scholarly journals Effects of HIV-1 reverse transcriptase connection subdomain mutations on polypurine tract removal and initiation of (+)-strand DNA synthesis

2015 ◽  
Vol 43 (4) ◽  
pp. 2259-2270 ◽  
Author(s):  
Gilberto Betancor ◽  
Mar Álvarez ◽  
Barbara Marcelli ◽  
Cristina Andrés ◽  
Miguel A. Martínez ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Dna Synthesis ◽  
Polypurine Tract ◽  
Hiv 1

scholarly journals Structures of Complexes Formed by HIV-1 Reverse Transcriptase at a Termination Site of DNA Synthesis

2001 ◽  
Vol 276 (33) ◽  
pp. 31439-31448 ◽  
Author(s):  
Marc Lavigne ◽  
Lucette Polomack ◽  
Henri Buc
Keyword(s):  
Reverse Transcriptase ◽  
Dna Synthesis ◽  
Hiv 1

scholarly journals Mutating a Region of HIV-1 Reverse Transcriptase Implicated in tRNALys-3Binding and the Consequences for (−)-Strand DNA Synthesis

1998 ◽  
Vol 273 (23) ◽  
pp. 14523-14532 ◽  
Author(s):  
Eric J. Arts ◽  
Jennifer T. Miller ◽  
Bernard Ehresmann ◽  
Stuart F. J. Le Grice
Keyword(s):  
Reverse Transcriptase ◽  
Dna Synthesis ◽  
Hiv 1

The double mutation L109M and R448M of HIV-1 reverse transcriptase decreases fidelity of DNA synthesis by promoting mismatch elongation

2015 ◽  
Vol 396 (12) ◽  
pp. 1315-1323
Author(s):  
Bianca Heyn ◽  
Nicole Pogodalla ◽  
Susanne Brakmann
Keyword(s):  
Reverse Transcriptase ◽  
Dna Synthesis ◽  
Error Rate ◽  
Double Mutant ◽  
Dissociation Rate ◽  
Double Mutation ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Simultaneous Substitution

Abstract Changes of Leu109 and Arg448 of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) have as yet not been associated with altered fitness. However, in a recent study, we described that the simultaneous substitution of L109 and R448 by methionine leads to an error-producing polymerase phenotype that is not observed for the isolated substitutions. The double mutant increased the error rate of DNA-dependent DNA synthesis 3.1-fold as compared to the wildtype enzyme and showed a mutational spectrum with a fraction of 28% frameshift mutations and 48% transitions. We show here that weaker binding of DNA:DNA primer-templates as indicated by an increased dissociation rate constant (koff) could account for the higher frameshift error rate. Furthermore, we were able to explain the prevalence of transition mutations with the finding that HIV-1 RT variant L109M/R448M preferred misincorporation of C opposite A and elongation of C:A mismatches.

scholarly journals SJP-L-5 inhibits HIV-1 polypurine tract primed plus-strand DNA elongation, indicating viral DNA synthesis initiation at multiple sites under drug pressure

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Xing-Jie Zhang ◽  
Rui-Rui Wang ◽  
Huan Chen ◽  
Rong-Hua Luo ◽  
Liu-Meng Yang ◽  
...  
Keyword(s):  
Dna Synthesis ◽  
Drug Pressure ◽  
Viral Dna ◽  
Polypurine Tract ◽  
Hiv 1

scholarly journals Crystal structure of HIV-1 reverse transcriptase in complex with a polypurine tract RNA:DNA

2001 ◽  
Vol 20 (6) ◽  
pp. 1449-1461 ◽  
Author(s):  
Stefan G. Sarafianos ◽  
Kalyan Das ◽  
Chris Tantillo ◽  
Arthur D. Clark ◽  
Jianping Ding ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Reverse Transcriptase ◽  
Polypurine Tract ◽  
Hiv 1

scholarly journals 4′-C-Methyl-2′-Deoxyadenosine and 4′-C-Ethyl-2′-Deoxyadenosine Inhibit HIV-1 Replication

2011 ◽  
Vol 55 (5) ◽  
pp. 2379-2389 ◽  
Author(s):  
B. Christie Vu ◽  
Paul L. Boyer ◽  
Maqbool A. Siddiqui ◽  
Victor E. Marquez ◽  
Stephen H. Hughes
Keyword(s):  
Reverse Transcriptase ◽  
Dna Synthesis ◽  
Cultured Cells ◽  
Nucleoside Analogs ◽  
Transcriptase Inhibitor ◽  
Resistance Mutations ◽  
Viral Dna ◽  
Infected Cells ◽  
Hiv 1

ABSTRACTIt is important to develop new anti-HIV drugs that are effective against the existing drug-resistant mutants. Because the excision mechanism is an important pathway for resistance to nucleoside analogs, we are preparing analogs that retain a 3′-OH and can be extended after they are incorporated by the viral reverse transcriptase. We show that 4′-C-alkyl-deoxyadenosine (4′-C-alkyl-dA) compounds can be phosphorylated in cultured cells and can inhibit the replication of HIV-1 vectors: 4′-C-methyl- and 4′-C-ethyl-dA show both efficacy and selectivity against HIV-1. The compounds are also effective against viruses that replicate using reverse transcriptases (RTs) that carry nucleoside reverse transcriptase inhibitor resistance mutations, with the exception of the M184V mutant. Analysis of viral DNA synthesis in infected cells showed that viral DNA synthesis is blocked by the incorporation of either 4′-C-methyl- or 4′-C-ethyl-2′-deoxyadenosine.In vitroexperiments with purified HIV-1 RT showed that 4′-C-methyl-2′-dATP can compete with dATP and that incorporation of the analog causes pausing in DNA synthesis. The 4′-C-ethyl compound also competes with dATP and shows a differential ability to block DNA synthesis on RNA and DNA templates. Experiments that measure the ability of the compounds to block DNA synthesis in infected cells suggest that this differential block to DNA synthesis also occurs in infected cells.

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