Differential evolution of a CXCR4-using HIV-1 strain in CCR5wt/wt and CCR5δ32/δ32 hosts revealed by longitudinal deep sequencing and phylogenetic reconstruction

Abstract

Rare individuals homozygous for a naturally-occurring 32 base pair deletion in the CCR5 gene (CCR5δ32/δ32) 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 CCR5δ32/δ32, 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 log 10 HIV-1 RNA copies/ml), CD4 counts in the CCR5wt/wt individual reached a nadir of <20 CD4 cells/mm 3 within 17 months but remained >250 cells/mm 3 in the CCR5δ32/δ32 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 individuals HIV-1 population gradually reverted from 100% X4 to ∼60% R5 over ∼4 years whereas the CCR5δ32/δ32 individuals 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.