Macrophage Protection by Nucleoside and Nucleotide Analogue Administration
Cells of the monocyte/macrophage lineage are currently recognized as important targets and reservoirs of human immunodeficiency virus (HIV-1) infection (1, 2). Therefore antiviral strategies, effective in inhibiting virus replication and in preventing transfer of HIV from already infected macrophages to target lymphocytes, must be devised. To date, the most successful anti-HIV therapies are based on compounds that interfere with reverse transcriptase, the viral enzyme required for HIV replication (3). Among these are several dideoxynucleosides, including azidothymidine (AZT), 2′,3′-dideoxycytidine (ddCyd) and 2′,3′-dideoxyinosine (ddI) etc. Each of these compounds is phosphorylated to the active triphosphate form after entring the cell and then acts as a DNA chain terminator and/or a competitor by blocking the incorporation of the respective normal deoxynucleoside-5′-triphosphate (4). The phosphorylation depends on specific cellular kinases whose levels in turn depend on the activation state of the target cells and on the cell types (5). Usually, quiescent cells have low levels of the enzymes responsible for nucleoside analogue phosphorylation, while activation (e.g., mitogen stimulation) results in increased activity levels. Because resting macrophages possess low levels of these kinases, a low efficacy of dideoxynucleoside analogues administration is thought.
KeywordsHuman Immunodeficiency Virus Acquire Immune Deficiency Syndrome Nucleoside Analogue Murine Macrophage Human Macrophage
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