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Título: | Analysis and molecular determinants of hiv rnase h cleavage specificity at the ppt/u3 junction |
Autor: | Álvarez, Mar CSIC ORCID; Sapena-Ventura, Enrique; Luczkowiak, Joanna; Menéndez-Arias, Luis CSIC ORCID ; Martín-Alonso, Samara CSIC ORCID | Palabras clave: | HIV Reverse transcriptase Antiretroviral drug resistance DNA synthesis Doravirine RNase H |
Fecha de publicación: | 18-ene-2021 | Editor: | Multidisciplinary Digital Publishing Institute | Citación: | VIRUSES 13 (2021) | Resumen: | 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-1 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-2 RT was further improved after substituting the sequence YQEPFKNLKT of HIV-1 RT (positions 342–351) for the equivalent residues of the HIV-2 enzyme (HQGDKILKV). Our results highlight the role of β-sheets 17 and 18 and their connecting loop (residues 342–350) in the connection subdomain of the large subunit, in determining the RNase H cleavage window of HIV RTs. | Versión del editor: | http://dx.doi.org/10.3390/v13010131 | URI: | http://hdl.handle.net/10261/256597 | DOI: | 10.3390/v13010131 | Identificadores: | doi: 10.3390/v13010131 issn: 1999-4915 |
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