Potent activity of the HIV-1 maturation inhibitor bevirimat in SCID-hu Thy/Liv mice.

Article Details

Citation

Copy to clipboard

Stoddart CA, Joshi P, Sloan B, Bare JC, Smith PC, Allaway GP, Wild CT, Martin DE

Potent activity of the HIV-1 maturation inhibitor bevirimat in SCID-hu Thy/Liv mice.

PLoS One. 2007 Nov 28;2(11):e1251.

PubMed ID

18043758 [ View in PubMed

]

Abstract

BACKGROUND: The HIV-1 maturation inhibitor, 3-O-(3',3'-dimethylsuccinyl) betulinic acid (bevirimat, PA-457) is a promising drug candidate with 10 nM in vitro antiviral activity against multiple wild-type (WT) and drug-resistant HIV-1 isolates. Bevirimat has a novel mechanism of action, specifically inhibiting cleavage of spacer peptide 1 (SP1) from the C-terminus of capsid which results in defective core condensation. METHODS AND FINDINGS: Oral administration of bevirimat to HIV-1-infected SCID-hu Thy/Liv mice reduced viral RNA by >2 log(10) and protected immature and mature T cells from virus-mediated depletion. This activity was observed at plasma concentrations that are achievable in humans after oral dosing, and bevirimat was active up to 3 days after inoculation with both WT HIV-1 and an AZT-resistant HIV-1 clinical isolate. Consistent with its mechanism of action, bevirimat caused a dose-dependent inhibition of capsid-SP1 cleavage in HIV-1-infected human thymocytes obtained from these mice. HIV-1 NL4-3 with an alanine-to-valine substitution at the N-terminus of SP1 (SP1/A1V), which is resistant to bevirimat in vitro, was also resistant to bevirimat treatment in the mice, and SP1/AIV had replication and thymocyte kinetics similar to that of WT NL4-3 with no evidence of fitness impairment in in vivo competition assays. Interestingly, protease inhibitor-resistant HIV-1 with impaired capsid-SP1 cleavage was hypersensitive to bevirimat in vitro with a 50% inhibitory concentration 140 times lower than for WT HIV-1. CONCLUSIONS: These results support further clinical development of this first-in-class maturation inhibitor and confirm the usefulness of the SCID-hu Thy/Liv model for evaluation of in vivo antiretroviral efficacy, drug resistance, and viral fitness.

DrugBank Data that Cites this Article

Drugs

Bevirimat

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Bevirimat	Gag-Pol polyprotein	Protein		Unknown	Not Available	Details