Document 0610
 DOCN  M9640610
 TI    Selective pressure of a quinoxaline nonnucleoside inhibitor of human
       immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) on
       HIV-1 replication results in the emergence of nucleoside
       RT-inhibitor-specific (RT Leu-74-->Val or Ile and Val-75-->Leu or Ile)
       HIV-1 mutants.
 DT    9604
 AU    Kleim JP; Rosner M; Winkler I; Paessens A; Kirsch R; Hsiou Y; Arnold E;
       Riess G; Hoechst AG, Frankfurt, Germany.
 SO    Proc Natl Acad Sci U S A. 1996 Jan 9;93(1):34-8. Unique Identifier :
       AIDSLINE MED/96133872
 AB    The quinoxaline nonnucleoside RT inhibitor (NNRTI)
       (S)-4-isopropoxycarbonyl-6-methoxy-3-(methylthiomethyl)-3,4-
       dihydroquinoxaline-2(1H)-thione (HBY 097) was used to select for
       drug-resistant HIV-1 variants in vitro. The viruses first developed
       mutations affecting the NNRTI-binding pocket, and five of six strains
       displayed the RT G190-->E substitution, which is characteristic for
       HIV-1 resistance against quinoxalines. In one variant, a new mutant
       (G190-->Q) most likely evolved from preexisting G190-->E mutants. The
       negative charge introduced by the G190-->E substitution was maintained
       at that site of the pocket by simultaneous selection for V179-->D
       together with G190-->Q. After continued exposure to the drug, mutations
       at positions so far known to be specific for resistance against
       nucleoside RT inhibitors (NRTIs) (L74-->V/I and V75-->L/I) were
       consistently detected in all cultures. The inhibitory activities of the
       cellular conversion product of 2',3'-dideoxyinosine (ddI, didanosine),
       2',3'-dideoxyadenosine (ddA) and of 2',3'-didehydro-3'-deoxythymidine
       (d4T, stavudine) against these late-passage viruses were shown to be
       enhanced with the L74-->V/I RT mutant virus as compared with the
       wild-type (wt) HIV-1MN isolate. Clonal analysis proved linkage of the
       codon 74 and codon 75 mutations to the NNRTI-specific mutations in all
       RT gene fragments. The nonnucleoside- and nucleoside-resistance mutation
       sites are separated by approximately 35 A. We propose that the two sites
       communicate through the template-primer which is situated in the
       DNA-binding cleft between these two sites. Quinoxalines cause high
       selective pressure on HIV-1 replication in vitro; however, the
       implication of these findings for the treatment of HIV-1 infection has
       yet to be determined.
 DE    Antiviral Agents/*PHARMACOLOGY  Base Sequence  Drug Resistance,
       Microbial  DNA Primers/CHEMISTRY  HIV-1/*GROWTH & DEVELOPMENT  Molecular
       Sequence Data  Mutation  Reverse Transcriptase Inhibitors/*PHARMACOLOGY
       RNA-Directed DNA Polymerase/*GENETICS  Selection (Genetics)  Support,
       Non-U.S. Gov't  Support, U.S. Gov't, P.H.S.  Virus Replication/*DRUG
       EFFECTS  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
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