title: Multiple CCR5 conformations on the cell surface are used differentially by human immunodeficiency viruses resistant or sensitive to CCR5 inhibitors.
abstract: Resistance to small-molecule CCR5 inhibitors arises when HIV-1 variants acquire the ability to use inhibitor-bound CCR5 while still recognizing free CCR5. Two isolates, CC101.19 and D1/85.16, became resistant via four substitutions in the gp120 V3 region and three in the gp41 fusion peptide (FP), respectively. The binding characteristics of a panel of monoclonal antibodies (MAbs) imply that several antigenic forms of CCR5 are expressed at different levels on the surfaces of U87-CD4-CCR5 cells and primary CD4(+) T cells, in a cell-type-dependent manner. CCR5 binding and HIV-1 infection inhibition experiments suggest that the two CCR5 inhibitor-resistant viruses altered their interactions with CCR5 in different ways. As a result, both mutants became generally more sensitive to inhibition by CCR5 MAbs, and the FP mutant is specifically sensitive to a MAb that stains discrete cell surface clusters of CCR5 that may correspond to lipid rafts. We conclude that some MAbs detect different antigenic forms of CCR5 and that inhibitor-sensitive and -resistant viruses can use these CCR5 forms differently for entry in the presence or absence of CCR5 inhibitors.
authors.affiliation: Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York, USA.
authors.forename: Reem
authors.initials: R
authors.lastname: Berro
authors.forename: Per Johan
authors.initials: PJ
authors.lastname: Klasse
authors.forename: Danny
authors.initials: D
authors.lastname: Lascano
authors.forename: Ayanna
authors.initials: A
authors.lastname: Flegler
authors.forename: Kirsten A
authors.initials: KA
authors.lastname: Nagashima
authors.forename: Rogier W
authors.initials: RW
authors.lastname: Sanders
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Sakmar
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hope
authors.forename: John P
authors.initials: JP
authors.lastname: Moore
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000378:metabolism; D065100:CCR5 Receptor Antagonists; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000821:virology; D002460:Cell Line; D002462:Cell Membrane; D003510:Cyclohexanes / Q000494:pharmacology; D024882:Drug Resistance, Viral; D000939:Epitopes; D005434:Flow Cytometry; D057809:HEK293 Cells; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000378:metabolism*; D015700:HIV Envelope Protein gp41 / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000077592:Maraviroc; D021962:Membrane Microdomains; D008856:Microscopy, Fluorescence; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D019713:Receptors, CCR5 / Q000276:immunology / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology; D014760:Viral Fusion Proteins / Q000235:genetics / Q000378:metabolism*; D053586:Virus Internalization / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D000911:Antibodies, Monoclonal; D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes; D000939:Epitopes; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; D010879:Piperazines; D011743:Pyrimidines; D019713:Receptors, CCR5; D014230:Triazoles; D014760:Viral Fusion Proteins; D000077592:Maraviroc; C486781:vicriviroc