title: The differential sensitivity of human and rhesus macaque CCR5 to small-molecule inhibitors of human immunodeficiency virus type 1 entry is explained by a single amino acid difference and suggests a mechanism of action for these inhibitors.
abstract: AD101 and SCH-C are two chemically related small molecules that inhibit the entry of human immunodeficiency virus type 1 (HIV-1) via human CCR5. AD101 also inhibits HIV-1 entry via rhesus macaque CCR5, but SCH-C does not. Among the eight residues that differ between the human and macaque versions of the coreceptor, only one, methionine-198, accounts for the insensitivity of macaque CCR5 to inhibition by SCH-C. Thus, the macaque coreceptor engineered to contain the natural human CCR5 residue (isoleucine) at position 198 is sensitive to HIV-1 entry inhibition by SCH-C, whereas a human CCR5 mutant containing the corresponding macaque residue (methionine) is resistant. Position 198 is in CCR5 transmembrane (TM) helix 5 and is not located within the previously defined binding site for AD101 and SCH-C, which involves residues in TM helices 1, 2, 3, and 7. SCH-C binds to human CCR5 whether residue 198 is isoleucine or methionine, and it also binds to macaque CCR5. However, the binding of a conformation-dependent monoclonal antibody to human CCR5 is inhibited by SCH-C only when residue 198 is isoleucine. These observations, taken together, suggest that the antiviral effects of SCH-C and AD101 involve stabilization, or induction, of a CCR5 conformation that is not compatible with HIV-1 infection. However, SCH-C is unable to exert this effect on CCR5 conformation when residue 198 is methionine. The region of CCR5 near residue 198 has, therefore, an important influence on the conformational state of this receptor.
authors.affiliation: Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York 10021, USA.
authors.forename: Erika
authors.initials: E
authors.lastname: Billick
authors.forename: Christoph
authors.initials: C
authors.lastname: Seibert
authors.forename: Pavel
authors.initials: P
authors.lastname: Pugach
authors.forename: Tom
authors.initials: T
authors.lastname: Ketas
authors.forename: Alexandra
authors.initials: A
authors.lastname: Trkola
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Endres
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Murgolo
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Coates
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Reyes
authors.forename: Bahige M
authors.initials: BM
authors.lastname: Baroudy
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Sakmar
authors.forename: John P
authors.initials: JP
authors.lastname: Moore
authors.forename: Shawn E
authors.initials: SE
authors.lastname: Kuhmann
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal; D065100:CCR5 Receptor Antagonists; D002460:Cell Line; D018946:Chemokine CCL5 / Q000037:antagonists & inhibitors; D003497:Cyclic N-Oxides / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000472:pathogenicity; D006801:Humans; D008253:Macaca mulatta; D008954:Models, Biological; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D010091:Oximes; D010880:Piperidines; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011725:Pyridines / Q000494:pharmacology; D019713:Receptors, CCR5 / Q000737:chemistry / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D013045:Species Specificity
chemical_list: D000911:Antibodies, Monoclonal; D065100:CCR5 Receptor Antagonists; D018946:Chemokine CCL5; D003497:Cyclic N-Oxides; D010091:Oximes; D010880:Piperidines; D011725:Pyridines; D019713:Receptors, CCR5; C438583:Ancriviroc