{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T11:45:27Z","timestamp":1775907927311,"version":"3.50.1"},"reference-count":58,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,1,18]],"date-time":"2021-01-18T00:00:00Z","timestamp":1610928000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004837","name":"Ministerio de Ciencia e Innovaci\u00f3n","doi-asserted-by":"publisher","award":["BIO2016-76716-R"],"award-info":[{"award-number":["BIO2016-76716-R"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"Ministerio de Ciencia e Innovaci\u00f3n","doi-asserted-by":"publisher","award":["PID2019-104176RB-I00\/AEI\/10.13039\/501100011033"],"award-info":[{"award-number":["PID2019-104176RB-I00\/AEI\/10.13039\/501100011033"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>HIV reverse transcriptases (RTs) convert viral genomic RNA into double-stranded DNA. During reverse transcription, polypurine tracts (PPTs) resilient to RNase H cleavage are used as primers for plus-strand DNA synthesis. Nonnucleoside RT inhibitors (NNRTIs) can interfere with the initiation of plus-strand DNA synthesis by enhancing PPT removal, while HIV RT connection subdomain mutations N348I and N348I\/T369I mitigate this effect by altering RNase H cleavage specificity. Now, we demonstrate that among approved nonnucleoside RT inhibitors (NNRTIs), nevirapine and doravirine show the largest effects. The combination N348I\/T369I in HIV-1BH10 RT has a dominant effect on the RNase H cleavage specificity at the PPT\/U3 site. Biochemical studies showed that wild-type HIV-1 and HIV-2 RTs were able to process efficiently and accurately all tested HIV PPT sequences. However, the cleavage accuracy at the PPT\/U3 junction shown by the HIV-2EHO RT was further improved after substituting the sequence YQEPFKNLKT of HIV-1BH10 RT (positions 342\u2013351) for the equivalent residues of the HIV-2 enzyme (HQGDKILKV). Our results highlight the role of \u03b2-sheets 17 and 18 and their connecting loop (residues 342\u2013350) in the connection subdomain of the large subunit, in determining the RNase H cleavage window of HIV RTs.<\/jats:p>","DOI":"10.3390\/v13010131","type":"journal-article","created":{"date-parts":[[2021,1,21]],"date-time":"2021-01-21T02:36:05Z","timestamp":1611196565000},"page":"131","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Analysis and Molecular Determinants of HIV RNase H Cleavage Specificity at the PPT\/U3 Junction"],"prefix":"10.3390","volume":"13","author":[{"given":"Mar","family":"\u00c1lvarez","sequence":"first","affiliation":[{"name":"Centro de Biolog\u00eda Molecular Severo Ochoa (Consejo Superior de Investigaciones Cient\u00edficas &amp; Universidad Aut\u00f3noma de Madrid), Campus de Cantoblanco-UAM, 28049 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Enrique","family":"Sapena-Ventura","sequence":"additional","affiliation":[{"name":"Centro de Biolog\u00eda Molecular Severo Ochoa (Consejo Superior de Investigaciones Cient\u00edficas &amp; Universidad Aut\u00f3noma de Madrid), Campus de Cantoblanco-UAM, 28049 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6950-9372","authenticated-orcid":false,"given":"Joanna","family":"Luczkowiak","sequence":"additional","affiliation":[{"name":"Centro de Biolog\u00eda Molecular Severo Ochoa (Consejo Superior de Investigaciones Cient\u00edficas &amp; Universidad Aut\u00f3noma de Madrid), Campus de Cantoblanco-UAM, 28049 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samara","family":"Mart\u00edn-Alonso","sequence":"additional","affiliation":[{"name":"Centro de Biolog\u00eda Molecular Severo Ochoa (Consejo Superior de Investigaciones Cient\u00edficas &amp; Universidad Aut\u00f3noma de Madrid), Campus de Cantoblanco-UAM, 28049 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1251-6640","authenticated-orcid":false,"given":"Luis","family":"Men\u00e9ndez-Arias","sequence":"additional","affiliation":[{"name":"Centro de Biolog\u00eda Molecular Severo Ochoa (Consejo Superior de Investigaciones Cient\u00edficas &amp; Universidad Aut\u00f3noma de Madrid), Campus de Cantoblanco-UAM, 28049 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,1,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"a006882","DOI":"10.1101\/cshperspect.a006882","article-title":"HIV-1 reverse transcription","volume":"2","author":"Hu","year":"2012","journal-title":"Cold Spring Harb. 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