Isolation of drug-resistant variants of HIV-1 from patients on long-term zidovudine therapy

Rooke, Ronald; Tremblay, Michel J.; Soudeyns, Hugo; Destephano, L; Yao, Xiaojian; Fanning, Mary M.; Js, Montaner; O’Shaughnessy, Michael V.; Gelmon, K.A.; Tsoukas, Christos

doi:10.1097/00002030-198907000-00001

Cited by 178 publications

(82 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These viruses were found to contain up to five mutations (four amino acid substitutions) in the pol gene of HIV (16). Other studies have now confirmed that HIV regularly acquires resistance during AZT therapy (3,12,24) and that this resistance is associated with the presence of one or more of these mutations (3,15,17).…”

mentioning

confidence: 92%

Human immunodeficiency virus type 1 pol gene mutations which cause decreased susceptibility to 2',3'-dideoxycytidine

Fitzgibbon

Howell

Haberzettl

et al. 1992

Antimicrob Agents Chemother

185

104

View full text Add to dashboard Cite

To investigate whether human immunodeficiency virus type 1 pol gene mutations are selected during prolonged 2',3'-dideoxycytidine (ddC) therapy, we used the polymerase chain reaction to amplify a portion of the reverse transcriptase segment of the pol gene from the peripheral blood mononuclear cell DNA of a patient with AIDS before and after an 80-week course of ddC therapy. The consensus sequence from the second sample contained a unique double mutation (ACT to GAT) in the codon for reverse transcriptase amino acid 69, causing substitution of aspartic acid (Asp) for the wild-type threonine (Thr). A mutation (ACA to ATA) also occurred in the codon for position 165, causing substitution of isoleucine (Ile) for Thr. The GAT (Asp) codon was introduced into the pol gene of a molecular clone of human immunodeficiency virus via site-directed mutagenesis. Following transfection, mutant and wild-type viruses were tested for susceptibility to ddC by a plaque reduction assay. The mutant virus was fivefold less susceptible to ddC than the wild type; crossresistance to 3'-azido-3'-deoxythymidine or 2'3'-dideoxyinosine was not found. The lle-165 mutation did not confer additional ddC resistance. The Asp-69 substitution may have contributed to the generation of resistant virus in this patient.

show abstract

mentioning

confidence: 92%

Human immunodeficiency virus type 1 pol gene mutations which cause decreased susceptibility to 2',3'-dideoxycytidine

Fitzgibbon

Howell

Haberzettl

et al. 1992

Antimicrob Agents Chemother

185

104

View full text Add to dashboard Cite

show abstract

“…Variants of HIV highly resistant to zidovudine (AZT, Retrovir) have been isolated from AIDS patients receiving prolonged treatment (Boucher et al, 1990;Land et al, 1990;Richman et al, 1990;Rooke et al, 1989). High level resistance to zidovudine can be mediated by the acquisition of four specific amino acid substitutions in the RT of HIV-1 (Asp-67 ~Asn; Lys-70~Arg; Thr-215 ~Tyr or Phe; Lys-219 ~Gln) (Larder & Kemp, 1989).…”

Section: Introductionmentioning

confidence: 99%

Zidovudine treatment results in the selection of human immunodeficiency virus type 1 variants whose genotypes confer increasing levels of drug resistance

Kellam

Boucher

Tijnagel

et al. 1994

Journal of General Virology

View full text Add to dashboard Cite

High level resistance to 3'-azido-3'-deoxythymidine (AZT, zidovudine or Retrovir) is conferred by the presence of four or five mutations (Met-41 ~ Leu; Asp-67 ~ Asn; Lys-70 ~ Arg; Thr-215 ~ Tyr or Phe; Lys-219 ~ Gin) in the human immunodeficiency virus (HIV) reverse transcriptase. The order of appearance of these five mutations in asymptomatic patients during therapy has been studied. This has enabled us to propose a model for the acquisition of zidovudine resistance mutations during the treatment of high-risk asymptomatic HIV-infeeted individuals. A consistent acquisition pattern of mutations at codons 41, 70 and 215 was observed in 17 individuals. Complex mixtures of HIV species containing different combinations of single and linked double resistance mutations were present early in zidovudine therapy in isolates from two patients studied in detail. From these mixtures the linked Leu-41/Tyr-215 genotype outgrew all others initially. The development of each new virus population is likely to be mediated primarily by the increase in the level of drug resistance rather than changes in the growth kinetics of the virus. This leads us to conclude that one major driving force in the outgrowth of different mutant viruses is the selective advantage conferred by higher levels of drug resistance.

show abstract

“…HIV-1 variants that possess a drug resistance phenotype can be isolated from patients undergoing prolonged antiviral chemotherapy Rooke et al, 1989) and can be selected in vitro by culture passage in the presence of increasing concentrations of drugs (Gao et al, 1992;Larder et al, 1991). HIV-1 resistance against a wide array of drugs has been identified (Eron et al, 1993;St Clair et al, 1991).…”

mentioning

confidence: 99%

“…In view of the fact that the development of HIV-1 drug resistance Rooke et al, 1989) and the SI phenotype (Boucher et al, 1992;Tersmette et aL, 1988) are independently associated with clinical progression, it is tempting to hypothesize that the fusion of HIV-l-infected cells contributes to genetic recombination in either of two ways. First, fusion and genomic recombination could result in the acquisition of double or multiple resistance, as hypothesized here.…”

mentioning

confidence: 99%

Possible involvement of cell fusion and viral recombination in generation of human immunodeficiency virus variants that display dual resistance to AZT and 3TC

Gao

Faust

et al. 1995

Journal of General Virology

View full text Add to dashboard Cite

Isolation of drug-resistant variants of HIV-1 from patients on long-term zidovudine therapy

Cited by 178 publications

References 0 publications

Human immunodeficiency virus type 1 pol gene mutations which cause decreased susceptibility to 2',3'-dideoxycytidine

Human immunodeficiency virus type 1 pol gene mutations which cause decreased susceptibility to 2',3'-dideoxycytidine

Zidovudine treatment results in the selection of human immunodeficiency virus type 1 variants whose genotypes confer increasing levels of drug resistance

Possible involvement of cell fusion and viral recombination in generation of human immunodeficiency virus variants that display dual resistance to AZT and 3TC

Contact Info

Product

Resources

About