hiv reverse transcriptase
Summary: A reverse transcriptase encoded by the POL GENE of HIV. It is a heterodimer of 66 kDa and 51 kDa subunits that are derived from a common precursor protein. The heterodimer also includes an RNAse H activity (RIBONUCLEASE H, HUMAN IMMUNODEFICIENCY VIRUS) that plays an essential role the viral replication process.
- Tang J, Vernekar S, Chen Y, Miller L, Huber A, Myshakina N, et al. Synthesis, biological evaluation and molecular modeling of 2-Hydroxyisoquinoline-1,3-dione analogues as inhibitors of HIV reverse transcriptase associated ribonuclease H and polymerase. Eur J Med Chem. 2017;133:85-96 pubmed publisher..Our data indicate that while some of these subtypes inhibited both the RNase H and polymerase (pol) functions of RT, potent and selective RNase H inhibition was achieved with subtypes 8-9 as exemplified with compounds 8c and 9c. ..
- Rivas E, Eddy S. A dynamic programming algorithm for RNA structure prediction including pseudoknots. J Mol Biol. 1999;285:2053-68 pubmed..Although the time and memory demands of the algorithm are steep, we believe this is the first algorithm to be able to fold optimal (minimum energy) pseudoknotted RNAs with the accepted RNA thermodynamic model. ..
- Samri A, Haas G, Duntze J, Bouley J, Calvez V, Katlama C, et al. Immunogenicity of mutations induced by nucleoside reverse transcriptase inhibitors for human immunodeficiency virus type 1-specific cytotoxic T cells. J Virol. 2000;74:9306-12 pubmed..Therefore, RT mutations induced by NRTI can increase the immunogenicity of RT for CTL and might allow a better immune control of resistant viruses in vivo, suggesting that specific immune therapy might help prevent these mutations. ..
- Uberla K, Stahl Hennig C, Bottiger D, Mätz Rensing K, Kaup F, Li J, et al. Animal model for the therapy of acquired immunodeficiency syndrome with reverse transcriptase inhibitors. Proc Natl Acad Sci U S A. 1995;92:8210-4 pubmed
- Zheng X, Mueller G, Kim K, Perera L, Derose E, London R. Identification of drivers for the metamorphic transition of HIV-1 reverse transcriptase. Biochem J. 2017;474:3321-3338 pubmed publisher..Spectral comparisons based on 15N-labeled constructs are all consistent with previous structural conclusions based on studies of 13C-methyl-labeled constructs. ..
- Masso M, Vaisman I. Sequence and structure based models of HIV-1 protease and reverse transcriptase drug resistance. BMC Genomics. 2013;14 Suppl 4:S3 pubmed publisher..In a novel application, we describe a technique for identifying every possible pair of RT inhibitors as either potentially effective together as part of a cocktail, or a combination that is to be avoided. ..
- Lange M, Nguyen P, Callaway M, Johnson M, Burke D. RNA-protein interactions govern antiviral specificity and encapsidation of broad spectrum anti-HIV reverse transcriptase aptamers. Nucleic Acids Res. 2017;45:6087-6097 pubmed publisher..This study provides new insights into HIV-1's capacity to escape aptamer-mediated inhibition, the potential utility of broad-spectrum aptamers to overcome resistance, and molecular interactions that occur during viral assembly...
- Rhee S, Varghese V, Holmes S, van Zyl G, Steegen K, Boyd M, et al. Mutational Correlates of Virological Failure in Individuals Receiving a WHO-Recommended Tenofovir-Containing First-Line Regimen: An International Collaboration. EBioMedicine. 2017;18:225-235 pubmed publisher..These 12 TDF-selected TRAMs will be important for monitoring TDF-associated transmitted drug-resistance and for determining the extent of reduced TDF susceptibility in individuals with VF on a TDF-containing regimen. ..
- Balzarini J, Weeger M, Camarasa M, De Clercq E, Uberla K. Sensitivity/resistance profile of a simian immunodeficiency virus containing the reverse transcriptase gene of human immunodeficiency virus type 1 (HIV-1) toward the HIV-1-specific non-nucleoside reverse transcriptase inhibitors. Biochem Biophys Res Commun. 1995;211:850-6 pubmed..Infection of macaques with RT-SHIV may be a useful tool for studying the mechanism of NNRTI-resistance development and the therapy of NNRTI-resistant viruses in an animal model. ..
