Intrinsic resistance of HIV-2 and SIV to the maturation inhibitor GSK2838232
GSK2838232 (GSK232) is a novel maturation inhibitor that blocks the proteolytic cleavage of HIV-1 Gag at the junction of capsid and spacer peptide 1 (CA/SP1), rendering newly-formed virions non-infectious. To our knowledge, GSK232 has not been tested against HIV-2, and there are limited data regardi...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2023-01-01
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| Series: | PLoS ONE |
| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9847912/?tool=EBI |
| _version_ | 1797943898499186688 |
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| author | Robert A. Smith Dana N. Raugi Robert S. Nixon Jennifer Song Moussa Seydi Geoffrey S. Gottlieb |
| author_facet | Robert A. Smith Dana N. Raugi Robert S. Nixon Jennifer Song Moussa Seydi Geoffrey S. Gottlieb |
| author_sort | Robert A. Smith |
| collection | DOAJ |
| description | GSK2838232 (GSK232) is a novel maturation inhibitor that blocks the proteolytic cleavage of HIV-1 Gag at the junction of capsid and spacer peptide 1 (CA/SP1), rendering newly-formed virions non-infectious. To our knowledge, GSK232 has not been tested against HIV-2, and there are limited data regarding the susceptibility of HIV-2 to other HIV-1 maturation inhibitors. To assess the potential utility of GSK232 as an option for HIV-2 treatment, we determined the activity of the compound against a panel of HIV-1, HIV-2, and SIV isolates in culture. GSK232 was highly active against HIV-1 isolates from group M subtypes A, B, C, D, F, and group O, with IC50 values ranging from 0.25–0.92 nM in spreading (multi-cycle) assays and 1.5–2.8 nM in a single cycle of infection. In contrast, HIV-2 isolates from groups A, B, and CRF01_AB, and SIV isolates SIVmac239, SIVmac251, and SIVagm.sab-2, were highly resistant to GSK232. To determine the role of CA/SP1 in the observed phenotypes, we constructed a mutant of HIV-2ROD9 in which the sequence of CA/SP1 was modified to match the corresponding sequence found in HIV-1. The resulting variant was fully susceptible to GSK232 in the single-cycle assay (IC50 = 1.8 nM). Collectively, our data indicate that the HIV-2 and SIV isolates tested in our study are intrinsically resistant to GSK232, and that the determinants of resistance map to CA/SP1. The molecular mechanism(s) responsible for the differential susceptibility of HIV-1 and HIV-2/SIV to GSK232 require further investigation. |
| first_indexed | 2024-04-10T20:31:24Z |
| format | Article |
| id | doaj.art-1175da4991c14ecfbc6aed43a688b7f7 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-10T20:31:24Z |
| publishDate | 2023-01-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS ONE |
| spelling | doaj.art-1175da4991c14ecfbc6aed43a688b7f72023-01-25T05:34:01ZengPublic Library of Science (PLoS)PLoS ONE1932-62032023-01-01181Intrinsic resistance of HIV-2 and SIV to the maturation inhibitor GSK2838232Robert A. SmithDana N. RaugiRobert S. NixonJennifer SongMoussa SeydiGeoffrey S. GottliebGSK2838232 (GSK232) is a novel maturation inhibitor that blocks the proteolytic cleavage of HIV-1 Gag at the junction of capsid and spacer peptide 1 (CA/SP1), rendering newly-formed virions non-infectious. To our knowledge, GSK232 has not been tested against HIV-2, and there are limited data regarding the susceptibility of HIV-2 to other HIV-1 maturation inhibitors. To assess the potential utility of GSK232 as an option for HIV-2 treatment, we determined the activity of the compound against a panel of HIV-1, HIV-2, and SIV isolates in culture. GSK232 was highly active against HIV-1 isolates from group M subtypes A, B, C, D, F, and group O, with IC50 values ranging from 0.25–0.92 nM in spreading (multi-cycle) assays and 1.5–2.8 nM in a single cycle of infection. In contrast, HIV-2 isolates from groups A, B, and CRF01_AB, and SIV isolates SIVmac239, SIVmac251, and SIVagm.sab-2, were highly resistant to GSK232. To determine the role of CA/SP1 in the observed phenotypes, we constructed a mutant of HIV-2ROD9 in which the sequence of CA/SP1 was modified to match the corresponding sequence found in HIV-1. The resulting variant was fully susceptible to GSK232 in the single-cycle assay (IC50 = 1.8 nM). Collectively, our data indicate that the HIV-2 and SIV isolates tested in our study are intrinsically resistant to GSK232, and that the determinants of resistance map to CA/SP1. The molecular mechanism(s) responsible for the differential susceptibility of HIV-1 and HIV-2/SIV to GSK232 require further investigation.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9847912/?tool=EBI |
| spellingShingle | Robert A. Smith Dana N. Raugi Robert S. Nixon Jennifer Song Moussa Seydi Geoffrey S. Gottlieb Intrinsic resistance of HIV-2 and SIV to the maturation inhibitor GSK2838232 PLoS ONE |
| title | Intrinsic resistance of HIV-2 and SIV to the maturation inhibitor GSK2838232 |
| title_full | Intrinsic resistance of HIV-2 and SIV to the maturation inhibitor GSK2838232 |
| title_fullStr | Intrinsic resistance of HIV-2 and SIV to the maturation inhibitor GSK2838232 |
| title_full_unstemmed | Intrinsic resistance of HIV-2 and SIV to the maturation inhibitor GSK2838232 |
| title_short | Intrinsic resistance of HIV-2 and SIV to the maturation inhibitor GSK2838232 |
| title_sort | intrinsic resistance of hiv 2 and siv to the maturation inhibitor gsk2838232 |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9847912/?tool=EBI |
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