title: 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.
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/mm(3) within 17 months but remained >250 cells/mm(3) 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.
authors.affiliation: Faculty of Health Sciences, Simon Fraser University, Burnaby, Canada.
authors.forename: Anh Q
authors.initials: AQ
authors.lastname: Le
authors.affiliation: British Columbia Centre for Excellence in HIV/AIDS, Vancouver, Canada.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Taylor
authors.affiliation: British Columbia Centre for Excellence in HIV/AIDS, Vancouver, Canada.
authors.forename: Winnie
authors.initials: W
authors.lastname: Dong
authors.affiliation: British Columbia Centre for Excellence in HIV/AIDS, Vancouver, Canada.
authors.forename: Rosemary
authors.initials: R
authors.lastname: McCloskey
authors.affiliation: British Columbia Centre for Excellence in HIV/AIDS, Vancouver, Canada.
authors.forename: Conan
authors.initials: C
authors.lastname: Woods
authors.affiliation: Faculty of Health Sciences, Simon Fraser University, Burnaby, Canada.
authors.forename: Ryan
authors.initials: R
authors.lastname: Danroth
authors.affiliation: British Columbia Centre for Excellence in HIV/AIDS, Vancouver, Canada.|Department of Medicine, University of British Columbia, Vancouver, Canada.
authors.forename: Kanna
authors.initials: K
authors.lastname: Hayashi
authors.affiliation: British Columbia Centre for Excellence in HIV/AIDS, Vancouver, Canada.|Department of Medicine, University of British Columbia, Vancouver, Canada.
authors.forename: M-J
authors.initials: MJ
authors.lastname: Milloy
authors.affiliation: Faculty of Health Sciences, Simon Fraser University, Burnaby, Canada.|British Columbia Centre for Excellence in HIV/AIDS, Vancouver, Canada.|Department of Medicine, University of British Columbia, Vancouver, Canada.
authors.forename: Art F Y
authors.initials: AF
authors.lastname: Poon
authors.affiliation: Faculty of Health Sciences, Simon Fraser University, Burnaby, Canada.|British Columbia Centre for Excellence in HIV/AIDS, Vancouver, Canada.
authors.forename: Zabrina L
authors.initials: ZL
authors.lastname: Brumme
mesh_terms: D005075:Biological Evolution; D018791:CD4 Lymphocyte Count; D015699:HIV Envelope Protein gp120 / Q000235:genetics; D015658:HIV Infections / Q000235:genetics / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000472:pathogenicity*; D059014:High-Throughput Nucleotide Sequencing; D054884:Host-Pathogen Interactions; D006801:Humans; D007963:Leukocytes, Mononuclear; D010446:Peptide Fragments / Q000235:genetics; D010802:Phylogeny; D012367:RNA, Viral; D019713:Receptors, CCR5 / Q000235:genetics* / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D019562:Viral Load
chemical_list: C584933:CCR5 protein, human; C527276:CXCR4 protein, human; D015699:HIV Envelope Protein gp120; C059762:HIV envelope protein gp120 (305-321); D010446:Peptide Fragments; D012367:RNA, Viral; D019713:Receptors, CCR5; D019718:Receptors, CXCR4