Development of a novel group of antiviral agents, acyclic nucleoside phosphonates, has provided a new perspective for treating human immunodeficiency virus (HIV) infection. One of the compounds, 9-(R)-[2-(phosphonomethoxy)propyl]adenine (PMPA) (tenofovir), has been shown to confer complete protection against AIDS in a simian model of the infection. The aim of our study was to investigate whether the antiviral efficacy of PMPA, which depends mainly on inhibition of virus-induced DNA polymerase or of reverse transcriptase, could be contributed by immunomodulatory potential of this drug. We screened for its ability to activate production of cytokines and chemokines that are known to interfere with the replication and/or the entry of HIV in cells. Using the in vitro test system of mouse macrophages and lymphocytes, it has been found that PMPA stimulates macrophage secretion of interleukin-1beta (IL-1beta), IL-10, and tumor necrosis factor alpha. Production of the chemokines RANTES and macrophage inflammatory protein 1alpha was activated in both macrophages and lymphocytes, and also in human cell line U937. Other cytokines--i.e., IL-2, IL-12, IL-13, and gamma interferon-remained uninfluenced by PMPA. The cytokines were stimulated in a dose-dependent fashion, with rapid onset, and peak concentrations were achieved within 5 to 24 h. The findings contribute to a more complex understanding of mechanisms of antiviral effectiveness of PMPA and support the view that this drug could become a promising candidate for therapeutic exploitation in anti-HIV preventive medicine.

• MeSH
• Adenine analogs & derivatives   pharmacology   MeSH
• Chemokine CCL4 MeSH
• Chemokine CCL5 metabolism   MeSH
• Chemokines physiology   MeSH
• Cytokines physiology   MeSH
• Interleukin-1 metabolism   MeSH
• Interleukin-10 metabolism   MeSH
• Cells, Cultured MeSH
• Anti-HIV Agents pharmacology   MeSH
• Macrophage Inflammatory Proteins metabolism   MeSH
• Macrophages drug effects   metabolism   MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Organophosphonates * MeSH
• Organophosphorus Compounds pharmacology   MeSH
• Tenofovir MeSH
• Tumor Necrosis Factor-alpha metabolism   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Adenine MeSH
• Chemokine CCL4 MeSH
• Chemokine CCL5 MeSH
• Chemokines MeSH
• Cytokines MeSH
• Interleukin-1 MeSH
• Interleukin-10 MeSH
• Anti-HIV Agents MeSH
• Macrophage Inflammatory Proteins MeSH
• Organophosphonates * MeSH
• Organophosphorus Compounds MeSH
• Tenofovir MeSH
• Tumor Necrosis Factor-alpha MeSH