HIV-1 escape from small-molecule antagonism of Vif

Mark E Sharkey, Natalia Sharova, Idrees Mohammed, Sarah E. Huff, Indrasena Reddy Kummetha, Gatikrushna Singh, Tariq M. Rana, Mario Stevenson

Research output: Contribution to journalArticle

Abstract

The HIV-1 accessory protein Vif, which counteracts the antiviral action of the DNA-editing cytidine deaminase APOBEC3G (A3G), is an attractive and yet un-exploited therapeutic target. Vif reduces the virion incorporation of A3G by targeting the restriction factor for proteasomal degradation in the virus-producing cell. Compounds that inhibit Vif-mediated degradation of A3G in cells targeted by HIV-1 would represent a novel antiviral therapeutic. We previously described small molecules with activity consistent with Vif antagonism. In this study, we derived inhibitor escape HIV-1 variants to characterize the mechanism by which these novel agents inhibit virus replication. Here we show that resistance to these agents is dependent on an amino acid substitution in Vif (V142I) and on a point mutation that likely up-regulates transcription by modifying the lymphocyte enhancing factor 1 (LEF-1) binding site. Molecular modeling demonstrated a docking site in the Vif-Elongin C complex that is disrupted by these inhibitors. This docking site is lost when Vif acquires the V142I mutation that leads to inhibitor resistance. Competitive fitness experiments indicated that the V142I Vif and LEF-1 binding site mutations created a virus that is better adapted to growing in the presence of A3G than the wild-type virus.IMPORTANCE Although antiretroviral therapy can suppress HIV-1 replication effectively, virus reservoirs persist in infected individuals and virus replication rapidly rebounds if therapy is interrupted. Currently, there is a need for therapeutic approaches that eliminate, reduce, or control persistent viral reservoirs if a cure is to be realized. This work focuses on the preclinical development of novel, small-molecule inhibitors of the HIV-1 Vif protein. Vif inhibitors represent a new class of antiretroviral drugs that may expand treatment options to more effectively suppress virus replication or to drive HIV-1 reservoirs to a nonfunctional state by harnessing the activity of the DNA-editing cytidine deaminase A3G, a potent, intrinsic restriction factor expressed in macrophage and CD4 + T cells. In this study, we derived inhibitor escape variants to characterize the mechanism by which these novel agents inhibit virus replication and to provide evidence for target validation.

Original languageEnglish (US)
Article numbere00144-19
JournalmBio
Volume10
Issue number1
DOIs
StatePublished - Jan 1 2019

Fingerprint

Virus Replication
HIV-1
Cytidine Deaminase
Viruses
Antiviral Agents
Binding Sites
Lymphocytes
Therapeutics
Intrinsic Factor
Mutation
DNA
Amino Acid Substitution
Point Mutation
Virion
Up-Regulation
Macrophages
T-Lymphocytes
Pharmaceutical Preparations
Human immunodeficiency virus 1 vif protein

Keywords

  • Antiretroviral agents
  • Antiretroviral resistance
  • APOBEC
  • HIV-1
  • Vif

ASJC Scopus subject areas

  • Microbiology
  • Virology

Cite this

Sharkey, M. E., Sharova, N., Mohammed, I., Huff, S. E., Kummetha, I. R., Singh, G., ... Stevenson, M. (2019). HIV-1 escape from small-molecule antagonism of Vif. mBio, 10(1), [e00144-19]. https://doi.org/10.1128/mBio.00144-19

HIV-1 escape from small-molecule antagonism of Vif. / Sharkey, Mark E; Sharova, Natalia; Mohammed, Idrees; Huff, Sarah E.; Kummetha, Indrasena Reddy; Singh, Gatikrushna; Rana, Tariq M.; Stevenson, Mario.

In: mBio, Vol. 10, No. 1, e00144-19, 01.01.2019.

Research output: Contribution to journalArticle

Sharkey, ME, Sharova, N, Mohammed, I, Huff, SE, Kummetha, IR, Singh, G, Rana, TM & Stevenson, M 2019, 'HIV-1 escape from small-molecule antagonism of Vif', mBio, vol. 10, no. 1, e00144-19. https://doi.org/10.1128/mBio.00144-19
Sharkey ME, Sharova N, Mohammed I, Huff SE, Kummetha IR, Singh G et al. HIV-1 escape from small-molecule antagonism of Vif. mBio. 2019 Jan 1;10(1). e00144-19. https://doi.org/10.1128/mBio.00144-19
Sharkey, Mark E ; Sharova, Natalia ; Mohammed, Idrees ; Huff, Sarah E. ; Kummetha, Indrasena Reddy ; Singh, Gatikrushna ; Rana, Tariq M. ; Stevenson, Mario. / HIV-1 escape from small-molecule antagonism of Vif. In: mBio. 2019 ; Vol. 10, No. 1.
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