title: Natural variation in the V3 crown of human immunodeficiency virus type 1 affects replicative fitness and entry inhibitor sensitivity.
abstract: Natural polymorphisms in the heterogeneous human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein may have an impact on both sensitivity to entry inhibitors and viral replicative fitness. Of significant interest is variation in the V3 crown due to its involvement in direct engagement with the coreceptor. Two positions in the crown (318 and 319) appear to be important in determining intrinsic susceptibility to multiple entry inhibitors. Thus, we evaluated a series of natural polymorphisms at positions 318 and 319 in three distinct CCR5-tropic envelope genetic backgrounds to address their role in replicative fitness and sensitivity to entry inhibitors. Change at position 319 to each of the three major consensus amino acids (A, T, and R) resulted in variation in sensitivity to entry inhibitors and altered replicative fitness, but the effects of any one amino acid depended on the envelope context. Change of the nearly invariant tyrosine at position 318 to a rare arginine resulted in increased sensitivity to entry inhibitors and decreased replicative fitness independent of envelope context. Polymorphisms in the V3 crown that showed increased susceptibility to entry inhibitors also exhibited decreased entry efficiency, replicative fitness in primary peripheral blood mononuclear cells, and ability to replicate in primary macrophages. These findings suggest that differences in coreceptor affinity and/or avidity may underlie these phenotypic characteristics.
authors.affiliation: Department of Molecular Biology and Microbiology, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Lobritz
authors.forename: Andre J
authors.initials: AJ
authors.lastname: Marozsan
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Troyer
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Arts
mesh_terms: D000577:Amides / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D019380:Anti-HIV Agents / Q000378:metabolism; D065100:CCR5 Receptor Antagonists; D002460:Cell Line; D018946:Chemokine CCL5 / Q000378:metabolism; D024882:Drug Resistance, Viral; D014644:Genetic Variation; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D023581:HIV Fusion Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D006801:Humans; D019259:Lamivudine / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000502:physiology; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D000644:Quaternary Ammonium Compounds / Q000378:metabolism; D019713:Receptors, CCR5 / Q000378:metabolism; D014779:Virus Replication
chemical_list: D000577:Amides; D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D018946:Chemokine CCL5; D015699:HIV Envelope Protein gp120; D023581:HIV Fusion Inhibitors; C059762:HIV envelope protein gp120 (305-321); D010446:Peptide Fragments; D000644:Quaternary Ammonium Compounds; C492865:RANTES, N(alpha)-(n-nonanoyl)-desSer(1)-(thioproline(2),cyclohexylglycine(3))-; D019713:Receptors, CCR5; D019259:Lamivudine; C119369:TAK 779