Document 1097
 DOCN  M94A1097
 TI    HIV-1 develops a set of novel mutations conferring multidrug resistance
       during combination chemotherapy.
 DT    9412
 AU    Shirasaka T; Kavlick MF; Gao WY; Kojima E; Yarchoan R; Mitsuya H;
       Medicine Branch, National Cancer Institute, Bethesda, MD 20892.
 SO    Int Conf AIDS. 1994 Aug 7-12;10(2):21 (abstract no. 377A). Unique
       Identifier : AIDSLINE ICA10/94371478
 AB    OBJECTIVE: To study the development of a set of novel pol gene mutations
       which confers on HIV-1 a reduced sensitivity to AZT, ddC, and ddI.
       METHODS: HIV-1 was isolated from a patient (ERS103) receiving a
       long-term chemotherapy of AZT and ddC in sequence at various time
       points. The 50% inhibitory concentration (IC50) of AZT, ddC, and ddI
       against each isolate was determined. Biochemical and genetic studies of
       viral isolates were also performed. RESULTS: IC50 values of AZT, ddC,
       and ddI against virus isolated before (HIV-1ERS103pre) and after
       (HIV-1ERS103post) 41 months of therapy were 0.07, 0.1, 1.6 microM and
       12.6, 1.6, 47 microM, respectively. The Kls for AZTTP against the
       activity of reverse transcriptase isolated from HIV-1ERS103pre and
       HIV-1ERS103post were 0.8 and 27.6 nM, respectively. HIV-1ERS103post had
       a set of 7 pol gene mutations: Ala62-->Val, Val75-->Ile, Phe77-->Leu,
       Phe116-->Tyr, Val118-->Ile, Gln151-->Met, and Ile202-->Val. Gln151-->Met
       first developed after 16 months of therapy when viremia level suddenly
       increased as assessed by quantitative PCR. Following the Gln151-->Met
       mutation, 3 mutations (Phe77-->Leu, Phe116-->Tyr, Ile202-->Val) appeared
       by 27 months, and then Ala62-->Val, Val75-->Ile, Val118-->Ile appeared
       by 38 months. Viremia further increased with the development of this set
       of mutations. DISCUSSION/CONCLUSIONS: HIV-1 can develop multi-drug
       resistance during long-term combination therapy with AZT/ddC by
       developing a set of novel mutations. This set of mutations has been seen
       elsewhere in patients receiving combination therapy with AZT plus ddI.
       The clinical significance of this set of mutations requires further
       research.
 DE    *Codon  Didanosine/ADMINISTRATION & DOSAGE/*PHARMACOLOGY/THERAPEUTIC USE
       Drug Resistance, Microbial/GENETICS  Drug Therapy, Combination  *Genes,
       pol  Human  HIV Infections/*DRUG THERAPY/MICROBIOLOGY  HIV-1/DRUG
       EFFECTS/ENZYMOLOGY/*GENETICS  *Mutation  Reverse
       Transcriptase/ANTAGONISTS & INHIB/GENETICS  Viremia/MICROBIOLOGY
       Zalcitabine/ADMINISTRATION & DOSAGE/*PHARMACOLOGY/THERAPEUTIC USE
       Zidovudine/ADMINISTRATION & DOSAGE/*PHARMACOLOGY/THERAPEUTIC USE
       MEETING ABSTRACT

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