HIV type 1 from a patient with baseline resistance to CCR5 antagonists uses drug-bound receptor for entry.
CCR5 antagonists are a new class of antiretroviral drugs that block viral entry by disrupting interactions between the viral envelope (Env) glycoprotein and coreceptor. During the CCR100136 (EPIC) Phase IIb study of the CCR5 antagonist aplaviroc (APL) in treatment-naive individuals, a patient was identified who harbored virus strains that exhibited partial resistance to APL at the time of virologic failure. Retrospectively, it was found that APL resistance was present at baseline as well. To investigate the mechanism of APL resistance in this patient, we cloned HIV-1 env genes from plasma obtained at baseline and after virologic failure. Approximately 85% of cloned Envs were functional, and all exhibited partial resistance to APL. All Envs were R5-tropic, were partially resistant to other CCR5 antagonists including maraviroc on cells with high CCR5 expression, but remained sensitive to the fusion inhibitor enfuvirtide. Competition studies with natural CCR5 ligands revealed that the mechanism of drug resistance entailed the use of the drug-bound conformation of CCR5 by the Env proteins obtained from this individual. The degree of drug resistance varied between Env clones, and also varied depending on the cell line used or the donor from whom the primary T cells were obtained. Thus, both virus and host factors contribute to CCR5 antagonist resistance. This study shows that R5 HIV-1 strains resistant to CCR5 inhibitors can arise in patients, confirming a mechanism of resistance previously characterized in vitro. In addition, some patients can harbor CCR5 antagonist-resistant viruses prior to treatment, which may have implications for the clinical use of this new class of antiretrovirals.
Tilton
John C
JC
Department of Microbiology, University of Pennsylvania, Philadelphia, 19104, USA.
Amrine-Madsen
Heather
H
Miamidian
John L
JL
Kitrinos
Kathryn M
KM
Pfaff
Jennifer
J
Demarest
James F
JF
Ray
Neelanjana
N
Jeffrey
Jerry L
JL
Labranche
Celia C
CC
Doms
Robert W
RW
D001565:Benzoates / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D002478:Cells, Cultured; D054659:Diketopiperazines; D024882:Drug Resistance, Viral; D023581:HIV Fusion Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015658:HIV Infections / Q000821:virology*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D020125:Mutation, Missense; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D015728:Receptors, HIV / Q000037:antagonists & inhibitors*; D017422:Sequence Analysis, DNA; D013141:Spiro Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D053586:Virus Internalization; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics
D001565:Benzoates; D054659:Diketopiperazines; D023581:HIV Fusion Inhibitors; D010879:Piperazines; D015728:Receptors, HIV; D013141:Spiro Compounds; D054299:env Gene Products, Human Immunodeficiency Virus; C499671:aplaviroc