Erythrocyte-Based Targeted Release to Macrophages of an Azidothymidine Homodinucleotide Prevents Retroviral Infection
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.
KeywordsNucleoside Analogue Mononuclear Phagocyte Macrophage Culture Nodeficiency Virus Diphosphate Ribose
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