Variations in HIV-1 pol gene associated with reduced sensitivity to antiretroviral drugs in treatment-naive patients

Birk, Markus; Sönnerborg, Anders

doi:10.1097/00002030-199818000-00005

Cited by 55 publications

(28 citation statements)

References 38 publications

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“…To examine the frequency of major (20M; 24I; 30N; 48V; 50V; 82A, 82F, or 82T; 84V; and 90 M) and secondary (10I, 10V, or 10R; 20R; 32I; 33F; 36I; 46I or 46L; 63P; 71V or 71T; 73S; 77I; and 88D) PI resistance-associated substitutions within the PR region, we analyzed the sequences at these 19 amino acid sites, which are associated in vivo with HIV-1 resistance to saquinavir, ritonavir, indinavir, nelfinavir, and amprenavir in subtype B viruses (3,12). Our data revealed the presence of such substitutions at six positions (103I or V, 203R or M, 243I, 363I, 633P, and 773I).…”

Section: Resultsmentioning

confidence: 99%

Human Immunodeficiency Virus Type 1 Group M Protease in Cameroon: Genetic Diversity and Protease Inhibitor Mutational Features

Fonjungo¹,

Mpoudi²,

Torimiro³

et al. 2002

J Clin Microbiol

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To establish a baseline for monitoring resistance to protease inhibitors (PIs) and examining the efficacy of their use among persons in Cameroon infected with human immunodeficiency virus type 1 (HIV-1), we analyzed genetic variability and PI resistance-associated substitutions in PCR-amplified protease (PR) sequences in strains isolated from 110 HIV-1-infected, drug-naïve Cameroonians. Of the 110 strains, 85 were classified into six HIV-1 PR subtypes, A (n ‫؍‬ 1), B (n ‫؍‬ 1), F (n ‫؍‬ 4), G (n ‫؍‬ 7), H (n ‫؍‬ 1), and J (n ‫؍‬ 7), and a circulating recombinant form, CRF02-AG (n ‫؍‬ 64). PR genes from the remaining 25 (23%) specimens were unclassifiable, whereas 2% (7 of 301) unclassifiable PR sequences were reported for a global collection. Two major PI resistance-associated mutations, 20M and 24I, were detected in strains from only two specimens, whereas secondary mutations were found in strains from all samples except one strain of subtype B and two strains of CRF02-AG. The secondary mutations showed the typical PI resistance-associated pattern for non-subtype B viruses in both classifiable and unclassifiable PR genes, with 36I being the predominant (99%) mutation, followed by 63P (18%), 20R (15%), 77I (13%), and 10I or 10V (11%). Of these mutations, dual and triple PI resistance-associated substitutions were found in 38% of all the Cameroonian strains. Compared with classifiable PR sequences, unclassifiable sequences had significantly more dual and triple substitutions (64% versus 30%; P ‫؍‬ 0.004). Phenotypic and clinical evaluations are needed to estimate whether PI resistance during antiretroviral drug treatment occurs more rapidly in individuals infected with HIV-1 strains harboring multiple PI resistance-associated substitutions. This information may be important for determination of appropriate drug therapies for HIV-1-infected persons in Cameroon, where more than one-third of HIV-1 strains were found to carry dual and triple minor PI resistance-associated mutations.

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Section: Resultsmentioning

confidence: 99%

Human Immunodeficiency Virus Type 1 Group M Protease in Cameroon: Genetic Diversity and Protease Inhibitor Mutational Features

Fonjungo¹,

Mpoudi²,

Torimiro³

et al. 2002

J Clin Microbiol

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“…Amino acid substitutions at positions 98, 138, 139, and 190, which have been associated with phenotypic or secondary (lowlevel) resistance to NNRTIs, were also observed. Additional mutations were detected, including K70R implicated in resistance to ZDV (8,35) and the common polymorphism L214F that has been previously suggested to play an accessory role in the presence of certain mutations that confer dual resistance to ZDV and lamivudine (37).…”

