title: V3 determinants of HIV-1 escape from the CCR5 inhibitors Maraviroc and Vicriviroc.
abstract: HIV-1 develops resistance to CCR5 antagonists such as Maraviroc (MVC) and Vicriviroc (VVC) both in vitro and in vivo, with most changes arising in the gp120 V3 region. Both compounds bind to the same hydrophobic cavity in CCR5 in subtly different ways. Here, we investigated which V3 sequence changes are most associated with MVC and VVC resistance and how they affect the interaction between gp120 and the CCR5 NT. We found that VVC- and MVC-selected amino acid changes map to different V3 locations and involve residues that interact with the CCR5 NT in different ways. Changes in VVC-selected, but not MVC-selected, variants often involve charged residues. Although the overall V3 charge tends not to change, the introduction or removal of charged residues at specific positions affects the local electrostatic potential and could have structural and functional implications. In summary, VVC and MVC trigger the evolution of distinct HIV-1 resistance patterns in V3.
authors.affiliation: Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10065, USA.
authors.forename: Reem
authors.initials: R
authors.lastname: Berro
authors.forename: Per Johan
authors.initials: PJ
authors.lastname: Klasse
authors.forename: Martin R
authors.initials: MR
authors.lastname: Jakobsen
authors.forename: Paul R
authors.initials: PR
authors.lastname: Gorry
authors.forename: John P
authors.initials: JP
authors.lastname: Moore
authors.forename: Rogier W
authors.initials: RW
authors.lastname: Sanders
mesh_terms: D000595:Amino Acid Sequence; D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes / Q000494:pharmacology*; D024882:Drug Resistance, Viral / Q000502:physiology*; D015699:HIV Envelope Protein gp120 / Q000235:genetics*; D023581:HIV Fusion Inhibitors / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D000077592:Maraviroc; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000235:genetics*; D010879:Piperazines / Q000494:pharmacology*; D011487:Protein Conformation; D011743:Pyrimidines / Q000494:pharmacology*; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes; D015699:HIV Envelope Protein gp120; D023581:HIV Fusion Inhibitors; C059762:HIV envelope protein gp120 (305-321); D010446:Peptide Fragments; D010879:Piperazines; D011743:Pyrimidines; D014230:Triazoles; D000077592:Maraviroc; C486781:vicriviroc