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.
Gladstone Institute of Virology and Immunology, University of California at San Francisco, San Francisco, California, United States of America. cheryl.stoddart@ucsf.edu
Cheryl A
CA
Stoddart
Pheroze
P
Joshi
Barbara
B
Sloan
Jennifer C
JC
Bare
Philip C
PC
Smith
Graham P
GP
Allaway
Carl T
CT
Wild
David E
DE
Martin
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