Secretion of antiretroviral chemokines by human cells cultured with acyclic nucleoside phosphonates

Abstract

Acyclic nucleoside phosphonates are novel class of clinically broadly used antivirotics effective against replication of both DNA viruses and retroviruses including human immunodeficiency virus (HIV). We have investigated their in vitro effects on immune defence mechanisms in human peripheral blood mononuclear cells, with the main emphasis on expression of cytokines which are able to suppress the entry of HIV in cells. Included in the study were prototype acyclic nucleoside phosphonates, i.e. 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA; adefovir), 9-[2-(phosphonomethoxy)ethyl]-2,6-diaminopurine (PMEDAP), (R)-and (S)-enantiomers of 9-[2-(phosphonomethoxy)propyl]adenine [(R)-PMPA; tenofovir] and [(S)-PMPA], and of 9-[2-(phosphonomethoxy)propyl]-2,6-diaminopurine [(R)-PMPDAP] and [(S)-PMPDAP], and their N(6)-substituted derivatives. Some of the compounds were found to substantially enhance secretion of chemokines such as macrophage inflammatory protein-1alpha (MIP-alpha/CCL3), and "regulated on activation of normal T cell expressed and secreted" (RANTES/CCL5). Secretion of MIP-1beta/CCL4 was only marginally increased, whereas production of interleukin-16 (IL-16) and interferon-gamma (IFN-gamma) remained uninfluenced. The most effective proved to be the N(6)-cyclooctyl-PMEDAP, N(6)-isobutyl-PMEDAP, N(6)-pyrrolidino-PMEDAP, N(6)-cyclopropyl-(R)-PMPDAP, and N(6)-cyclopentyl-(R)-PMPDAP derivatives. Remarkably enhanced secretion of chemokines was reached within 2-4 h of the cell culture, and was observed at concentration of 2-5 microM. It may be suggested that acyclic nucleoside phosphonates represent a new generation of antivirotics with combined antimetabolic and therapeutically prospective immunostimulatory properties.