ANTIRETROVIRAL AGENT (R)-9-(2-PHOSPHONOMETHOXYPROPYL)ADENINE STIMULATES CYTOKINE AND NITRIC-OXIDE PRODUCTION

The immunomodulatory properties of (R)-enantiomer of 9-(2-phoshonometh oxypropyl)adenine ((R)-PMPA), one of the most potent acyclic nucleotid e analogs effective against human immunodeficiency virus (HIV), were i nvestigated under in vitro conditions using murine peritoneal macropha ges. Remaining without influence on interferon-gamma and interleukin-2 expression, (R)-PMPA dramatically stimulated in a concentration-and t ime-dependent manner the secretion of tumor necrosis factor alpha (TNF -alpha) and interleukin-10. It also substantially augmented the produc tion of nitric oxide (NO) induced by exogenous interferon-gamma. Inhib itory experiments using neutralizing antibodies against TNF-alpha and/ or interleukin-10 demonstrated that these two cytokines are major fact ors responsible for triggering the underlying mechanism(s) leading to enhanced NO production. The novel findings on the immunomodulatory pot ential of acyclic nucleotide analogs are discussed in the context of t heir possible implication in antiviral therapeutic efficacy. (C) 1997 Elsevier Science B.V.