Document 0755
 DOCN  M9610755
 TI    Decreased thymidine kinase levels in peripheral blood cells from
       HIV-seropositive individuals: implications for zidovudine metabolism.
 DT    9601
 AU    Jacobsson B; Britton S; He Q; Karlsson A; Eriksson S; Department of
       Infectious Diseases, Huddinge Hospital, Sweden.
 SO    AIDS Res Hum Retroviruses. 1995 Jul;11(7):805-11. Unique Identifier :
       AIDSLINE MED/96053843
 AB    Azidothymidine (zidovudine, AZT) used for treatment of HIV infection
       blocks the viral reverse transcriptase after phosphorylation by cellular
       enzymes. The first step in this reaction is the formation of AZT
       monophosphate, primarily catalyzed by host cytoplasmatic thymidine
       kinase (TK1). The activity of TK1 was determined in extracts of
       PHA-stimulated peripheral blood mononuclear cells (PBMCs) from 20
       healthy volunteers and 49 HIV-infected patients at different stages of
       disease. In both groups we found a large intra- and interindividual
       variation of TK activity. Because TK1 expression is cell cycle regulated
       the proportion of stimulated cells was determined in the samples and the
       median thymidine kinase activity calculated. It was 3.0 pmol/mg/min x %
       S phase in the HIV-seronegative group and 1.1 pmol/mg/min x % S phase in
       HIV-infected individuals. The difference in thymidine kinase activity is
       statistically significant (p = 0.0001). The concentration of TK1 protein
       in the same extracts was also determined by immunoblotting. A positive
       correlation (r = 0.74) was observed between TK activity and amount of
       TK1 protein. The reason for this downregulation of TK is still unknown
       but may be related to the anergy observed in lymphocytes from
       HIV-infected persons. The reduced capacity for intracellular
       phosphorylation of AZT in HIV-infected individuals may be an important
       factor in the emergence of clinical AZT resistance and should also be
       accounted for in testing AZT resistance in vitro with PBMCs from healthy
       blood donors.
 DE    Antiviral Agents/BLOOD/*METABOLISM/THERAPEUTIC USE  Cell Cycle  Cells,
       Cultured  Comparative Study  CD4 Lymphocyte Count  Flow Cytometry  Human
       HIV Infections/DRUG THERAPY  HIV Seronegativity  HIV
       Seropositivity/*BLOOD/DRUG THERAPY/IMMUNOLOGY  Kinetics
       Lymphocytes/*ENZYMOLOGY/IMMUNOLOGY  Reference Values  Support, Non-U.S.
       Gov't  Thymidine Kinase/*BLOOD  Zidovudine/BLOOD/*METABOLISM/THERAPEUTIC
       USE  JOURNAL ARTICLE

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