title: High intrapatient HIV-1 evolutionary rate is associated with CCR5-to-CXCR4 coreceptor switch.
abstract: In approximately 70% of individuals infected with HIV-1 subtype B, the virus switches coreceptor use from exclusively CCR5 use (R5 virus) to either inclusion of or exclusively CXCR4 use (X4 virus) during infection. This switch is associated with an accelerated loss of CD4(+) T-cells and a faster progression to AIDS. Despite intensive research, the mechanisms responsible for coreceptor switch remains elusive. In the present study, we investigated associations between viral evolutionary rate and selection pressure versus viral coreceptor use and rate of disease progression in eight patients with longitudinally sampled HIV-1 env V1-V3 sequences. By employing a Bayesian hierarchical phylogenetic model, we found that the HIV-1 evolutionary rate was more strongly associated with coreceptor switch than with rate of disease progression in terms of CD4(+)T-cell decline. Phylogenetic analyses showed that X4 variants evolved from R5 populations. In addition, coreceptor switch was associated with higher evolutionary rates on both the synonymous and non-synonymous substitution level, but not with dN/dS ratio rates. Our findings suggest that X4 viruses evolved from pre-existing R5 viral populations and that the evolution of coreceptor switch is governed by high replication rates rather than by selective pressure. Furthermore, the association of viral evolutionary rate was more strongly associated with coreceptor switch than disease progression. This adds to the understanding of the complex virus-host interplay that influences the evolutionary dynamics of HIV-1 coreceptor use.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden; Department of Virology, Swedish Institute for Infectious Disease Control, Solna, Sweden. Electronic address: mattias.mild@smi.se.
authors.forename: Mattias
authors.initials: M
authors.lastname: Mild
authors.forename: Rebecca R
authors.initials: RR
authors.lastname: Gray
authors.forename: Anders
authors.initials: A
authors.lastname: Kvist
authors.forename: Philippe
authors.initials: P
authors.lastname: Lemey
authors.forename: Maureen M
authors.initials: MM
authors.lastname: Goodenow
authors.forename: Eva Maria
authors.initials: EM
authors.lastname: Fenyö
authors.forename: Jan
authors.initials: J
authors.lastname: Albert
authors.forename: Marco
authors.initials: M
authors.lastname: Salemi
authors.forename: Joakim
authors.initials: J
authors.lastname: Esbjörnsson
authors.forename: Patrik
authors.initials: P
authors.lastname: Medstrand
mesh_terms: D001499:Bayes Theorem; D019143:Evolution, Molecular; D015658:HIV Infections / Q000378:metabolism* / Q000821:virology*; D015497:HIV-1 / Q000145:classification / Q000235:genetics* / Q000472:pathogenicity / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D010802:Phylogeny; D019713:Receptors, CCR5 / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D056189:Viral Tropism
chemical_list: D019713:Receptors, CCR5; D019718:Receptors, CXCR4
keywords: CCR5 and CXCR4 use; Coreceptor switch; Hierarchical phylogenetic model; Intrapatient HIV-1 evolutionary rate; R5 and X4 virus populations; Synonymous and non-synonymous substitutions