The efficacy of 9-(2-phosphonylmethoxyethyl)adenine (PMEA) against the replication of human immunodeficiency virus (HIV) and herpes simplex virus type 1 (HSV-1) and its cellular metabolism were investigated in human primary macrophages from seronegative donors. PMEA potently inhibited the replication of both HIV and HSV-1 in macrophages, with similar EC(50) values (0.025 and 0.032 mu M, respectively), whereas the EC(50) values of PMEA in lymphocytic C8166 cells and fibroblastoid Vero cells were 150-200-fold higher (3.5 and 7.9 mu M, respectively). Granulocyte/macrophage colony-stimulating factor and macrophage colony-stimulating factor, two cytokine enhancers of the replication of HIV (and HSV-1), decreased the activity of PMEA against both viruses, yet EC(50) values were still lower than in lymphocytes and fibroblasts. Thus, the selectivity index of PMEA in macrophages was > 2 orders of magnitude higher than that in lymphocytes and fibroblasts and still > 1 log higher under conditions of enhancement of virus replication in macrophages. The intracellular levels of 2'-deoxyadenosine-5'triphosphate, the natural competitor of PMEA-diphosphate at the level of viral DNA polymerase (either RNA or DNA dependent), were 5-12-fold lower in macrophages than in other cells. Furthermore, intracellular concentrations of PMEA-diphosphate (the active metabolite of PMEA) were unusually much higher in macrophages (with or without cytokines) than in lymphocytes and fibroblasts. Consequently, the ratio of PMEA-diphosphate to 2'-deoxyadenosine-5'-triphosphate in monocytes/macrophages was similar to 2 orders of magnitude higher in macrophages than in the other cells and correlated closely with the pronounced antiviral potency of PMEA. The dual potent activity of PMEA against HIV and HSV-1 stresses the importance of clinical trials to assess the role of this drug in the therapy of HIV-related disease.

Perno, C.F., Balestra, E., Aquaro, S., Panti, S., Cenci, A., Lazzarino, G., et al. (1996). Potent inhibition of human immunodeficiency virus and herpes simplex virus type 1 by 9-(2-phosphonylmethoxyethyl)adenine in primary macrophages is determined by drug metabolism, nucleotide pools, and cytokines. MOLECULAR PHARMACOLOGY, 50(2), 359-366.

Potent inhibition of human immunodeficiency virus and herpes simplex virus type 1 by 9-(2-phosphonylmethoxyethyl)adenine in primary macrophages is determined by drug metabolism, nucleotide pools, and cytokines

PERNO, CARLO FEDERICO;BALESTRA, EMANUELA;AQUARO, STEFANO;TAVAZZI, BARBARA;
1996

Abstract

The efficacy of 9-(2-phosphonylmethoxyethyl)adenine (PMEA) against the replication of human immunodeficiency virus (HIV) and herpes simplex virus type 1 (HSV-1) and its cellular metabolism were investigated in human primary macrophages from seronegative donors. PMEA potently inhibited the replication of both HIV and HSV-1 in macrophages, with similar EC(50) values (0.025 and 0.032 mu M, respectively), whereas the EC(50) values of PMEA in lymphocytic C8166 cells and fibroblastoid Vero cells were 150-200-fold higher (3.5 and 7.9 mu M, respectively). Granulocyte/macrophage colony-stimulating factor and macrophage colony-stimulating factor, two cytokine enhancers of the replication of HIV (and HSV-1), decreased the activity of PMEA against both viruses, yet EC(50) values were still lower than in lymphocytes and fibroblasts. Thus, the selectivity index of PMEA in macrophages was > 2 orders of magnitude higher than that in lymphocytes and fibroblasts and still > 1 log higher under conditions of enhancement of virus replication in macrophages. The intracellular levels of 2'-deoxyadenosine-5'triphosphate, the natural competitor of PMEA-diphosphate at the level of viral DNA polymerase (either RNA or DNA dependent), were 5-12-fold lower in macrophages than in other cells. Furthermore, intracellular concentrations of PMEA-diphosphate (the active metabolite of PMEA) were unusually much higher in macrophages (with or without cytokines) than in lymphocytes and fibroblasts. Consequently, the ratio of PMEA-diphosphate to 2'-deoxyadenosine-5'-triphosphate in monocytes/macrophages was similar to 2 orders of magnitude higher in macrophages than in the other cells and correlated closely with the pronounced antiviral potency of PMEA. The dual potent activity of PMEA against HIV and HSV-1 stresses the importance of clinical trials to assess the role of this drug in the therapy of HIV-related disease.
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore MED/07 - Microbiologia e Microbiologia Clinica
English
Con Impact Factor ISI
adefovir; antiviral activity; article; drug activity; drug efficacy; drug metabolism; herpes simplex virus 1; human; human cell; human immunodeficiency virus infection; macrophage activation; nucleotide sequence; priority journal; seroconversion; virus replication; Adenine; Animals; Antiviral Agents; Cercopithecus aethiops; Deoxyadenine Nucleotides; Granulocyte-Macrophage Colony-Stimulating Factor; Herpesvirus 1, Human; HIV; Humans; Macrophage Colony-Stimulating Factor; Macrophages; Phosphonic Acids; Vero Cells
Perno, C.F., Balestra, E., Aquaro, S., Panti, S., Cenci, A., Lazzarino, G., et al. (1996). Potent inhibition of human immunodeficiency virus and herpes simplex virus type 1 by 9-(2-phosphonylmethoxyethyl)adenine in primary macrophages is determined by drug metabolism, nucleotide pools, and cytokines. MOLECULAR PHARMACOLOGY, 50(2), 359-366.
Perno, Cf; Balestra, E; Aquaro, S; Panti, S; Cenci, A; Lazzarino, G; Tavazzi, B; Di Pierro, D; Balzarini, J; Calio, R
Articolo su rivista
File in questo prodotto:
Non ci sono file associati a questo prodotto.

Questo articolo è pubblicato sotto una Licenza Licenza Creative Commons Creative Commons

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2108/49773
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact