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...
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| creator | Smith, Robert A Raugi, Dana N Nixon, Robert S Song, Jennifer Seydi, Moussa Gottlieb, Geoffrey S |
| 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. |
| doi_str_mv | 10.1371/journal.pone.0280568 |
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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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0280568</identifier><identifier>PMID: 36652466</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Anti-HIV Agents - pharmacology ; Antiviral agents ; Biology and Life Sciences ; Capsid Proteins - genetics ; Cell culture ; Clinical trials ; Cloning ; Computer software industry ; Drug dosages ; Drug therapy ; Engineering and Technology ; gag Gene Products, Human Immunodeficiency Virus - genetics ; Gag protein ; Health aspects ; HIV ; HIV (Viruses) ; HIV Seropositivity ; HIV testing ; HIV-2 - genetics ; Human immunodeficiency virus ; Humans ; Inhibitors ; Maturation ; Medicine and Health Sciences ; Peptides ; Peptides - pharmacology ; Pharmaceutical research ; Phenotypes ; Proteins ; Proteolysis ; Research and Analysis Methods ; Scientific equipment and supplies industry ; Simian immunodeficiency virus ; Testing ; Triterpenes - pharmacology ; Viral drug resistance ; Virions ; Virus Replication</subject><ispartof>PloS one, 2023-01, Vol.18 (1), p.e0280568-e0280568</ispartof><rights>Copyright: © 2023 Smith et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</rights><rights>COPYRIGHT 2023 Public Library of Science</rights><rights>2023 Smith et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2023 Smith et al 2023 Smith et al</rights><rights>2023 Smith et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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The molecular mechanism(s) responsible for the differential susceptibility of HIV-1 and HIV-2/SIV to GSK232 require further investigation.</description><subject>Anti-HIV Agents - pharmacology</subject><subject>Antiviral agents</subject><subject>Biology and Life Sciences</subject><subject>Capsid Proteins - genetics</subject><subject>Cell culture</subject><subject>Clinical trials</subject><subject>Cloning</subject><subject>Computer software industry</subject><subject>Drug dosages</subject><subject>Drug therapy</subject><subject>Engineering and Technology</subject><subject>gag Gene Products, Human Immunodeficiency Virus - genetics</subject><subject>Gag protein</subject><subject>Health aspects</subject><subject>HIV</subject><subject>HIV (Viruses)</subject><subject>HIV Seropositivity</subject><subject>HIV testing</subject><subject>HIV-2 - genetics</subject><subject>Human immunodeficiency virus</subject><subject>Humans</subject><subject>Inhibitors</subject><subject>Maturation</subject><subject>Medicine and Health Sciences</subject><subject>Peptides</subject><subject>Peptides - pharmacology</subject><subject>Pharmaceutical research</subject><subject>Phenotypes</subject><subject>Proteins</subject><subject>Proteolysis</subject><subject>Research and Analysis Methods</subject><subject>Scientific equipment and supplies industry</subject><subject>Simian immunodeficiency virus</subject><subject>Testing</subject><subject>Triterpenes - pharmacology</subject><subject>Viral drug resistance</subject><subject>Virions</subject><subject>Virus Replication</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNkl-LEzEUxQdR3N3qNxAdEBZ9aM2fmWTyIiyL7g4WFqz2NWQyd9qUadJNMqLf3tTOLq344FNC8rvn3ns4WfYKoxmmHH_YuMFb1c92zsIMkQqVrHqSnWNByZQRRJ8e3c-yixA2CJW0Yux5dkYZK0nB2Hk2r230xgajcw_BhKishtx1-W29nJJc2TZf1Ms8ujyuId-qOHgVjbO5sWvTmOh8frP4QipaEUpeZM861Qd4OZ6T7PvnT9-ub6fzu5v6-mo-1aykcQpl1yjUlpw0VBPOuxIzDAxaSkqsCQGuRUGaRjeasbYUnAKiXHNBcNOKoqGT7M1Bd9e7IEcjgiScMSYE4ygR9YFondrInTdb5X9Jp4z88-D8Siofje5BYszLVhVCYI0L0F1qqqAtqGJV1fCOJ62PY7eh2UKrITmm-hPR0x9r1nLlfkhRFVxgkgTejQLe3Q8QotyaoKHvlQU3HObmBKOCJfTtX-i_txuplUoLGNu51FfvReUVpzSJFcnoSfb-hNLORvgZV2oIQdaLr__P3i1P2csjdg2qj-vg-mEfi3AKFgdQexeCh-7RM4zkPsMPy8l9huWY4VT2-tjvx6KH0NLfm3Hp2g</recordid><startdate>20230118</startdate><enddate>20230118</enddate><creator>Smith, Robert