Immunomodulatory properties of antiviral acyclic nucleotide analogues: Cytokine stimulatory and nitric oxide costimulatory effects

Abstract

Acyclic nucleotide analogues exhibit strong activity against a broad range of viruses, including HIV-1 and -2. We have investigated their effects on in vitro secretion of cytokines and production of nitric oxide (NO) by murine peritoneal macrophages, factors known to play a role in virus replication. Included in the study were the most prominent compounds of the series: 9-(2-phosphonomethoxyethyl)adenine, 9-(2-phosphonomethoxyethyl)-2,6-diaminopurine, the ( R)- and ( S)-enantiomers of 9-(2-phosphonomethoxypropyl) adenine [( R)- or ( S)-PMPA], ( R)- and ( S)-enantiomers of 9-(2-phosphonomethoxypropyl)-2,6-diaminopurine [( R)- or ( S)-PMPDAP], 9-(2-phosphonomethoxyethyl)guanine (PMEG), and ( S)-enantiomer of 1-(3-hydroxy-2-phosphonomethoxypropyl)cytosine [( S)-HPMPC]. PMEG, (R)-PMPA, and (S)-PMPA greatly enhanced the secretion of both tumour necrosis factor-α (TNF-α) and interleukin-10 (IL-10), ( R)-PMPDAP stimulated only TNF-α, other test compounds were ineffective. None of them influenced the secretion of IL-2 or interferon-γ (IFN-γ). Both TNF-α and IL-10 have been found to be major factors determining enhancing effects of PMEG, ( R)-PMPA, and ( S)-PMPA on production of NO generated by exogenous IFN-γ. The study points to a possible implication of immunomodulatory properties in the antiviral effects of some acyclic nucleotide analogues. In addition, our data support the view that endogenous IL-10 can stimulate certain macrophage functions.