Inhibition of human immunodeficiency virus type-1 reverse transcriptase by a novel peptide derived from the viral integrase

2007 ◽  
Vol 458 (2) ◽  
pp. 202-212 ◽  
Author(s):  
Iris Oz Gleenberg ◽  
Alon Herschhorn ◽  
Yehuda Goldgur ◽  
Amnon Hizi
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Immunodeficiency Virus

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

scholarly journals Novel Nonnucleoside Inhibitors That Select Nucleoside Inhibitor Resistance Mutations in Human Immunodeficiency Virus Type 1 Reverse Transcriptase

2006 ◽  
Vol 50 (8) ◽  
pp. 2772-2781 ◽  
Author(s):  
Zhijun Zhang ◽  
Michelle Walker ◽  
Wen Xu ◽  
Jae Hoon Shim ◽  
Jean-Luc Girardet ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Immunodeficiency Virus ◽  
Nonnucleoside Inhibitors ◽  
Rt Inhibitors ◽  
Hiv 1 ◽  
M184v Mutation

ABSTRACT Mutations in and around the catalytic site of the reverse transcriptase (RT) of human immunodeficiency virus type 1 (HIV-1) are associated with resistance to nucleoside RT inhibitors (NRTIs), whereas changes in the hydrophobic pocket of the RT are attributed to nonnucleoside RT inhibitor (NNRTI) resistance. In this study, we report a novel series of nonnucleoside inhibitors of HIV-1, exemplified by VRX-329747 and VRX-413638, which inhibit both NNRTI- and NRTI-resistant HIV-1 isolates. Enzymatic studies indicated that these compounds are HIV-1 RT inhibitors. Surprisingly, however, following prolonged (6 months) tissue culture selection, this series of nonnucleoside inhibitors did not select NNRTI-resistant mutations in HIV-1 RT. Rather, four mutations (M41L, A62T/V, V118I, and M184V) known to cause resistance to NRTIs and two additional novel mutations (S68N and G112S) adjacent to the catalytic site of the enzyme were selected. Although the M184V mutation appears to be the initial mutation to establish resistance, this mutation alone confers only a two- to fourfold decrease in susceptibility to VRX-329747 and VRX-413638. At least two additional mutations must accumulate for significant resistance. Moreover, while VRX-329747-selected viruses are resistant to lamivudine and emtricitabine due to the M184V mutation, they remain susceptible to zidovudine, stavudine, dideoxyinosine, abacavir, tenofovir, and efavirenz. These results directly demonstrate that VRX-329747 and VRX-413638 are novel nonnucleoside inhibitors of HIV-1 RT with the potential to augment current therapies.

scholarly journals Biochemical Studies on the Mechanism of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Resistance to 1-(β-d-Dioxolane)Thymine Triphosphate

2007 ◽  
Vol 51 (6) ◽  
pp. 2078-2084 ◽  
Author(s):  
Johan Lennerstrand ◽  
Chung K. Chu ◽  
Raymond F. Schinazi
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Nucleoside Analogs ◽  
Nucleotide Analogs ◽  
Immunodeficiency Virus ◽  
Large Panel ◽  
Tenofovir Diphosphate

ABSTRACT A large panel of drug-resistant mutants of human immunodeficiency virus type 1 reverse transcriptase (RT) was used to study the mechanisms of resistance to 1-(β-d-dioxolane)thymine triphosphate (DOT-TP) and other nucleotide analogs. RT containing thymidine analog-associated mutations (TAM) or RT with a T69S-SG insertion in combination with TAM removed 3′-azido-3′-deoxythymidine-5′-monophosphate or tenofovir more efficiently than DOT-monophosphate from chain-terminated DNA primer/template through ATP-mediated pyrophosphorolysis. For non-ATP-dependent discrimination toward DOT-TP, high levels of resistance were found for RT bearing the Q151M mutation with family mutations, while RT bearing only the M184V or the Y115F mutation conferred no resistance to DOT-TP. A lower degree of resistance to DOT-TP than to tenofovir diphosphate or carbovir-TP was found for RT containing the K65R mutation. In the present studies, 1-(β-d-dioxolane)guanine triphosphate, another nucleotide with a dioxolane sugar moiety, showed a resistance profile similar to that of DOT-TP. The results suggest that DOT, compared with other approved nucleoside analogs, is overall more resilient to mutations such as TAM, M184V, and K65R, which are commonly found in viruses derived from subjects failing multinucleoside therapy.

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