A</creator><creator>Raugi, Dana N</creator><creator>Nixon, Robert S</creator><creator>Song, Jennifer</creator><creator>Seydi, Moussa</creator><creator>Gottlieb, Geoffrey S</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PHGZM</scope><scope>PHGZT</scope><scope>PIMPY</scope><scope>PJZUB</scope><scope>PKEHL</scope><scope>PPXIY</scope><scope>PQEST</scope><scope>PQGLB</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-5749-481X</orcidid><orcidid>https://orcid.org/0000-0003-3202-1650</orcidid></search><sort><creationdate>20230118</creationdate><title>Intrinsic resistance of HIV-2 and SIV to the maturation inhibitor GSK2838232</title><author>Smith, Robert A ; Raugi, Dana N ; Nixon, Robert S ; Song, Jennifer ; Seydi, Moussa ; Gottlieb, Geoffrey S</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c653t-e5fba0d572b3c277f5161e6ed3251c22e7c942bbcbc66d5973e037c7921bd94b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Anti-HIV Agents - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Smith, Robert A</au><au>Raugi, Dana N</au><au>Nixon, Robert S</au><au>Song, Jennifer</au><au>Seydi, Moussa</au><au>Gottlieb, Geoffrey S</au><aucorp>University of Washington-Senegal HIV-2 Study Group</aucorp><aucorp>on behalf of the University of Washington-Senegal HIV-2 Study Group</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Intrinsic resistance of HIV-2 and SIV to the maturation inhibitor GSK2838232</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2023-01-18</date><risdate>2023</risdate><volume>18</volume><issue>1</issue><spage>e0280568</spage><epage>e0280568</epage><pages>e0280568-e0280568</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>36652466</pmid><doi>10.1371/journal.pone.0280568</doi><tpages>e0280568</tpages><orcidid>https://orcid.org/0000-0002-5749-481X</orcidid><orcidid>https://orcid.org/0000-0003-3202-1650</orcidid><oa>free_for_read</oa></addata></record> |
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| issn | 1932-6203 1932-6203 |
| language | eng |
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| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; PMC (PubMed Central); DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Free Full-Text Journals in Chemistry |
| subjects | Anti-HIV Agents - pharmacology Antiviral agents Biology and Life Sciences Capsid Proteins - genetics Cell culture Clinical trials Cloning Computer software industry Drug dosages Drug therapy Engineering and Technology gag Gene Products, Human Immunodeficiency Virus - genetics Gag protein Health aspects HIV HIV (Viruses) HIV Seropositivity HIV testing HIV-2 - genetics Human immunodeficiency virus Humans Inhibitors Maturation Medicine and Health Sciences Peptides Peptides - pharmacology Pharmaceutical research Phenotypes Proteins Proteolysis Research and Analysis Methods Scientific equipment and supplies industry Simian immunodeficiency virus Testing Triterpenes - pharmacology Viral drug resistance Virions Virus Replication |
| title | Intrinsic resistance of HIV-2 and SIV to the maturation inhibitor GSK2838232 |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-18T07%3A03%3A10IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Intrinsic%20resistance%20of%20HIV-2%20and%20SIV%20to%20the%20maturation%20inhibitor%20GSK2838232&rft.jtitle=PloS%20one&rft.au=Smith,%20Robert%20A&rft.aucorp=University%20of%20Washington-Senegal%20HIV-2%20Study%20Group&rft.date=2023-01-18&rft.volume=18&rft.issue=1&rft.spage=e0280568&rft.epage=e0280568&rft.pages=e0280568-e0280568&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0280568&rft_dat=%3Cgale_plos_%3EA733672465%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2766699670&rft_id=info:pmid/36652466&rft_galeid=A733672465&rft_doaj_id=oai_doaj_org_article_1175da4991c14ecfbc6aed43a688b7f7&rfr_iscdi=true |