title: Env sequence determinants in CXCR4-using human immunodeficiency virus type-1 subtype C.
abstract: HIV-1 subtype C (HIV-1C) CXCR4-using virus is isolated infrequently and is poorly characterized. Understanding HIV-1C env characteristics has implications for the clinical use of antiretrovirals that target viral entry. A total of 209 env clones derived from 10 samples with mixed CCR5-(R5), CXCR4-using (X4) or dual-tropic HIV-1C were phenotyped for coreceptor usage. Intra-patient X4 and R5 variants generally formed distinct monophyletic phylogenetic clusters. X4 compared to R5 envs had significantly greater amino acid variability and insertions, higher net positive charge, fewer glycosylation sites and increased basic amino acid substitutions in the GPGQ crown. Basic amino acid substitution and/or insertion prior to the crown are highly sensitive characteristics for predicting X4 viruses. Chimeric env functional studies suggest that the V3 loop is necessary but often not sufficient to impart CXCR4 utilization. Our studies provide insights into the unique genotypic characteristics of X4 variants in HIV-1C.
authors.affiliation: Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Nina H
authors.initials: NH
authors.lastname: Lin
authors.forename: Carlos
authors.initials: C
authors.lastname: Becerril
authors.forename: Francoise
authors.initials: F
authors.lastname: Giguel
authors.forename: Vladimir
authors.initials: V
authors.lastname: Novitsky
authors.forename: Sikhulile
authors.initials: S
authors.lastname: Moyo
authors.forename: Joseph
authors.initials: J
authors.lastname: Makhema
authors.forename: Myron
authors.initials: M
authors.lastname: Essex
authors.forename: Shahin
authors.initials: S
authors.lastname: Lockman
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Kuritzkes
authors.forename: Manish
authors.initials: M
authors.lastname: Sagar
mesh_terms: D000328:Adult; D000465:Algorithms; D000595:Amino Acid Sequence; D005260:Female; D015752:Genes, env; D014644:Genetic Variation; D005838:Genotype; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D015658:HIV Infections / Q000235:genetics / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000145:classification / Q000235:genetics* / Q000276:immunology* / Q000502:physiology; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000276:immunology; D006801:Humans; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D010802:Phylogeny; D019713:Receptors, CCR5 / Q000276:immunology; D019718:Receptors, CXCR4 / Q000276:immunology*; D017386:Sequence Homology, Amino Acid; D053586:Virus Internalization; D055815:Young Adult; D054299:env Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000235:genetics* / Q000276:immunology
chemical_list: C527276:CXCR4 protein, human; D015699:HIV Envelope Protein gp120; C059762:HIV envelope protein gp120 (305-321); D010446:Peptide Fragments; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D054299:env Gene Products, Human Immunodeficiency Virus