Erythrocyte-mediated delivery of a new homodinucleotide active against human immunodeficiency virus and herpes simplex virus

Monocyte-derived macrophages (MDMs) play a central role in the pathogenesis of infection by human immunodeficiency virus (HIV-1) and represent one of the main reservoirs of the virus in the body. In addition, MDMs can easily be infected by various herpes viruses, including herpes simplex virus type 1 (HSV-1). We have synthesized a new antiviral agent (Bis-PMEA) that consis ts of two 9-(2-phosphonylmethoxyethyl)adenine (PMEA) molecules bound by a p hosphate bridge. This nucleotide analogue, like the parent compound PMEA, h as strong and selective activity against HIV-1 and HSV-1. A drug-targeting system previously developed in our laboratory was used for the selective de livery of these drugs to macrophages. Bis-PMEA and PMEA were encapsulated i nto autologous erythrocytes by a procedure of hypotonic dialysis and isoton ic resealing. Loaded erythrocytes were modified to increase their recogniti on and phagocytosis by human macrophages. By administering Bis-PMEA-loaded erythrocytes to macrophages, 47% of Bis-PMEA and 28% of PMEA was still pres ent 10 days after phagocytosis; in contrast, only 12% of PMEA was found in macrophages receiving PMEA-loaded erythrocytes. Bis-PMEA-loaded erythrocyte s were then added to macrophages infected with HIV-1 and HSV-1 and their an tiviral activity evaluated. Remarkable protection was obtained against HIV- 1 and HSV-1 infection (95 and 85%, respectively). Therefore, Bis-PMEA acts as an efficient antiviral prodrug that, following selective targeting to ma crophages by means of loaded erythrocytes, can protect a refractory cell co mpartment.