scholarly journals Broad Nucleoside‐Analogue Resistance Implications for Human Immunodeficiency Virus Type 1 Reverse‐Transcriptase Mutations at Codons 44 and 118

2002 ◽  
Vol 185 (7) ◽  
pp. 898-904 ◽  
Author(s):  
Laura Romano ◽  
Giulietta Venturi ◽  
Stuart Bloor ◽  
Richard Harrigan ◽  
Brendan A. Larder ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Nucleoside Analogue ◽  
Immunodeficiency Virus

scholarly journals Influence of naturally occurring insertions in the fingers subdomain of human immunodeficiency virus type 1 reverse transcriptase on polymerase fidelity and mutation frequencies in vitro

2006 ◽  
Vol 87 (2) ◽  
pp. 419-428 ◽  
Author(s):  
Kenneth Curr ◽  
Snehlata Tripathi ◽  
Johan Lennerstrand ◽  
Brendan A. Larder ◽  
Vinayaka R. Prasad
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Nucleoside Analogue ◽  
Binding Pocket ◽  
Resistance Mutations ◽  
Immunodeficiency Virus

The fingers subdomain of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) is a hotspot for nucleoside analogue resistance mutations. Some multi-nucleoside analogue-resistant variants contain a T69S substitution along with dipeptide insertions between residues 69 and 70. This set of mutations usually co-exists with classic zidovudine-resistance mutations (e.g. M41L and T215Y) or an A62V mutation and confers resistance to multiple nucleoside analogue inhibitors. As insertions lie in the vicinity of the dNTP-binding pocket, their influence on RT fidelity was investigated. Commonly occurring insertion mutations were selected, i.e. T69S-AG, T69S-SG and T69S-SS alone, in combination with 3′-azido-2′,3′-deoxythymidine-resistance mutations M41L, L210W, R211K, L214F, T215Y (LAGAZ and LSGAZ) or with an alternate set where A62V substitution replaces M41L (VAGAZ, VSGAZ and VSSAZ). Using a lacZα gapped duplex substrate, the forward mutation frequencies of recombinant wild-type and mutant RTs bearing each of the above sets of mutations were measured. All of the mutants displayed significant decreases in mutation frequencies. Whereas the dipeptide insertions alone showed the least decrease (4·0- to 7·5-fold), the VAG series showed an intermediate reduction (5·0- to 11·4-fold) and the LAG set showed the largest reduction in mutation frequencies (15·3- and 16·3-fold for LAGAZ and LSGAZ, respectively). Single dNTP exclusion assays for mutants LSGAZ and LAGAZ confirmed their large reduction in misincorporation efficiencies. The increased in vitro fidelity was not due to excision of the incorrect nucleotide via ATP-dependent removal. There was also no direct correlation between increased fidelity and template–primer affinity, suggesting a change in the active site that is conducive to better discrimination during dNTP insertion.

scholarly journals Convergent Evolution of Reverse Transcriptase (RT) Genes of Human Immunodeficiency Virus Type 1 Subtypes E and B following Nucleoside Analogue RT Inhibitor Therapies

2000 ◽  
Vol 74 (11) ◽  
pp. 5357-5362 ◽  
Author(s):  
Hironori Sato ◽  
Yasuhiro Tomita ◽  
Kayo Shibamura ◽  
Teiichiro Shiino ◽  
Tuyoshi Miyakuni ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Amino Acid ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Nucleoside Analogue ◽  
Subtype B ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Changes in the drug susceptibility, gene lineage, and deduced amino acid sequences of the reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) subtype E following 3′-azido-3′-deoxythymidine (AZT) monotherapy or AZT–2′,3′-dideoxyinosine combination therapy were examined with sequential virus isolates from a single family. The changes were compared to those reported for HIV-1 subtype B, revealing striking similarities in selected phenotype and amino acids independent of differences in the RT backbone sequences that constantly distinguish the two subtypes. Particularly, identical amino acid substitutions were present simultaneously at four different positions (D67N, K70R, T215F, and K219Q) for high-level AZT resistance. These data suggest that HIV-1 subtypes E and B evolve convergently at the phenotypic and amino acid levels when the nucleoside analogue RT inhibitors act as selective forces.

Mutational analysis of Phe160 within the “palm” subdomain of human immunodeficiency virus type 1 reverse transcriptase 1 1Edited by J. Karn

1999 ◽  
Vol 290 (3) ◽  
pp. 615-625 ◽  
Author(s):  
Mónica Gutiérrez-Rivas ◽  
Ángela Ibáñez ◽  
Miguel A Martı́nez ◽  
Esteban Domingo ◽  
Luis Menéndez-Arias
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Mutational Analysis ◽  
Immunodeficiency Virus
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