- Madison M, Lawson D, Elliott J, OzantÃ¼rk A, Koneru P, Townsend D, et al. Allosteric HIV-1 Integrase Inhibitors Lead to Premature Degradation of the Viral RNA Genome and Integrase in Target Cells. J Virol. 2017;91: pubmed publisher..We propose that IN-RNA interactions ensure the packaging of both vRNPs and IN within the protective capsid cores to facilitate subsequent reverse transcription and productive infection in target cells. ..
- Machado L, Costa I, Folha M, da Luz A, Vallinoto A, Ishak R, et al. Lower genetic variability of HIV-1 and antiretroviral drug resistance in pregnant women from the state of Pará, Brazil. BMC Infect Dis. 2017;17:270 pubmed publisher..3%. These results showed a low frequency of strains resistant to antiretroviral drugs, the prevalence of subtypes B and F, and the persistent low transmission of subtype C in pregnant of the state of Pará, Brazil. ..
- Wei X, Ghosh S, Taylor M, Johnson V, Emini E, Deutsch P, et al. Viral dynamics in human immunodeficiency virus type 1 infection. Nature. 1995;373:117-22 pubmed
- Tuerk C, MacDougal S, Gold L. RNA pseudoknots that inhibit human immunodeficiency virus type 1 reverse transcriptase. Proc Natl Acad Sci U S A. 1992;89:6988-92 pubmed..We demonstrated that at least one of the ligands inhibits cDNA synthesis by HIV reverse transcriptase but fails to inhibit other reverse transcriptases...
- Pandey A, Dixit U, Kholodovych V, Comollo T, Pandey V. The ?1'-?2' Motif of the RNase H Domain of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Is Responsible for Conferring Open Conformation to the p66 Subunit by Displacing the Connection Domain from the Polymerase Cleft. Biochemistry. 2017;56:3434-3442 pubmed publisher..The unstable elongated p66 molecule may then readily dimerize with p51 to assume a stable dimeric conformation. ..
- Ren J, Milton J, Weaver K, Short S, Stuart D, Stammers D. Structural basis for the resilience of efavirenz (DMP-266) to drug resistance mutations in HIV-1 reverse transcriptase. Structure. 2000;8:1089-94 pubmed
- Weber I, Harrison R. Decoding HIV resistance: from genotype to therapy. Future Med Chem. 2017;9:1529-1538 pubmed publisher..Adding classifiers such as information on the atomic structure of the protein can further enhance the predictions...
- Durant J, Clevenbergh P, Halfon P, Delgiudice P, Porsin S, Simonet P, et al. Drug-resistance genotyping in HIV-1 therapy: the VIRADAPT randomised controlled trial. Lancet. 1999;353:2195-9 pubmed..Further study of the use of genotypic-resistance testing in assisting clinical decision-making is warranted. ..
- Trono D. Partial reverse transcripts in virions from human immunodeficiency and murine leukemia viruses. J Virol. 1992;66:4893-900 pubmed..A similar observation was made with murine amphotropic retrovirus particles. It is therefore likely that all retroviruses contain partial reverse transcripts. ..
- Modi M, Nutan -, Pancholi B, Kulshrestha S, Rawat A, Malhotra S, et al. Anti-HIV-1 activity, protease inhibition and safety profile of extracts prepared from Rhus parviflora. BMC Complement Altern Med. 2013;13:158 pubmed publisher..The studies reported herein showed in vitro anti-HIV activity and preliminary safety profile of the extracts prepared from the leaves of R. parviflora. ..
- Huang B, Wang X, Liu X, Chen Z, Li W, Sun S, et al. Discovery of novel DAPY-IAS hybrid derivatives as potential HIV-1 inhibitors using molecular hybridization based on crystallographic overlays. Bioorg Med Chem. 2017;25:4397-4406 pubmed publisher..Preliminary structure-activity relationships (SARs), structure-cytotoxicity relationships, molecular modeling studies, and in silico calculation of physicochemical properties of these new inhibitors were also discussed. ..
- Arts E, Mak J, Kleiman L, Wainberg M. Mature reverse transcriptase (p66/p51) is responsible for low levels of viral DNA found in human immunodeficiency virus type 1 (HIV-1). Leukemia. 1994;8 Suppl 1:S175-8 pubmed..These results indicate that only mature RT (p66/p51) and not its precursor (p160gag-pol) is responsible for the presence of viral DNA in HIV. ..
