Resistance to CCR5 inhibitors caused by sequence changes in the fusion peptide of HIV-1 gp41.
We have investigated the mechanism of resistance of a HIV type 1 (HIV-1) R5 primary isolate, D1/85.16, to the small molecule CCR5 inhibitor, vicriviroc (VVC). Unlike other viruses resistant to this class of compound, D1/85.16 lacks sequence changes in the V3 region of the gp120 surface glycoprotein. Inspection of env sequences from D1/85.16 compared with those derived from the parental, inhibitor-sensitive virus, CC1/85, revealed a cluster of 3 conservative changes in the fusion peptide (FP) of the gp41 transmembrane glycoprotein that tracked with the resistance phenotype. Studies with engineered Env-chimeric and point-substituted viruses confirmed that these 3 FP residues were substantially responsible for VVC resistance without altering coreceptor usage, as assessed in both peripheral blood mononuclear cells and the TZM-bl cell line. VVC resistance is manifested differently in the 2 cell types, and there are assay-dependent complexities to the dose-response curves for the engineered resistant viruses. To explain them, we created a model for resistance and generated theoretical VVC inhibition curves that closely mimic the experimental data for the resistant viruses. The basis for the model is the existence of distinct forms of CCR5, with varying affinities for small molecule CCR5 inhibitors that are presumed to be present in different proportions on different cell types, and are used selectively by resistant HIV-1 variants when ligated with an inhibitor. Together, the experimental results and theoretical model may help understand how HIV-1 uses CCR5 to enter target cells under various conditions.
Anastassopoulou
Cleo G
CG
Department of Microbiology and Immunology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021, USA.
Ketas
Thomas J
TJ
Klasse
Per Johan
PJ
Moore
John P
JP
D000595:Amino Acid Sequence; D000596:Amino Acids; D065100:CCR5 Receptor Antagonists; D002478:Cells, Cultured; D004351:Drug Resistance; D015700:HIV Envelope Protein gp41 / Q000737:chemistry*; D023581:HIV Fusion Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000472:pathogenicity*; D006801:Humans; D008958:Models, Molecular; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D019713:Receptors, CCR5 / Q000737:chemistry
D000596:Amino Acids; D065100:CCR5 Receptor Antagonists; D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D019713:Receptors, CCR5; C486781:vicriviroc