HIV-1 Escape from Small-Molecule Antagonism of Vif

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 unexploited therapeutic target. Vif reduces the virion incorporation of A3G by targeting the restriction factor for proteasomal degradation...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Mark Sharkey, Natalia Sharova, Idrees Mohammed, Sarah E. Huff, Indrasena Reddy Kummetha, Gatikrushna Singh, Tariq M. Rana, Mario Stevenson
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	HIV-1 Vif antiretroviral agents antiretroviral resistance APOBEC Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/4d8741ca218e4772905c111bd892ffb2
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:4d8741ca218e4772905c111bd892ffb2
record_format	dspace
spelling	oai:doaj.org-article:4d8741ca218e4772905c111bd892ffb22021-11-15T15:55:14ZHIV-1 Escape from Small-Molecule Antagonism of Vif10.1128/mBio.00144-192150-7511https://doaj.org/article/4d8741ca218e4772905c111bd892ffb22019-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00144-19https://doaj.org/toc/2150-7511ABSTRACT The HIV-1 accessory protein Vif, which counteracts the antiviral action of the DNA-editing cytidine deaminase APOBEC3G (A3G), is an attractive and yet unexploited 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 upregulates 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.Mark SharkeyNatalia SharovaIdrees MohammedSarah E. HuffIndrasena Reddy KummethaGatikrushna SinghTariq M. RanaMario StevensonAmerican Society for MicrobiologyarticleHIV-1Vifantiretroviral agentsantiretroviral resistanceAPOBECMicrobiologyQR1-502ENmBio, Vol 10, Iss 1 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	HIV-1 Vif antiretroviral agents antiretroviral resistance APOBEC Microbiology QR1-502
spellingShingle	HIV-1 Vif antiretroviral agents antiretroviral resistance APOBEC Microbiology QR1-502 Mark Sharkey Natalia Sharova Idrees Mohammed Sarah E. Huff Indrasena Reddy Kummetha Gatikrushna Singh Tariq M. Rana Mario Stevenson HIV-1 Escape from Small-Molecule Antagonism of Vif
description	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 unexploited 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 upregulates 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.
format	article
author	Mark Sharkey Natalia Sharova Idrees Mohammed Sarah E. Huff Indrasena Reddy Kummetha Gatikrushna Singh Tariq M. Rana Mario Stevenson
author_facet	Mark Sharkey Natalia Sharova Idrees Mohammed Sarah E. Huff Indrasena Reddy Kummetha Gatikrushna Singh Tariq M. Rana Mario Stevenson
author_sort	Mark Sharkey
title	HIV-1 Escape from Small-Molecule Antagonism of Vif
title_short	HIV-1 Escape from Small-Molecule Antagonism of Vif
title_full	HIV-1 Escape from Small-Molecule Antagonism of Vif
title_fullStr	HIV-1 Escape from Small-Molecule Antagonism of Vif
title_full_unstemmed	HIV-1 Escape from Small-Molecule Antagonism of Vif
title_sort	hiv-1 escape from small-molecule antagonism of vif
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/4d8741ca218e4772905c111bd892ffb2
work_keys_str_mv	AT marksharkey hiv1escapefromsmallmoleculeantagonismofvif AT nataliasharova hiv1escapefromsmallmoleculeantagonismofvif AT idreesmohammed hiv1escapefromsmallmoleculeantagonismofvif AT sarahehuff hiv1escapefromsmallmoleculeantagonismofvif AT indrasenareddykummetha hiv1escapefromsmallmoleculeantagonismofvif AT gatikrushnasingh hiv1escapefromsmallmoleculeantagonismofvif AT tariqmrana hiv1escapefromsmallmoleculeantagonismofvif AT mariostevenson hiv1escapefromsmallmoleculeantagonismofvif
_version_	1718427214639267840

HIV-1 Escape from Small-Molecule Antagonism of Vif

Ejemplares similares