Decreased thymidine kinase levels in peripheral blood cells from HIV-seropositive individuals: implications for zidovudine metabolism.

Important note: Information in this article was accurate in 1996. The state of the art may have changed since the publication date.

Decreased thymidine kinase levels in peripheral blood cells from HIV-seropositive individuals: implications for zidovudine metabolism.

AIDS Res Hum Retroviruses. 1995 Jul;11(7):805-11. Unique Identifier : AIDSLINE MED/96053843
Jacobsson B; Britton S; He Q; Karlsson A; Eriksson S; Department of Infectious Diseases, Huddinge Hospital, Sweden.

Abstract: 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.

Keywords: 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

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