- Jaeger J, Restle T, Steitz T. The structure of HIV-1 reverse transcriptase complexed with an RNA pseudoknot inhibitor. EMBO J. 1998;17:4535-42 pubmed..Presumably, this RNA ligand inhibits reverse transcriptase by binding to a site that partly overlaps the primer-template binding site. ..
- Lori F, di Marzo Veronese F, De Vico A, Lusso P, Reitz M, Gallo R. Viral DNA carried by human immunodeficiency virus type 1 virions. J Virol. 1992;66:5067-74 pubmed..The DNA carried by human immunodeficiency virus type 1 virions presumably originates from reverse transcription which takes place prior to or during formation of the mature virus particle. ..
- Palaniappan C, Wisniewski M, Jacques P, Le Grice S, Fay P, Bambara R. Mutations within the primer grip region of HIV-1 reverse transcriptase result in loss of RNase H function. J Biol Chem. 1997;272:11157-64 pubmed..Since mutants P226A and F227A carried out these latter reactions normally, these two residues specifically influence 5'-RNA-directed RNase H catalysis. ..
- Zeng P, Liu Y, He M, Wang J, Keating S, Mao W, et al. The infection staging and profile of genotypic distribution and drug resistance mutation among the human immunodeficiency virus-1 infected blood donors from five Chinese blood centers, 2012-2014. PLoS ONE. 2017;12:e0179328 pubmed publisher..27 samples had DRMs, yielding a drug resistance prevalence of 13.2% (27/205). Our findings provide important information for developing strategies for comprehensive HIV control and improving anti-retroviral treatment in China. ..
- Wei L, Wang H, Huang L, Chen C, Morris Natschke S, Lee K, et al. Drug-like property-driven optimization of 4-substituted 1,5-diarylanilines as potent HIV-1 non-nucleoside reverse transcriptase inhibitors against rilpivirine-resistant mutant virus. Bioorg Med Chem Lett. 2017;27:2788-2792 pubmed publisher..Thus, three amide-DAANs 8e, 4a, and 4b were identified with high potency against wild-type and rilpivirine-resistant viral strains and multiple desirable drug-like properties. ..
- Tisdale M, Kemp S, Parry N, Larder B. Rapid in vitro selection of human immunodeficiency virus type 1 resistant to 3'-thiacytidine inhibitors due to a mutation in the YMDD region of reverse transcriptase. Proc Natl Acad Sci U S A. 1993;90:5653-6 pubmed..Assessment of the interactive effects of multiple drug-resistance mutations may help to establish a rationale for using these drugs in the future therapy of HIV disease. ..
- Barnard J, Borkow G, Parniak M. The thiocarboxanilide nonnucleoside UC781 is a tight-binding inhibitor of HIV-1 reverse transcriptase. Biochemistry. 1997;36:7786-92 pubmed..7 x 10(6) M(-1) s(-1)), but that dissociation is slow (k(off) approximately 1.6 x 10(-3) s(-1)). UC781 is therefore a rapid tight-binding inhibitor of HIV-1 RT, the first NNI to demonstrate this property. ..
- Althaus I, Chou J, Gonzales A, Deibel M, Chou K, Kezdy F, et al. Kinetic studies with the non-nucleoside HIV-1 reverse transcriptase inhibitor U-88204E. Biochemistry. 1993;32:6548-54 pubmed..The inhibitor did not inhibit the RNase H function of HIV-1 RT nor did it impair the RNA-directed DNA polymerase activity of HIV-2 RT. These data thus demonstrate the unique specificity of U-88204E for HIV-1 RT. ..
- Frączek T, Kaminski R, Krakowiak A, Naessens E, Verhasselt B, Paneth P. Diaryl ethers with carboxymethoxyphenacyl motif as potent HIV-1 reverse transcriptase inhibitors with improved solubility. J Enzyme Inhib Med Chem. 2018;33:9-16 pubmed publisher..Furthermore, SupT1 and CD4+ cell infectivity assays for the most promising (7e) have confirmed its strong antiviral potential while docking studies indicate a novel binding interactions responsible for high activity...
- Derudas M, Vanpouille C, Carta D, Zicari S, Andrei G, Snoeck R, et al. Virtual Screening of Acyclovir Derivatives as Potential Antiviral Agents: Design, Synthesis, and Biological Evaluation of New Acyclic Nucleoside ProTides. J Med Chem. 2017;60:7876-7896 pubmed publisher..A carboxypeptidase-mediated hydrolysis study was performed for a selection of compounds to assess the formation of putative metabolites and support the biological activity observed...
