title: Intercompartmental recombination of HIV-1 contributes to env intrahost diversity and modulates viral tropism and sensitivity to entry inhibitors.
abstract: HIV-1 circulates within an infected host as a genetically heterogeneous viral population. Viral intrahost diversity is shaped by substitutional evolution and recombination. Although many studies have speculated that recombination could have a significant impact on viral phenotype, this has never been definitively demonstrated. We report here phylogenetic and subsequent phenotypic analyses of envelope genes obtained from HIV-1 populations present in different anatomical compartments. Assessment of env compartmentalization from immunologically discrete tissues was assessed utilizing a single genome amplification approach, minimizing in vitro-generated artifacts. Genetic compartmentalization of variants was frequently observed. In addition, multiple incidences of intercompartment recombination, presumably facilitated by low-level migration of virus or infected cells between different anatomic sites and coinfection of susceptible cells by genetically divergent strains, were identified. These analyses demonstrate that intercompartment recombination is a fundamental evolutionary mechanism that helps to shape HIV-1 env intrahost diversity in natural infection. Analysis of the phenotypic consequences of these recombination events showed that genetic compartmentalization often correlates with phenotypic compartmentalization and that intercompartment recombination results in phenotype modulation. This represents definitive proof that recombination can generate novel combinations of phenotypic traits which differ subtly from those of parental strains, an important phenomenon that may have an impact on antiviral therapy and contribute to HIV-1 persistence in vivo.
authors.affiliation: School of Molecular Medical Sciences, The University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, United Kingdom.
authors.forename: Richard J P
authors.initials: RJ
authors.lastname: Brown
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Peters
authors.forename: Catherine
authors.initials: C
authors.lastname: Caron
authors.forename: Maria Paz
authors.initials: MP
authors.lastname: Gonzalez-Perez
authors.forename: Leanne
authors.initials: L
authors.lastname: Stones
authors.forename: Chiambah
authors.initials: C
authors.lastname: Ankghuambom
authors.forename: Kemebradikumo
authors.initials: K
authors.lastname: Pondei
authors.forename: C Patrick
authors.initials: CP
authors.lastname: McClure
authors.forename: George
authors.initials: G
authors.lastname: Alemnji
authors.forename: Stephen
authors.initials: S
authors.lastname: Taylor
authors.forename: Paul M
authors.initials: PM
authors.lastname: Sharp
authors.forename: Paul R
authors.initials: PR
authors.lastname: Clapham
authors.forename: Jonathan K
authors.initials: JK
authors.lastname: Ball
mesh_terms: D015752:Genes, env / Q000235:genetics; D014644:Genetic Variation; D057809:HEK293 Cells; D023581:HIV Fusion Inhibitors / Q000494:pharmacology*; D015658:HIV Infections / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000145:classification / Q000187:drug effects / Q000235:genetics* / Q000472:pathogenicity*; D006367:HeLa Cells; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D010641:Phenotype; D010802:Phylogeny; D011995:Recombination, Genetic; D017422:Sequence Analysis, DNA; D056189:Viral Tropism / Q000235:genetics*; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics*
chemical_list: D023581:HIV Fusion Inhibitors; D054299:env Gene Products, Human Immunodeficiency Virus