       Document 0658
 DOCN  M9640658
 TI    Multidrug-resistant human immunodeficiency virus type 1 strains
       resulting from combination antiretroviral therapy.
 DT    9604
 AU    Iversen AK; Shafer RW; Wehrly K; Winters MA; Mullins JI; Chesebro B;
       Merigan TC; Division of Infectious Diseases and Geographic Medicine,
       Stanford; University, California 94305, USA.
 SO    J Virol. 1996 Feb;70(2):1086-90. Unique Identifier : AIDSLINE
       MED/96135222
 AB    Multidrug-resistant human immunodeficiency virus type 1 (HIV-1) strains
       with reverse transcriptase (RT) mutations at codons A62-->V, V75-->I,
       F77-->L, F116-->Y, and Q151-->M have been reported in patients receiving
       combination therapy with zidovudine (AZT) and didanosine (ddI).
       Infectious clones with each mutation alone, all five mutations together,
       and various combinations of mutations were created by site-directed
       mutagenesis. Mutation Q151-->M conferred partial resistance to AZT, ddI,
       zalcitibine, and stavudine, whereas a combination of four mutations
       conferred increased resistance to AZT, ddI, zalcitibine, and stavudine.
       The positions of residues 75, 77, and 151 in the three-dimensional
       crystal structure of HIV-1 RT suggest that these residues may affect the
       ability of the enzyme to discriminate between deoxynucleoside
       triphosphates and nucleoside analog RT inhibitors. Replication
       experiments showed that clones with mutation F77-->L but without V75-->I
       (HIV-1(77), HIV-1(77,151), and HIV-1(77,116,151) had attenuated growth
       compared with that of the original HIV-1NL4-3 strain and strains
       containing mutations at both positions 75 and 77 (HIV-1(75,77,151) and
       HIV-1(75,77,116,15)). Sequence analysis of viral RNA and proviral DNA
       from several patients indicated that RT mutations developed in a
       sequential and cumulative pattern over the course of a 2- to 4-year
       observation period. The present results suggest that drug resistance and
       viral replicative capacity both may play a role in selection of HIV-1 RT
       mutations.
 DE    Animal  Antiviral Agents/*PHARMACOLOGY  Base Sequence  Cell Line
       Didanosine/*PHARMACOLOGY  Drug Resistance, Microbial/GENETICS  Drug
       Resistance, Multiple/GENETICS  Drug Therapy, Combination  DNA Primers
       DNA, Viral  Hela Cells  Human  HIV Infections/DRUG THERAPY/*VIROLOGY
       HIV-1/*DRUG EFFECTS/ENZYMOLOGY/GENETICS  Molecular Sequence Data
       Mutagenesis, Site-Directed  Reverse Transcriptase
       Inhibitors/*PHARMACOLOGY  RNA-Directed DNA Polymerase/*GENETICS
       Support, Non-U.S. Gov't  Support, U.S. Gov't, P.H.S.  Virus Replication
       Zidovudine/*PHARMACOLOGY  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