Section: Vol 46 2002 Hiv Subtype Differences In Nnrti Resistance 2089mentioning

confidence: 97%

“…Characterization of the genotypic divergence of pol sequences among different HIV-1 subtypes is not yet complete, although the reverse transcriptase (RT) and protease (PR) enzymes are the major targets of antiretroviral therapy (3,8,10,11). Both in vitro and in vivo evolution of RT polymorphism and the appearance of resistance mutations have been extensively documented for subtype B viruses (8,16,17,31,33,35). Little information is available on the impact of viral subtype diversity on natural susceptibility to antiretroviral drugs.…”

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confidence: 99%

Genetic Divergence of Human Immunodeficiency Virus Type 1 Ethiopian Clade C Reverse Transcriptase (RT) and Rapid Development of Resistance against Nonnucleoside Inhibitors of RT

Loemba

Brenner

Parniak

et al. 2002

Antimicrob Agents Chemother

109

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We sequenced and phylogenetically analyzed the reverse transcriptase (RT) region of five human immunodeficiency virus type 1 isolates from treatment-naive Ethiopian émigrés to Israel. Heteroduplex mobility assays were performed to confirm the clade C status of env genomic regions. The RT sequences showed that the strains clustered phylogenetically with clade C viruses, and a KVEQ-specific motif of silent mutations (amino acids 65, 106, 138, and 161, respectively) at resistance sites was present in the polymerase region of all studied Ethiopian isolates and subtype C reference strains. In addition, many other silent mutations were observed in the clade C viruses at various resistance sites. In general, the Ethiopian isolates were more closely related genotypically to a clade C reference strain from Botswana (southern Africa) than to previously sequenced Ethiopian reference strains. Genotypic analysis showed that two Ethiopian isolates naturally harbored the mutations K70R and G190A associated with resistance to ZDV and nonnucleoside reverse transcriptase inhibitors, respectively. Phenotypic assays revealed that the K70R substitution in this context did not reduce susceptibility to ZDV, whereas the G190A substitution resulted in high-level resistance to nevirapine (NVP). Moreover, variants resistant to NVP, delavirdine (DLV), and efavirenz (EFV) were more rapidly selected at lower drug doses culture with clade C than with clade B wild-type isolates. In the case of subtype C, selection with NVP and/or EFV led to the appearance of several previously unseen mutations in RT, i.e., V106M and S98I, as well as other mutations that have been previously reported (e.g., K103N, V106A, V108I, and Y181C). After selection with DLV, a polymorphism, A62A, initially observed in the Ethiopian isolate 4762, mutated to A62V; the latter is a secondary substitution associated with multidrug resistance against nucleoside RT inhibitors. Phenotypic analysis of clade C mutants selected against NVP, DLV, and EFV revealed broad cross-resistance, particularly in regard to NVP and DLV. These findings suggest that RT genotypic diversity may influence the emergence of drug resistance.

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“…The protease from a sample of untreated patients has shown substitutions affecting more than 45% of the amino acid residues, compatible with sufficient flexibility of the enzyme (13,24). The impact of these polymorphisms on treatment outcome has yet to be understood (1,2). Primary resistance mutations located at the active site arise upon treatment.…”

mentioning

confidence: 99%

Variant Human Immunodeficiency Virus Type 1 Proteases and Response to Combination Therapy Including a Protease Inhibitor

Servais¹,

Lambert²,

Fontaine³

et al. 2001

Antimicrob Agents Chemother

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Variations in HIV-1 pol gene associated with reduced sensitivity to antiretroviral drugs in treatment-naive patients

Cited by 55 publications

References 38 publications

Human Immunodeficiency Virus Type 1 Group M Protease in Cameroon: Genetic Diversity and Protease Inhibitor Mutational Features

Human Immunodeficiency Virus Type 1 Group M Protease in Cameroon: Genetic Diversity and Protease Inhibitor Mutational Features

Genetic Divergence of Human Immunodeficiency Virus Type 1 Ethiopian Clade C Reverse Transcriptase (RT) and Rapid Development of Resistance against Nonnucleoside Inhibitors of RT

Variant Human Immunodeficiency Virus Type 1 Proteases and Response to Combination Therapy Including a Protease Inhibitor

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