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.