of primary infections[18,19,20,21,22,23]. Phylogenetic ancestral reconstruction techniques can been applied to longitudinal single-template HIV-1 sequence datasets–even those sampled weeks or months following infection–to estimate infection dates, reconstruct T/F virus sequences and study within-host HIV-1 evolution in detail[11,47,48,49]. We apply longitudinal next-generation sequencing and phylogenetic approaches to study a far more rare occurrence: a case where two individuals-one CCR5wt/wt and one CCR5∆32/∆32–were infected with a highly genetically similar X4 HIV-1 strain

Methods

Results

Conclusion