Potent activity of the HIV-1 maturation inhibitor bevirimat in SCID-hu Thy/Liv mice.
<h4>Background</h4>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 mecha...
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Public Library of Science (PLoS)
2007-11-01
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| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0001251&type=printable |
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| author | Cheryl A Stoddart Pheroze Joshi Barbara Sloan Jennifer C Bare Philip C Smith Graham P Allaway Carl T Wild David E Martin |
| author_facet | Cheryl A Stoddart Pheroze Joshi Barbara Sloan Jennifer C Bare Philip C Smith Graham P Allaway Carl T Wild David E Martin |
| author_sort | Cheryl A Stoddart |
| collection | DOAJ |
| description | <h4>Background</h4>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.<h4>Methods and findings</h4>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.<h4>Conclusions</h4>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. |
| format | Article |
| id | doaj-art-767cee83f8bd4f77a00802dac5c2710b |
| institution | OA Journals |
| issn | 1932-6203 |
| language | English |
| publishDate | 2007-11-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-767cee83f8bd4f77a00802dac5c2710b2025-08-20T02:00:54ZengPublic Library of Science (PLoS)PLoS ONE1932-62032007-11-01211e125110.1371/journal.pone.0001251Potent activity of the HIV-1 maturation inhibitor bevirimat in SCID-hu Thy/Liv mice.Cheryl A StoddartPheroze JoshiBarbara SloanJennifer C BarePhilip C SmithGraham P AllawayCarl T WildDavid E Martin<h4>Background</h4>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.<h4>Methods and findings</h4>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.<h4>Conclusions</h4>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.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0001251&type=printable |
| spellingShingle | Cheryl A Stoddart Pheroze Joshi Barbara Sloan Jennifer C Bare Philip C Smith Graham P Allaway Carl T Wild David E Martin Potent activity of the HIV-1 maturation inhibitor bevirimat in SCID-hu Thy/Liv mice. PLoS ONE |
| title | Potent activity of the HIV-1 maturation inhibitor bevirimat in SCID-hu Thy/Liv mice. |
| title_full | Potent activity of the HIV-1 maturation inhibitor bevirimat in SCID-hu Thy/Liv mice. |
| title_fullStr | Potent activity of the HIV-1 maturation inhibitor bevirimat in SCID-hu Thy/Liv mice. |
| title_full_unstemmed | Potent activity of the HIV-1 maturation inhibitor bevirimat in SCID-hu Thy/Liv mice. |
| title_short | Potent activity of the HIV-1 maturation inhibitor bevirimat in SCID-hu Thy/Liv mice. |
| title_sort | potent activity of the hiv 1 maturation inhibitor bevirimat in scid hu thy liv mice |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0001251&type=printable |
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