Inhibition of HIV-1 replication in macrophages by a heterodinucleotide of lamivudine and tenofovir

Luigia Rossi, Palmarisa Franchetti, Francesca Pierigé, Loredana Cappellacci, Sonja Serafini, Emanuela Balestra, Carlo Federico Perno, Mario Grifantini, Raffaele Caliò, Mauro Magnani

Research output: Contribution to journalArticlepeer-review


Objectives: (i) To generate a new heterodinucleotide (3TCpPMPA) comprising the drugs lamivudine and tenofovir which have been shown to act synergistically and (ii) to protect macrophages from 'de novo' HIV-1-infection through its administration. Methods: 3TCpPMPA was obtained by coupling the morpholidate derivative of tenofovir with the mono n-tri-butylammonium salt of lamivudine 5′-monophosphate. Stability and metabolism were evaluated in vitro and in vivo in mice. 3TCpPMPA was encapsulated into autologous erythrocytes by a procedure of hypotonic dialysis, isotonic resealing and reannealing. 3TCpPMPA-loaded erythrocytes were modified to increase their phagocytosis by human macrophages. Macrophages were infected by HIV-1Ba-L and inhibition of HIV-1 replication was assessed by HIV p24gag quantification. Results: Pharmacokinetic studies in mice revealed a rapid disappearance of the heterodinucleotide from circulation (t1/2 = 15 min) without any advantage compared with the administration of single drugs. Adding free 3TCpPMPA to macrophages (18 h), a 90% inhibition of viral replication up to 35 days post-treatment was achieved, while only a 60% inhibition was obtained by the combined treatment 3TC and (R)PMPA. When 3TCpPMPA was selectively targeted to the macrophage compartment by a single addition of loaded erythrocytes, the protection of macrophages from 'de novo' infection (99% protection 3 weeks post-treatment) was nearly complete. Conclusions: Erythrocytes loaded with 3TCpPMPA and modified to increase their phagocytosis are able to protect macrophages from 'de novo' HIV-1 infection. 3TCpPMPA acts as an efficient antiviral pro-drug that, once inside macrophages, can be slowly converted into 3TCMP and (R)PMPA protecting these cells for a longer period of time.

Original languageEnglish
Pages (from-to)666-675
Number of pages10
JournalJournal of Antimicrobial Chemotherapy
Issue number4
Publication statusPublished - Apr 2007


  • Drug-delivery
  • Nucleoside analogues
  • Phagocytes

ASJC Scopus subject areas

  • Pharmacology
  • Microbiology


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