scholarly journals Human Immunodeficiency Virus Type 1 Isolates with the Reverse Transcriptase (RT) Mutation Q145M Retain Nucleoside and Nonnucleoside RT Inhibitor Susceptibility

2009 ◽  
Vol 53 (5) ◽  
pp. 2196-2198 ◽  
Author(s):  
Vici Varghese ◽  
Yumi Mitsuya ◽  
Rajin Shahriar ◽  
Michael H. Bachmann ◽  
W. Jeffrey Fessel ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Resistance Mutation ◽  
Immunodeficiency Virus ◽  
Inhibitor Resistance ◽  
Rt Inhibitors

ABSTRACT Q145M, a mutation in a conserved human immunodeficiency virus type 1 reverse transcriptase (RT) region, was reported to decrease susceptibility to multiple RT inhibitors. We report that Q145M and other Q145 mutations do not emerge with RT inhibitors nor decrease RT inhibitor susceptibility. Q145M should not, therefore, be considered an RT inhibitor resistance mutation.

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.

Effects of Human Immunodeficiency Virus Type 1 Resistance to Protease Inhibitors on Reverse Transcriptase Processing, Activity, and Drug Sensitivity

1999 ◽  
Vol 73 (4) ◽  
pp. 3455-3459 ◽  
Author(s):  
Laurence Carron de la Carrière ◽  
Sylvie Paulous ◽  
François Clavel ◽  
Fabrizio Mammano
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Protease Inhibitors ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Resistance Mutations ◽  
Immunodeficiency Virus ◽  
Rt Inhibitors ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) variants resistant to protease inhibitors often display a reduced replicative capacity as a result of an impairment of protease function. Such fitness-impaired viruses display Gag precursor maturation defects. Here, we report that some protease inhibitor-resistant viruses also display abnormalities in the processing of reverse transcriptase (RT) by the protease. In three recombinant viruses carrying resistant protease sequences from patient plasma, we observed a marked decrease in the amount of mature RT subunits and of particle-associated RT activity compared to their parental pretherapy counterparts. We investigated the possibility that a decrease in the amount of particle-associated mature RT could affect the sensitivity of the corresponding virus to RT inhibitors. We observed a twofold increase of sensitivity to zidovudine (AZT) when a virus which carried AZT mutations was processed by a resistant protease. Interestingly, the presence of AZT-resistance mutations partially rescued the replication defect associated with the mutated protease. The interplay between resistance to protease inhibitors and to RT inhibitors described here may be relevant to the therapeutic control of HIV-1 infection.

scholarly journals Genotypic and phenotypic changes during culture of a multinucleoside-resistant human immunodeficiency virus type 1 strain in the presence and absence of additional reverse transcriptase inhibitors.

1996 ◽  
Vol 40 (12) ◽  
pp. 2887-2890 ◽  
Author(s):  
R W Shafer ◽  
M A Winters ◽  
A K Iversen ◽  
T C Merigan
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Reverse Transcriptase Inhibitors ◽  
Lamivudine Resistance ◽  
Immunodeficiency Virus ◽  
Rt Inhibitors ◽  
Hiv 1

The observation that human immunodeficiency virus type 1 (HIV-1) mutations conferring resistance to one reverse transcriptase (RT) inhibitor may suppress resistance to other RT inhibitors provides a rationale for treating HIV-1 with certain RT inhibitor combinations. We examined phenotypic and genotypic changes during culture of a multinucleoside (zidovudine, didanosine, zalcitibine, and stavudine)-resistant HIV-1 strain with and without additional RT inhibitors (nevirapine and lamivudine). The development of nevirapine or lamivudine resistance by the multinucleoside-resistant strain was not accompanied by a reduction in zidovudine or didanosine resistance.

scholarly journals Variants Other than Aspartic Acid at Codon 69 of the Human Immunodeficiency Virus Type 1 Reverse Transcriptase Gene Affect Susceptibility to Nucleoside Analogs

2001 ◽  
Vol 45 (8) ◽  
pp. 2276-2279 ◽  
Author(s):  
Mark A. Winters ◽  
Thomas C. Merigan
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Gene Mutations ◽  
Nucleoside Analogs ◽  
Drug Susceptibility ◽  
Immunodeficiency Virus ◽  
Rt Inhibitors

ABSTRACT The T69D mutation in the human immunodeficiency virus type 1 reverse transcriptase (RT) gene has been associated with reduced susceptibility to dideoxycytosine (ddC); however, several other mutations at codon 69 have been observed in antiretroviral drug-treated patients. The Stanford HIV RT and Protease Sequence Database was interrogated and showed that 23% of patients treated with nucleoside RT inhibitors (NRTI) had mutations at codon 69. These variants included T69N, -S, -A, -G, -E, -I, and -K mutations that were present in patients treated with NRTI but not in drug-naive patients. Treatment history information showed that a substantial percentage of these codon 69 changes occurred in patients administered non-ddC-containing regimens. Different and specific patterns of other RT gene mutations were associated with the various codon 69 mutations. Drug susceptibility assays showed that viral constructs containing codon 69 variants could have reduced susceptibility to ddC and other RT inhibitors. These results suggest that the T69D mutation is not the only codon 69 variant associated with drug resistance and that ddC is not the only drug affected.

