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


RESULTS
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.
Stoddart
Cheryl A
CA
Gladstone Institute of Virology and Immunology, University of California at San Francisco, San Francisco, California, United States of America. cheryl.stoddart@ucsf.edu
Joshi
Pheroze
P
Sloan
Barbara
B
Bare
Jennifer C
JC
Smith
Philip C
PC
Allaway
Graham P
GP
Wild
Carl T
CT
Martin
David E
DE
D000284:Administration, Oral; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D015153:Blotting, Western; D005434:Flow Cytometry; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D016513:Mice, SCID; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013386:Succinates / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D013950:Thymus Gland / Q000821:virology; D014315:Triterpenes / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects; D053978:Pentacyclic Triterpenes
D019380:Anti-HIV Agents; D013386:Succinates; D014315:Triterpenes; C479935:bevirimat; D053978:Pentacyclic Triterpenes