Back to Search
Start Over
Mechanistic Studies and Modeling Reveal the Origin of Differential Inhibition of Gag Polymorphic Viruses by HIV-1 Maturation Inhibitors.
- Source :
-
PLoS pathogens [PLoS Pathog] 2016 Nov 28; Vol. 12 (11), pp. e1005990. Date of Electronic Publication: 2016 Nov 28 (Print Publication: 2016). - Publication Year :
- 2016
-
Abstract
- HIV-1 maturation inhibitors (MIs) disrupt the final step in the HIV-1 protease-mediated cleavage of the Gag polyprotein between capsid p24 capsid (CA) and spacer peptide 1 (SP1), leading to the production of infectious virus. BMS-955176 is a second generation MI with improved antiviral activity toward polymorphic Gag variants compared to a first generation MI bevirimat (BVM). The underlying mechanistic reasons for the differences in polymorphic coverage were studied using antiviral assays, an LC/MS assay that quantitatively characterizes CA/SP1 cleavage kinetics of virus like particles (VLPs) and a radiolabel binding assay to determine VLP/MI affinities and dissociation kinetics. Antiviral assay data indicates that BVM does not achieve 100% inhibition of certain polymorphs, even at saturating concentrations. This results in the breakthrough of infectious virus (partial antagonism) regardless of BVM concentration. Reduced maximal percent inhibition (MPI) values for BVM correlated with elevated EC50 values, while rates of HIV-1 protease cleavage at CA/SP1 correlated inversely with the ability of BVM to inhibit HIV-1 Gag polymorphic viruses: genotypes with more rapid CA/SP1 cleavage kinetics were less sensitive to BVM. In vitro inhibition of wild type VLP CA/SP1 cleavage by BVM was not maintained at longer cleavage times. BMS-955176 exhibited greatly improved MPI against polymorphic Gag viruses, binds to Gag polymorphs with higher affinity/longer dissociation half-lives and exhibits greater time-independent inhibition of CA/SP1 cleavage compared to BVM. Virological (MPI) and biochemical (CA/SP1 cleavage rates, MI-specific Gag affinities) data were used to create an integrated semi-quantitative model that quantifies CA/SP1 cleavage rates as a function of both MI and Gag polymorph. The model outputs are in accord with in vitro antiviral observations and correlate with observed in vivo MI efficacies. Overall, these findings may be useful to further understand antiviral profiles and clinical responses of MIs at a basic level, potentially facilitating further improvements to MI potency and coverage.<br />Competing Interests: We report the following conflicts of interest: ZLin, JC, HL, BNS, TP, TY, HY, ZLiu, DD, ARR, NAM, MC, MK, ML and ID are employees or former employees of and shareholders in Bristol-Myers Squibb. This does not alter our adherence to all PLOS policies on sharing data and materials.
- Subjects :
- Cell Line
HIV-1 genetics
Humans
Microbial Sensitivity Tests
Succinates pharmacology
Triterpenes pharmacology
Virus Assembly drug effects
Anti-HIV Agents pharmacology
Drug Resistance, Viral genetics
HIV-1 drug effects
Virus Replication drug effects
gag Gene Products, Human Immunodeficiency Virus genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1553-7374
- Volume :
- 12
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- PLoS pathogens
- Publication Type :
- Academic Journal
- Accession number :
- 27893830
- Full Text :
- https://doi.org/10.1371/journal.ppat.1005990