A Drug Resistance Mutation in the Inhibitor Binding Pocket of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Impairs DNA Synthesis and RNA Degradation†

Biochemistry ◽  
1996 ◽  
Vol 35 (30) ◽  
pp. 9737-9745 ◽  
Author(s):  
Naisheng Fan ◽  
Kenneth B. Rank ◽  
David E. Slade ◽  
Susan M. Poppe ◽  
David B. Evans ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Drug Resistance ◽  
Dna Synthesis ◽  
Resistance Mutation ◽  
Drug Resistance Mutation ◽  
Binding Pocket ◽  
Rna Degradation ◽  
Inhibitor Binding ◽  
Immunodeficiency Virus

scholarly journals Human Immunodeficiency Virus-1 Sequence Changes and Drug Resistance Mutation Among Virologic Failures of Lopinavir/Ritonavir Monotherapy: AIDS Clinical Trials Group Protocol A5230

2016 ◽  
Vol 3 (3) ◽  
Author(s):  
Saran Vardhanabhuti ◽  
David Katzenstein ◽  
John Bartlett ◽  
Nagalingeswaran Kumarasamy ◽  
Carole L. Wallis
Keyword(s):  
Human Immunodeficiency Virus ◽  
Drug Resistance ◽  
Reverse Transcriptase ◽  
Genetic Distance ◽  
Hamming Distance ◽  
Virologic Failure ◽  
Resistance Mutation ◽  
Drug Resistance Mutation ◽  
Immunodeficiency Virus ◽  
Human Immunodeficiency Virus 1

Abstract Background.  The mechanism of virologic failure (VF) of lopinavir/ritonavir (LPV/r) monotherapy is not well understood. We assessed sequence changes in human immunodeficiency virus-1 reverse-transcriptase (RT) and protease (PR) regions. Methods.  Human immunodeficiency virus-1 pol sequences from 34 participants who failed second-line LPV/r monotherapy were obtained at study entry (SE) and VF. Sequence changes were evaluated using phylogenetic analysis and hamming distance. Results.  Human immunodeficiency virus-1 sequence change was higher over drug resistance mutation (DRM) sites (median genetic distance, 2.2%; Q1 to Q3, 2.1%–2.5%) from SE to VF compared with non-DRM sites (median genetic distance, 1.3%; Q1 to Q3, 1.0%–1.4%; P < .0001). Evolution over DRM sites was mainly driven by changes in the RT (median genetic distance, 2.7%; Q1 to Q3, 2.2%–3.2%) compared with PR (median genetic distance, 1.1%; Q1 to Q3, 0.0%–1.1%; P < .0001). Most RT DRMs present at SE were lost at VF. At VF, 19 (56%) and 26 (76%) were susceptible to efavirenz/nevirapine and etravirine (ETV)/rilpivirine (RPV), respectively, compared with 1 (3%) and 12 (35%) at SE. Participants who retained nonnucleoside reverse-transcriptase inhibitor (NNRTI) DRMs and those without evolution of LPV/r DRMs had significantly shorter time to VF. Conclusions.  The selection of LPV/r DRMs in participants with longer time to VF suggests better adherence and more selective pressure. Fading NNRTI mutations and an increase in genotypic susceptibility to ETV and RPV could allow for the reuse of NNRTI. Further studies are warranted to understand mechanisms of PR failure.

scholarly journals Drug Resistance Mutations in the Nucleotide Binding Pocket of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Differentially Affect the Phosphorolysis-Dependent Primer Unblocking Activity in the Presence of Stavudine and Zidovudine and Its Inhibition by Efavirenz

2005 ◽  
Vol 49 (1) ◽  
pp. 342-349 ◽  
Author(s):  
Emmanuele Crespan ◽  
Giada A. Locatelli ◽  
Reynel Cancio ◽  
Ulrich Hübscher ◽  
Silvio Spadari ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Drug Resistance ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Nucleotide Binding ◽  
Binding Pocket ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) derivatives with D113E, Y115F, F116Y, Q151E/N, and M184V mutations were studied for their phosphorolysis-mediated resistance to the nucleoside RT inhibitors (NRTIs) zidovudine and stavudine and for their inhibition by the nonnucleoside analogs (NNRTIs) efavirenz and nevirapine. The results presented here indicate that these single amino acid substitutions within the nucleotide binding pocket of the viral RT can independently affect different enzymatic properties, such as catalytic efficiency, drug binding, and phosphorolytic activity. Moreover, small local alterations of the physicochemical properties of the microenvironment around the active site can have profound effects on some NRTIs while hardly affecting other ones. In conclusion, even though different mutations within the nucleotide binding pocket of HIV-1 RT can result in a common phenotype (i.e., drug resistance), the molecular mechanisms underlying this phenotype can be very different. Moreover, the same mutation can give rise to different phenotypes depending on the nature of the substrates and/or inhibitors.

scholarly journals Pretreatment human immunodeficiency virus type 1 (HIV-1) drug resistance in transmission clusters of the Cologne-Bonn region, Germany

2019 ◽  
Vol 25 (2) ◽  
pp. 253.e1-253.e4 ◽  
Author(s):  
M. Stecher ◽  
A. Chaillon ◽  
A.M. Eis-Hübinger ◽  
C. Lehmann ◽  
G. Fätkenheuer ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Drug Resistance ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Immunodeficiency Virus ◽  
Hiv 1
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