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HIV type 1 from a patient with baseline resistance to CCR5 antagonists uses drug-bound receptor for entry.

Publication ,  Journal Article
Tilton, JC; Amrine-Madsen, H; Miamidian, JL; Kitrinos, KM; Pfaff, J; Demarest, JF; Ray, N; Jeffrey, JL; Labranche, CC; Doms, RW
Published in: AIDS Res Hum Retroviruses
January 2010

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.

Duke Scholars

Published In

AIDS Res Hum Retroviruses

DOI

EISSN

1931-8405

Publication Date

January 2010

Volume

26

Issue

1

Start / End Page

13 / 24

Location

United States

Related Subject Headings

  • env Gene Products, Human Immunodeficiency Virus
  • Virus Internalization
  • Virology
  • Spiro Compounds
  • Sequence Analysis, DNA
  • Receptors, HIV
  • Piperazines
  • Mutation, Missense
  • Microbial Sensitivity Tests
  • Humans
 

Citation

APA
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MLA
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Tilton, J. C., Amrine-Madsen, H., Miamidian, J. L., Kitrinos, K. M., Pfaff, J., Demarest, J. F., … Doms, R. W. (2010). HIV type 1 from a patient with baseline resistance to CCR5 antagonists uses drug-bound receptor for entry. AIDS Res Hum Retroviruses, 26(1), 13–24. https://doi.org/10.1089/aid.2009.0132
Tilton, John C., Heather Amrine-Madsen, John L. Miamidian, Kathryn M. Kitrinos, Jennifer Pfaff, James F. Demarest, Neelanjana Ray, Jerry L. Jeffrey, Celia C. Labranche, and Robert W. Doms. “HIV type 1 from a patient with baseline resistance to CCR5 antagonists uses drug-bound receptor for entry.AIDS Res Hum Retroviruses 26, no. 1 (January 2010): 13–24. https://doi.org/10.1089/aid.2009.0132.
Tilton JC, Amrine-Madsen H, Miamidian JL, Kitrinos KM, Pfaff J, Demarest JF, et al. HIV type 1 from a patient with baseline resistance to CCR5 antagonists uses drug-bound receptor for entry. AIDS Res Hum Retroviruses. 2010 Jan;26(1):13–24.
Tilton, John C., et al. “HIV type 1 from a patient with baseline resistance to CCR5 antagonists uses drug-bound receptor for entry.AIDS Res Hum Retroviruses, vol. 26, no. 1, Jan. 2010, pp. 13–24. Pubmed, doi:10.1089/aid.2009.0132.
Tilton JC, Amrine-Madsen H, Miamidian JL, Kitrinos KM, Pfaff J, Demarest JF, Ray N, Jeffrey JL, Labranche CC, Doms RW. HIV type 1 from a patient with baseline resistance to CCR5 antagonists uses drug-bound receptor for entry. AIDS Res Hum Retroviruses. 2010 Jan;26(1):13–24.
Journal cover image

Published In

AIDS Res Hum Retroviruses

DOI

EISSN

1931-8405

Publication Date

January 2010

Volume

26

Issue

1

Start / End Page

13 / 24

Location

United States

Related Subject Headings

  • env Gene Products, Human Immunodeficiency Virus
  • Virus Internalization
  • Virology
  • Spiro Compounds
  • Sequence Analysis, DNA
  • Receptors, HIV
  • Piperazines
  • Mutation, Missense
  • Microbial Sensitivity Tests
  • Humans