- Ferro S, Buemi M, De Luca L, Agharbaoui F, Pannecouque C, Monforte A. Searching for novel N1-substituted benzimidazol-2-ones as non-nucleoside HIV-1 RT inhibitors. Bioorg Med Chem. 2017;25:3861-3870 pubmed publisher..Finally, molecular docking studies were performed in order to rationalize the observed activity of the most promising compound. ..
- Tzou P, Huang X, Shafer R. NucAmino: a nucleotide to amino acid alignment optimized for virus gene sequences. BMC Bioinformatics. 2017;18:138 pubmed publisher..NucAmino is a nucleotide-to-amino acid alignment program with several advantages for clinical laboratories performing virus sequencing compared with older programs designed for gene finding. ..
- Back N, Nijhuis M, Keulen W, Boucher C, Oude Essink B, Van Kuilenburg A, et al. Reduced replication of 3TC-resistant HIV-1 variants in primary cells due to a processivity defect of the reverse transcriptase enzyme. EMBO J. 1996;15:4040-9 pubmed..If the level of virus replication can be similarly reduced in 3TC-treated patients that develop drug-resistant HIV-1 variants, this may be of considerable clinical benefit. ..
- Arion D, Borkow G, Gu Z, Wainberg M, Parniak M. The K65R mutation confers increased DNA polymerase processivity to HIV-1 reverse transcriptase. J Biol Chem. 1996;271:19860-4 pubmed..We postulate that the increased processivity of the K65R RT may be a compensatory response to the decreased affinity of this mutant for certain dNTP substrates, allowing normal viral replication kinetics. ..
- Quan Y, Inouye P, Liang C, Rong L, Gotte M, Wainberg M. Dominance of the E89G substitution in HIV-1 reverse transcriptase in regard to increased polymerase processivity and patterns of pausing. J Biol Chem. 1998;273:21918-25 pubmed..Thus, the E89G substitution is a dominant determinant in regard to each of the koff values from an RT.template/primer complex, RT processivity, and specific patterns of pausing during DNA polymerization. ..
- Cunningham P, Smith D, Satchell C, Cooper D, Brew B. Evidence for independent development of resistance to HIV-1 reverse transcriptase inhibitors in the cerebrospinal fluid. AIDS. 2000;14:1949-54 pubmed..These findings may have important implications in guiding antiretroviral therapy in HIV-1 infection. ..
- Schinazi R, McMillan A, Cannon D, Mathis R, Lloyd R, Peck A, et al. Selective inhibition of human immunodeficiency viruses by racemates and enantiomers of cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. Antimicrob Agents Chemother. 1992;36:2423-31 pubmed..oligo(dC)19-24 template primer was used. These results suggest that further development of the (-)-Beta-enantiomer of FTC is warranted as an antiviral agent for infections caused by human immunodeficiency viruses. ..
- Bebenek K, Beard W, Darden T, Li L, Prasad R, Luton B, et al. A minor groove binding track in reverse transcriptase. Nat Struct Biol. 1997;4:194-7 pubmed
- Suzuki K, Craddock B, Okamoto N, Kano T, Steigbigel R. Poly A-linked colorimetric microtiter plate assay for HIV reverse transcriptase. J Virol Methods. 1993;44:189-98 pubmed..The total assay required for performing the colorimetric assay, including the RT reaction, was 40 min. ..
- Rosenwirth B, ten Haaft P, Bogers W, Nieuwenhuis I, Niphuis H, Kuhn E, et al. Antiretroviral therapy during primary immunodeficiency virus infection can induce persistent suppression of virus load and protection from heterologous challenge in rhesus macaques. J Virol. 2000;74:1704-11 pubmed..By this chemotherapeutic attenuation, the replication kinetics of attenuated viruses could be mimicked and a vaccination effect similar to that induced by live attenuated simian immunodeficiency virus vaccines was achieved. ..
- Arts E, Mak J, Kleiman L, Wainberg M. DNA found in human immunodeficiency virus type 1 particles may not be required for infectivity. J Gen Virol. 1994;75 ( Pt 7):1605-13 pubmed..However such viruses were as infections for CD4+ cells as wild-type virus. We conclude that retrovirus-derived DNA in HIV-1 particles is not required for infection and does not play a significant role in this process. ..
