In vivo resistance to a human immunodeficiency virus type 1 proteinase inhibitor: mutations, kinetics, and frequencies.

Met exchange was the predominant resistance mutation in vivo; Gly48-->Val or doubly mutant virus was rarely observed. After 8-12 months of treatment with saquinavir alone (600 mg, 3 times/day) or in combination with zidovudine (200 mg, 3 times/day), approximately 45% of all patients carried provirus with mutant proteinase; the incidence was lower (22%) in patients treated with a combination of saquinavir, zidovudine, and dideoxycytidine. There was a good relationship between genotypic analysis of saquinavir resistance and data from virus assays, confirming that Leu90-->Met and Gly48-->Val are the essential exchanges in the proteinase that determine loss of sensitivity to this inhibitor. Absence of genotypic resistance correlated with a sustained decrease in plasma viral RNA. There was a positive correlation between a Met90 mutation and some residues at natural polymorphic sites (positions 10, 36, 63, and 71). -->
Substance Nomenclature: 0 (Antiviral Agents)
0 (DNA, Viral)
0 (HIV Protease Inhibitors)
0 (Isoquinolines)
0 (Quinolines)
0 (RNA, Viral)
0 (Viral Structural Proteins)
EC 3.4.23.- (HIV Protease)
L3JE09KZ2F (Saquinavir)
Entry Date(s): Date Created: 19960601 Date Completed: 19960725 Latest Revision: 20190512
Update Code: 20221213
DOI: 10.1093/infdis/173.6.1379
PMID: 8648209
Autor: Jacobsen H; F. Hoffman-La Roche AG, PRP/Gene Technology, Basel, Switzerland., Hänggi M, Ott M, Duncan IB, Owen S, Andreoni M, Vella S, Mous J
Jazyk: angličtina
Zdroj: The Journal of infectious diseases [J Infect Dis] 1996 Jun; Vol. 173 (6), pp. 1379-87.
DOI: 10.1093/infdis/173.6.1379
Abstrakt: Resistance to saquinavir (Ro 31-8959), an inhibitor of human immunodeficiency virus type I proteinase, was studied in peripheral blood mononuclear cell-derived proviral DNA from patients undergoing prolonged treatment. A Leu90-->Met exchange was the predominant resistance mutation in vivo; Gly48-->Val or doubly mutant virus was rarely observed. After 8-12 months of treatment with saquinavir alone (600 mg, 3 times/day) or in combination with zidovudine (200 mg, 3 times/day), approximately 45% of all patients carried provirus with mutant proteinase; the incidence was lower (22%) in patients treated with a combination of saquinavir, zidovudine, and dideoxycytidine. There was a good relationship between genotypic analysis of saquinavir resistance and data from virus assays, confirming that Leu90-->Met and Gly48-->Val are the essential exchanges in the proteinase that determine loss of sensitivity to this inhibitor. Absence of genotypic resistance correlated with a sustained decrease in plasma viral RNA. There was a positive correlation between a Met90 mutation and some residues at natural polymorphic sites (positions 10, 36, 63, and 71).
Databáze: MEDLINE
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