scholarly journals Minority Human Immunodeficiency Virus Type 1 Variants in Antiretroviral-Naive Persons with Reverse Transcriptase Codon 215 Revertant Mutations

2008 ◽  
Vol 82 (21) ◽  
pp. 10747-10755 ◽  
Author(s):  
Yumi Mitsuya ◽  
Vici Varghese ◽  
Chunlin Wang ◽  
Tommy F. Liu ◽  
Susan P. Holmes ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Resistance Mutations ◽  
Immunodeficiency Virus ◽  
Inhibitor Resistance ◽  
Hiv 1 ◽  
Control Samples

ABSTRACT T215 revertant mutations such as T215C/D/E/S that evolve from the nucleoside reverse transcriptase (RT) inhibitor mutations T215Y/F have been found in about 3% of human immunodeficiency virus type 1 (HIV-1) isolates from newly diagnosed HIV-1-infected persons. We used a newly developed sequencing method—ultradeep pyrosequencing (UDPS; 454 Life Sciences)—to determine the frequency with which T215Y/F or other RT inhibitor resistance mutations could be detected as minority variants in samples from untreated persons that contain T215 revertants (“revertant” samples) compared with samples from untreated persons that lack such revertants (“control” samples). Among the 22 revertant and 29 control samples, UDPS detected a mean of 3.8 and 4.8 additional RT amino acid mutations, respectively. In 6 of 22 (27%) revertant samples and in 4 of 29 control samples (14%; P = 0.4), UDPS detected one or more RT inhibitor resistance mutations. T215Y or T215F was not detected in any of the revertant or control samples; however, 4 of 22 revertant samples had one or more T215 revertants that were detected by UDPS but not by direct PCR sequencing. The failure to detect viruses with T215Y/F in the 22 revertant samples in this study may result from the overwhelming replacement of transmitted T215Y variants by the more fit T215 revertants or from the primary transmission of a T215 revertant in a subset of persons with T215 revertants.

scholarly journals Genotypic and Phenotypic Resistance Patterns of Human Immunodeficiency Virus Type 1 Variants with Insertions or Deletions in the Reverse Transcriptase (RT): Multicenter Study of Patients Treated with RT Inhibitors

2001 ◽  
Vol 45 (6) ◽  
pp. 1836-1842 ◽  
Author(s):  
Bernard Masquelier ◽  
Esther Race ◽  
Catherine Tamalet ◽  
Diane Descamps ◽  
Jacques Izopet ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Multicenter Study ◽  
Phenotypic Resistance ◽  
Immunodeficiency Virus ◽  
Rt Inhibitors ◽  
Hiv 1

ABSTRACT Genomic rearrangements in the 5′ part of the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) have been involved in multidrug resistance to nucleoside RT inhibitors (NRTI). We carried out a retrospective, multicenter study to investigate the prevalence, variability, and phenotypic consequences of such rearrangements. Data concerning the HIV-1 RT genotype and the biological and clinical characteristics of NRTI-treated patients were collected from 10 virology laboratories. Sensitivities of the different HIV-1 variants to RT inhibitors were analyzed in a single-cycle recombinant virus assay. Fifty-two of 2,152 (2.4%) RT sequences had a rearrangement in the 5′ part of the RT, with an extensive molecular variation. The number of codons inserted between positions 68 and 69 ranged from 1 (3 samples) or 2 (41 samples) to 5 and 11 in one case each. In four cases, codon 67 was deleted. High levels of phenotypic resistance to zidovudine (AZT), lamivudine (3TC), stavudine (d4T), abacavir (ABC), and didanosine (ddI) were found in 95, 92, 72, 62, and 15% of the 40 samples analyzed, respectively. Resistance to AZT, d4T, and ABC could be found in the absence of the T215Y/F mutations. Resistance to 3TC could develop in the absence of specific mutations. Low-level resistance to ddI was noticed in 40% of the patients. The deletions of codon 67 seemed to have little effect on NRTI sensitivity. Most of the rearrangements were shown to contribute to cross-resistance to NRTI. The results regarding susceptibility to ddI raise the question of the interpretation of the phenotypic data concerning this drug.

scholarly journals The Level of Reverse Transcriptase (RT) in Human Immunodeficiency Virus Type 1 Particles Affects Susceptibility to Nonnucleoside RT Inhibitors but Not to Lamivudine

2006 ◽  
Vol 80 (5) ◽  
pp. 2578-2581 ◽  
Author(s):  
Zandrea Ambrose ◽  
John G. Julias ◽  
Paul L. Boyer ◽  
Vineet N. KewalRamani ◽  
Stephen H. Hughes
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Nonnucleoside Reverse Transcriptase Inhibitors ◽  
Immunodeficiency Virus ◽  
Rt Inhibitors ◽  
The Relationship ◽  
Hiv 1

ABSTRACT We investigated the relationship between the level of reverse transcriptase (RT) in human immunodeficiency virus type 1 (HIV-1) particles and susceptibility to nonnucleoside reverse transcriptase inhibitors (NNRTIs). HIV-1 virions containing different active levels of RT were generated. Susceptibility to the NNRTIs efavirenz and nevirapine was inversely proportional to the level of enzymatically active RT. However, the sensitivity of HIV-1 to the nucleoside analog 3TC was not affected by the level of RT per particle. These data indicate that the susceptibility of HIV-1 to NNRTIs is influenced by RT activity.

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