Summary
Mononuclear phagocytes, representing a known reservoir of HIV-1, feature a poor response to the nucleoside analogues currently used in AIDS therapy. The main reason is a weak phosphorylating activity to start metabolic activation that terminates with the intracellular synthesis of the retroviral reverse transcriptase inhibitors, i.e. the corresponding nucleoside triphosphates. The azidothymidine homodinucleotide (AZTp2AZT) recently designed and synthesized in our laboratories proved to be suitable to overcome this limitation. AZTp2AZT was encapsulated in erythrocytes where it showed a remarkable stability. This allowed to selectively perturb the membrane of the AZTp2AZT-loaded erythrocytes, thereby triggering subsequent opsonization and uptake by macrophage cultures. Macrophages exposed to carrier erythrocytes showed a significant resistance to infection by immunodeficiency viruses. Protection was observed with human, feline and murine macrophages against infection by HIV-1, FIV and LP-BM5 retroviral strains, respectively. These data demonstrate that AZTp2AZT-loaded and opsonized erythrocytes represent an efficient “trojan horse” resulting in significant protection of macrophages from retroviral infection.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Benatti, U., Giovine, M, Damonte, G., Gasparini, A., Scarfi, S., De Flora, A., Fraternale, A., Rossi, L., Magnani, M. Azidothymidine homodinucleotide-loaded erythrocytes as bioreactors for slow delivery of the antiretroviral drug azidothymidine. Biochem. Biophys. Res. Comm., 220, 20–25, 1996.
Fraternale, A., Casabianca, A., Rossi, L., Chiarantini, L., Brandi, G., Aluigi, G., Schiavano, G.F., Magnani, M. Inibition of murine AIDS by combination of AZT and dideoxycytidine 5′-triphosphate. J. Acquir. Immune Defic. Syndr. 12, 164–173, 1996.
Gendelman H.E., Meltzer M.S. Mononuclear phagocytes and the human immunodeficiency virus. Curr. Opin. Immunol. 2, 414–419, 1990.
Giovine, M., Scarfi, S., Gasparini, A., Millo, E., Damonte, G., De Flora, A., Magnani, M., Fraternale, A., Rossi, L., Williams, R., Benatti, U. Synthesis, characterization and erythrocyte encapsulation of an azidothymidine homodinucleotide behaving as a prodrug of azidothymidine. Biological Carriers in Medicine (U. Sprandel and J.L. Way Eds.) Plenum Press, New York, in press.
Lewis, W., Dalakas, M.C., Mitochondrial toxicity of antiviral drugs. Nat. Med. 1, 417–422, 1995.
Magnani, M., Rossi, L., Brandi, G., Schiavano, G.F., Montroni, M., Piedimonte, G. Targeting antiretroviral nucleoside analogues in phosphorylated form to macrophages: in vitro ed in vivo studies. Proc. Natl. Acad. Sci. USA 89, 6477–6481, 1992.
Magnani, M., Giovine, M., Fraternale, A., Damonte, G., Rossi, L., Scarfi, S., Benatti, U., De Flora, A. Red Blood Cells as a Delivery System for AZT. Drug Delivery, 2, 57–61, 1995.
Magnani, M., Casabianca, A., Fraternale, A., Brandi G., Gessani, S., Williams, R., Giovine, M., Damonte, G., De Flora, A., Benatti, U. Synthesis and targeted delivery of an azidothymidine homodinucleotide conferring protection to macrophages against retroviral infection. Proc. Natl. Acad. Sci. USA 93, 4403–1408, 1996.
Parker, W.B., Cheng, Y.C., Mitochondrial toxicity of antiviral analogs. J. NIH Res. 6, 57–61, 1994.
Perno, C.F., Yarchoan, R., Cooney, D.A., Hartman, N.R., Gartner, S., Popovic, M., Hao, Z., Gerrard, T.L., Wilson, Y.A., Johns, D.G. and Broder, S. J. Inhibition of human immunodeficiency virus (HIV-1/HTLV-II-IBa-L) replication in fresh and cultured human peripheral blood monocytes/macrophages by azidothymidine and related 2′, 3′-′dideoxynucleosides. J. Exp. Med. 168, 1111–1125, 1988.
Perno CF., Santoro N., Balestra, E., Aquaro S., Lazzarino G., Di Pierro D., Tavazzi B., Balzarini, J., Garaci, E., Grimaldi, S. and Caliò, R. Red blood cells mediated delivery of 9-(2-phosphonyl-methoxyethyl) adenine to primary macrophages: efficiency, metabolism and activity against human immunodeficiency virus or herpes simplex virus. Antiv. Res. 33, 153–164, 1997.
Robbins, B.L., Rodman, J., McDonald, C, Srinivas, R.V., Flynn, P.M., Fridland, A. Enzymatic assay for measurement of zidovudine triphosphate in peripheral blood mononuclear cells. Antimicrob. Agents Chemother. 38, 115–121, 1994.
Rossi, L., Brandi, G:, Fraternale, A., Schiavano, G.F., Chiarantini, L., Magnani, M. Inibition of murine retrovirus induced immunodeficiency disease by dideoxycytidine and dideoxycytidine 5′ triphosphate J. Acquir. Immune Defic. Syndr. 6, 1179–1186, 1993.
Zocchi, E., Guida, L., Franco, L., Silvestro, L., Guerrini, M., Benatti, U. and De Flora, A. Free Adenosine diphosphate ribose in human erythrocytes: pathways of intraerythrocytic conversion and non-enzymic binding to membrane proteins. Biochem. J. 295, 121–130, 1993.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1997 Springer Science+Business Media New York
About this chapter
Cite this chapter
Benatti, U. et al. (1997). Erythrocyte-Based Targeted Release to Macrophages of an Azidothymidine Homodinucleotide Prevents Retroviral Infection. In: Sprandel, U., Way, J.L. (eds) Erythrocytes as Drug Carriers in Medicine. Springer, Boston, MA. https://doi.org/10.1007/978-1-4899-0044-9_7
Download citation
DOI: https://doi.org/10.1007/978-1-4899-0044-9_7
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4899-0046-3
Online ISBN: 978-1-4899-0044-9
eBook Packages: Springer Book Archive