Metabolic activation of nucleoside and nucleotide reverse transcriptase inhibitors in dendritic and Langerhans cells.
BACKGROUND
Langerhans cells and interstitial dendritic cells are the earliest targets for HIV infection through sexual transmission of HIV. Metabolism of nucleoside analogues markedly differs in proliferating T lymphocytes and resting monocyte/macrophages, and thus their antiviral efficacy can substantially differ between both cell types.


METHODS
The metabolism of radio-labelled zidovudine (ZDV), lamivudine (3TC) and tenofovir (PMPA) to their antivirally active metabolites was studied in primary cells, representative of early in vivo targets of HIV [i.e. monocyte-derived dendritic cells (MO-DC), MO-derived Langerhans cells (MO-LC), PHA/IL-2-activated T-blast cells] as well as in a laboratory T-lymphocyte (CEM) cell line.


RESULTS
Whereas lamivudine metabolism to its active triphosphate derivative (3TC-TP) did not markedly differ between T-cells and MO-derived LC and DC, zidovudine was much better converted to ZDV-TP in T-cells than in MO-LC and MO-DC. In contrast, tenofovir was markedly more abundantly converted to its antivirally active diphosphate metabolite PMPApp in MO-DC and MO-LC than zidovudine and lamivudine.


CONCLUSIONS
Our metabolic data suggest that tenofovir may be superior to zidovudine and lamivudine for inhibition of HIV replication in dendritic/Langerhans cells, the first-line cell types targeted by a primary HIV infection.
Balzarini
Jan
J
Laboratory of Virology & Chemotherapy, Rega Institute for Medical Research, B-3000 Leuven, Belgium. jan.balzarini@rega.kuleuven.ac.be
Van Herrewege
Yven
Y
Vanham
Guido
G
D000225:Adenine / Q000031:analogs & derivatives* / Q000378:metabolism*; D019380:Anti-HIV Agents / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000378:metabolism / Q000821:virology*; D006801:Humans; D019259:Lamivudine / Q000378:metabolism*; D007801:Langerhans Cells / Q000378:metabolism / Q000821:virology*; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000378:metabolism*; D010641:Phenotype; D018894:Reverse Transcriptase Inhibitors / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism / Q000821:virology; D000068698:Tenofovir; D015215:Zidovudine / Q000378:metabolism*
D019380:Anti-HIV Agents; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D015215:Zidovudine; D000068698:Tenofovir; D000225:Adenine