title: Coreceptor tropism in human immunodeficiency virus type 1 subtype D: high prevalence of CXCR4 tropism and heterogeneous composition of viral populations.
abstract: In human immunodeficiency virus type 1 (HIV-1) subtype B, CXCR4 coreceptor use ranges from approximately 20% in early infection to approximately 50% in advanced disease. Coreceptor use by non-subtype B HIV is less well characterized. We studied coreceptor tropism of subtype A and D HIV-1 collected from 68 pregnant, antiretroviral drug-naive Ugandan women (HIVNET 012 trial). None of 33 subtype A or 10 A/D-recombinant viruses used the CXCR4 coreceptor. In contrast, nine (36%) of 25 subtype D viruses used both CXCR4 and CCR5 coreceptors. Clonal analyses of the nine subtype D samples with dual or mixed tropism revealed heterogeneous viral populations comprised of X4-, R5-, and dual-tropic HIV-1 variants. In five of the six samples with dual-tropic strains, V3 loop sequences of dual-tropic clones were identical to those of cocirculating R5-tropic clones, indicating the presence of CXCR4 tropism determinants outside of the V3 loop. These dual-tropic variants with R5-tropic-like V3 loops, which we designated "dual-R," use CCR5 much more efficiently than CXCR4, in contrast to dual-tropic clones with X4-tropic-like V3 loops ("dual-X"). These observations have implications for pathogenesis and treatment of subtype D-infected individuals, for the association between V3 sequence and coreceptor tropism phenotype, and for understanding potential mechanisms of evolution from exclusive CCR5 use to efficient CXCR4 use by subtype D HIV-1.
authors.affiliation: Monogram Biosciences, 345 Oyster Point Blvd., South San Francisco, CA 94080, USA. whuang@monogrambio.com
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.forename: Susan H
authors.initials: SH
authors.lastname: Eshleman
authors.forename: Jonathan
authors.initials: J
authors.lastname: Toma
authors.forename: Signe
authors.initials: S
authors.lastname: Fransen
authors.forename: Eric
authors.initials: E
authors.lastname: Stawiski
authors.forename: Ellen E
authors.initials: EE
authors.lastname: Paxinos
authors.forename: Jeannette M
authors.initials: JM
authors.lastname: Whitcomb
authors.forename: Alicia M
authors.initials: AM
authors.lastname: Young
authors.forename: Deborah
authors.initials: D
authors.lastname: Donnell
authors.forename: Francis
authors.initials: F
authors.lastname: Mmiro
authors.forename: Philippa
authors.initials: P
authors.lastname: Musoke
authors.forename: Laura A
authors.initials: LA
authors.lastname: Guay
authors.forename: J Brooks
authors.initials: JB
authors.lastname: Jackson
authors.forename: Neil T
authors.initials: NT
authors.lastname: Parkin
authors.forename: Christos J
authors.initials: CJ
authors.lastname: Petropoulos
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D005260:Female; D015686:Gene Products, env / Q000235:genetics / Q000378:metabolism; D014644:Genetic Variation; D015658:HIV Infections / Q000821:virology; D015497:HIV-1 / Q000276:immunology / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D010641:Phenotype; D010802:Phylogeny; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000821:virology; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D019562:Viral Load
chemical_list: D015686:Gene Products, env; D019713:Receptors, CCR5; D019718:Receptors, CXCR4