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Titolo:
Impact of clinical reverse transcriptase sequences on the replication capacity of HIV-1 drug-resistant mutants
Autore:
Dykes, C; Fox, K; Lloyd, A; Chiulli, M; Morse, E; Demeter, LM;
Indirizzi:
Univ Rochester, Med Ctr, Dept Med, Infect Dis Unit, Rochester, NY 14642 USA Univ Rochester Rochester NY USA 14642 t Dis Unit, Rochester, NY 14642 USA SUNY Buffalo, Dept Pharm Practice, Buffalo, NY 14260 USA SUNY Buffalo Buffalo NY USA 14260 t Pharm Practice, Buffalo, NY 14260 USA Univ Rochester, Dept Microbiol & Immunol, Rochester, NY 14642 USA Univ Rochester Rochester NY USA 14642 & Immunol, Rochester, NY 14642 USA
Titolo Testata:
VIROLOGY
fascicolo: 2, volume: 285, anno: 2001,
pagine: 193 - 203
SICI:
0042-6822(20010705)285:2<193:IOCRTS>2.0.ZU;2-6
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN-IMMUNODEFICIENCY-VIRUS; PROTEASE INHIBITORS; NONNUCLEOSIDE INHIBITORS; DELAVIRDINE MONOTHERAPY; TYPE-1 RESISTANCE; IN-VITRO; MUTATIONS; THERAPY; FITNESS; ZIDOVUDINE;
Keywords:
human immunodeficiency virus type-1 (HIV-1); nonnucleoside reverse transcriptase inhibitors (NNRTIs); reverse transcriptase; replication fitness; compensatory mutations; drug resistance;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
40
Recensione:
Indirizzi per estratti:
Indirizzo: Demeter, LM Univ Rochester, Med Ctr, Dept Med, Infect Dis Unit, Box 689,601 Elmwood Ave, Rochester, NY 14642 USA Univ Rochester Box 689,601 Elmwood Ave Rochester NY USA 14642
Citazione:
C. Dykes et al., "Impact of clinical reverse transcriptase sequences on the replication capacity of HIV-1 drug-resistant mutants", VIROLOGY, 285(2), 2001, pp. 193-203

Abstract

We have shown that the HIV-1 laboratory strain NL4-3 that contains P236L [a reverse transcriptase mutation conferring resistance to the nonnucleosidereverse transcriptase inhibitor (NRTI) delavirdine] replicates more slowlythan wild type NL4-3. Other NNRTI-resistance mutations, such as K103N and Y181C, do not reduce the replication capacity of NL4-3 as much as P236L anddevelop more frequently in HIV-1 isolates from patients failing delavirdine. However, a minority of patients on delavirdine therapy still have isolates with P236L. We postulated that reverse transcriptase (RT) sequences fromthese patient isolates contain other mutations that compensate for the adverse effect of P236L. To test this hypothesis, we created 15 chimeric NL4-3isolates that contained a delavirdine-resistant RT sequences derived from eight patient isolates and characterized their replication kinetics. Nine of 10 patient-derived clones containing P236L replicated as slowly as NL4-3 with P236L. In contrast, three of five clones that did not have P236L (but had either K103N or Y181C) replicated significantly better than NL4-3 with P236L. Thus, the majority of patients who acquire P236L during delavirdine therapy do not have RT mutations that compensate for the replication defectconferred by P236L. We hypothesize that HIV-1 isolates with P236L may havea compensatory mutation outside RT. Alternatively, variants of HIV-1 with reduced replication fitness may be selected during antiretroviral therapy, suggesting that stochastic events rather than viral replication fitness maydetermine which drug-resistant mutants emerge early during antiretroviral failure. In some isolates, it appears that the background RT sequence can contribute significantly to the replication fitness of drug-resistant HIV-1 variants. (C) 2001 Academic Press.

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Documento generato il 13/07/20 alle ore 08:01:18