- Iversen A, Shafer R, Wehrly K, Winters M, Mullins J, Chesebro B, et al. Multidrug-resistant human immunodeficiency virus type 1 strains resulting from combination antiretroviral therapy. J Virol. 1996;70:1086-90 pubmed..The present results suggest that drug resistance and viral replicative capacity both may play a role in selection of HIV-1 RT mutations. ..
- Mansky L, Temin H. Lower in vivo mutation rate of human immunodeficiency virus type 1 than that predicted from the fidelity of purified reverse transcriptase. J Virol. 1995;69:5087-94 pubmed..Our data suggest that the fidelity of purified HIV-1 reverse transcriptase may not accurately reflect the level of genetic variation in a natural infection. ..
- Rittinger K, Divita G, Goody R. Human immunodeficiency virus reverse transcriptase substrate-induced conformational changes and the mechanism of inhibition by nonnucleoside inhibitors. Proc Natl Acad Sci U S A. 1995;92:8046-9 pubmed..10), while the affinity of the primer/template duplex is increased by at least a factor of 10. The major effect of nonnucleoside inhibitors is on the chemical step (nucleotide transfer). ..
- Kew Y, Qingbin S, Prasad V. Subunit-selective mutagenesis of Glu-89 residue in human immunodeficiency virus reverse transcriptase. Contribution of p66 and p51 subunits to nucleoside analog sensitivity, divalent cation preference, and steady state kinetic properties. J Biol Chem. 1994;269:15331-6 pubmed..However, the increased Vmax displayed by the mutant enzyme (p66m/p51m) appeared to be determined by both of the subunits. ..
- Powell M, Beard W, Bebenek K, Howard K, Le Grice S, Darden T, et al. Residues in the alphaH and alphaI helices of the HIV-1 reverse transcriptase thumb subdomain required for the specificity of RNase H-catalyzed removal of the polypurine tract primer. J Biol Chem. 1999;274:19885-93 pubmed..Our results indicate that residues in the thumb subdomain and the minor groove binding track in particular, are crucial for unique interactions between RT and the PPT required for correct positioning and precise RNase H cleavage. ..
- Yasukawa K, Iida K, Okano H, Hidese R, Baba M, Yanagihara I, et al. Next-generation sequencing-based analysis of reverse transcriptase fidelity. Biochem Biophys Res Commun. 2017;492:147-153 pubmed publisher..Overall, our method could precisely evaluate the fidelity of various RTs with different reaction conditions in a high-throughput manner without the use of expensive optics and troublesome adaptor ligation. ..
- Ichimura H, Levy J. Polymerase substrate depletion: a novel strategy for inhibiting the replication of the human immunodeficiency virus. Virology. 1995;211:554-60 pubmed..MPA provides a novel strategy for inhibiting the replication of HIV and should be considered in clinical trials of antiviral therapies. ..
- Burke D, Scates L, Andrews K, Gold L. Bent pseudoknots and novel RNA inhibitors of type 1 human immunodeficiency virus (HIV-1) reverse transcriptase. J Mol Biol. 1996;264:650-66 pubmed..We model their interactions with RT as mimicking the 40 to 45 degrees bend in dsDNA co-crystallized with RT. ..
- Schmit J, Cogniaux J, Hermans P, van Vaeck C, Sprecher S, Van Remoortel B, et al. Multiple drug resistance to nucleoside analogues and nonnucleoside reverse transcriptase inhibitors in an efficiently replicating human immunodeficiency virus type 1 patient strain. J Infect Dis. 1996;174:962-8 pubmed..The multi-ddN-resistant isolate was not eliminated in a competition culture with the wild type isolate. Sequential therapy did not prevent the appearance of multidrug-resistant virus with a conserved replication rate. ..
- . Virological response to a triple nucleoside/nucleotide analogue regimen over 48 weeks in HIV-1-infected adults in Africa. AIDS. 2006;20:1391-9 pubmed..In this population, who were infected with HIV-1 subtypes A, C or D, M184V with or without NAMs was the most common route to resistance, whereas K65R was identified less often. ..
- Balzarini J, De Clercq E, Uberla K. SIV/HIV-1 hybrid virus expressing the reverse transcriptase gene of HIV-1 remains sensitive to HIV-1-specific reverse transcriptase inhibitors after passage in rhesus macaques. J Acquir Immune Defic Syndr Hum Retrovirol. 1997;15:1-4 pubmed..Nevertheless, this report further supports the suitability, reliability, and usefulness of the RT-SHIV/macaque model to investigate the antiviral properties of most RT inhibitors in an in vivo setting. ..