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Basic Characteristics of Mutations
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Mutation Site
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M184V |
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Mutation Site Sentence
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Additional analyses carried out with rilpivirine resistance-associated mutations E138K/M184I or E138K/M184V showed that the combination of amino acid substitutions N348I and T369I had a dominant effect on the RNase H cleavage patterns observed with the PPT-containing 29RNA/28DNA template-primer complex (Figure 5). |
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Mutation Level
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Amino acid level |
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Mutation Type
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nonsynonymous substitution |
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Gene/Protein/Region
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RT |
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Standardized Encoding Gene
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gag-pol:155348
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Genotype/Subtype
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HIV-1 |
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Viral Reference
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AH002345.2;X05291;U27200
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Functional Impact and Mechanisms
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Disease
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HIV Infections
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Immune
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- |
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Target Gene
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-
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Clinical and Epidemiological Correlations
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Clinical Information
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- |
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Treatment
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rilpivirine |
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Location
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- |
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Literature Information
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PMID
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33477685
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Title
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Analysis and Molecular Determinants of HIV RNase H Cleavage Specificity at the PPT/U3 Junction
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Author
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Alvarez M,Sapena-Ventura E,Luczkowiak J,Martin-Alonso S,Menendez-Arias L
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Journal
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Viruses
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Journal Info
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2021 Jan 18;13(1):131
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Abstract
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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(BH10) 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(EHO) RT was further improved after substituting the sequence YQEPFKNLKT of HIV-1(BH10) RT (positions 342-351) for the equivalent residues of the HIV-2 enzyme (HQGDKILKV). Our results highlight the role of beta-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.
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Sequence Data
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-
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