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

@article{Jacobsson1995DecreasedTK,
  title={Decreased thymidine kinase levels in peripheral blood cells from HIV-seropositive individuals: implications for zidovudine metabolism.},
  author={Bengt Jacobsson and Sven Britton and Q. He and Anna Karlsson and Staffan K Eriksson},
  journal={AIDS research and human retroviruses},
  year={1995},
  volume={11 7},
  pages={
          805-11
        }
}
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… 
Activity of Cellular Thymidine Kinase 1 in PBMC of HIV-1-Infected Patients: Novel Therapy Marker
TLDR
It is demonstrated that TK1 deficiency in PBMC of HIV-1 infected patients may develop due to continuous treatment with thymidine analogs and correlates with a more progressed stage of disease expressed as diminished CD4 cell count and increased viral load.
Inosine Triphosphate Pyrophosphohydrolase Expression: Decreased in Leukocytes of HIV-Infected Patients Using Combination Antiretroviral Therapy
TLDR
HIV-infection seems to be interfering with the nucleotide metabolism in leukocytes, including CD4+ lymphocytes, by decreasing ITPase expression, independently of ITPA genotype, and these results warrant further research towards effectiveness and adverse events of purine analogues and ITP enzyme activity.
Influence of Prior Exposure to Zidovudine on Stavudine Phosphorylation In Vivo and Ex Vivo
TLDR
The ability of HIV-infected patients to phosphorylate d4T in vivo and ex vivo was unchanged with increasing exposure to ZDV, and the capacity of cells toosphorylate addedd4T was also measured.
A critical analysis of the pharmacology of AZT and its use in AIDS.
TLDR
A critical analysis of the presently available data shows that no evidence of AZT possessing an anti-HIV effect exists, an outcome not unexpected given the pharmacological data on AZT.
Erythrocyte Inosine Triphosphatase Activity Is Decreased in HIV-Seropositive Individuals
TLDR
ITPA population genetics were identical in HIV+ and control populations, however, the majority of HIV+-patients had decreased erythrocyte ITPase activity compared to controls, probably due to decreased amounts of ITP enzyme protein.
Human Immunodeficiency Virus Resistance to AZT in MOLT4/8 Cells is Associated with a Lack of AZT Phosphorylation and is Bypassed by AZT-Monophosphate SATE Prodrugs
TLDR
It is demonstrated that MOLT4/8rAZT250 cells exert resistance to the anti-HIV activity of the drug mainly owing to the lack of AZT phosphorylation and that resistance may be bypassed by using AZT-monophosphate SATE prodrugs.
Use of herpes simplex virus thymidine kinase to improve the antiviral activity of zidovudine.
TLDR
The results show enhanced AZT phosphorylation in HSV-1 TK-expressing lymphoid and monoblastoid cells, which correlated with significantly improved antiviral activity against different strains of HIV-1, suggesting that gene transfer might be envisioned for genetic pharmacomodulation of antiviral drugs.
Long-term AZT Exposure Alters the Metabolic Capacity of Cultured Human Lymphoblastoid Cells
TLDR
Data suggest that in addition to known mutagenic mechanisms, cells may become resistant to AZT partially through inactivation of TK-1 and through modulation of cell cycle components.
Differential gene expression in human hepatocyte cell lines exposed to the antiretroviral agent zidovudine
TLDR
Data indicate that molecular pathways involved with cell death and survival, cell cycle, cell growth and proliferation, and DNA replication, recombination, and repair are involved in the toxicities associated with AZT in both human cell lines, and that HepG2 cells are more sensitive than THLE2 cells to the toxicity of AZT.
...
...

References

SHOWING 1-10 OF 27 REFERENCES
Intracellular metabolism of 3'-azidothymidine in isolated human peripheral blood mononuclear cells.
TLDR
A large variation in the amount of products formed between PBMC treated at different times from the same individual as well as between the PBMC from different individuals is found, which may explain why lowering the doses of AZT still gives therapeutically efficient levels of the active metabolite AZTTP.
HIV‐1 biological phenotype and the development of zidovudine resistance in relation to disease progression in asymptomatic individuals during treatment
TLDR
Conversion to the SI phenotype cannot be prevented by zidovudine treatment, and the presence or appearance of an SI virus heralded disease progression in zidvudine-treated individuals.
Inhibition of human immunodeficiency virus (HIV-1/HTLV-IIIBa-L) replication in fresh and cultured human peripheral blood monocytes/macrophages by azidothymidine and related 2',3'- dideoxynucleosides
TLDR
The results suggest that the ratio of dideoxynucleoside triphosphate is a crucial factor in determining the antiviral activity of didespecifics in HIV target cells, and that the lower levels of dTTP may account for the antiretroviralActivity of AZT in the face of inefficient phosphorylation of this compound.
Restoration of T‐cell function in HIV infection by reduction of intracellular cAMP levels with adenosine analogues
TLDR
It is indicated that high intracellular cAMP concentrations contribute to pathogenesis of T-cell anergy in HIV infection and that drugs that decrease cAMP levels may be beneficial in the treatment of AIDS.
3'-Azido-3'-deoxythymidine (BW A509U): an antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus in vitro.
TLDR
The antiviral effects of a thymidine analogue,3'-azido-3'-deoxythymidine (BW A509U), which, as a triphosphate, inhibits the reverse transcriptase of HTLV-III/LAV, and the in vitro immune functions of normal T cells remain basically intact.
In vivo activity against HIV and favorable toxicity profile of 2',3'-dideoxyinosine.
TLDR
Results suggest that serious short-term toxicity at therapeutic doses is not an inherent feature in the profile of agents with clinical anti-HIV activity and further controlled studies to define the safety and efficacy of this agent may be worth considering.
Lymphoproliferative responses to mitogen and antigen in HIV-infected children.
TLDR
It is concluded that children are particularly susceptible to the immunologic effects of HIV infection because loss of lymphoproliferative responses to antigen occurs early in infected children and precedes the loss of CD4+ helper cells and of PHA responsiveness.
...
...