Macrophages play a key role in
AIDS pathogenesis and thus controlling infectivity and viral replication in these cells is a key issue in any antiretroviral
therapy. In the present study, using a murine model of
AIDS, we evaluated new therapeutic approaches specifically designed for the protection of macrophages. Based on previous observations, we took advantage of the unique ability of autologous erythrocytes to deliver drugs selectively to macrophages. The
antiviral drugs selected were a new homodimer of AZT (
AZTp2AZT) and
reduced glutathione (GSH). The addition of an oral
drug for the protection of lymphocytes (i.e., AZT) was also investigated. C57BL/6 mice infected with the retroviral complex LP-BM5 were treated with GSH-loaded erythrocytes, GSH-loaded erythrocytes plus oral AZT, or GSH/
AZTp2AZT-loaded erythrocytes plus oral AZT. The treatments including AZT and erythrocytes loaded with GSH alone or with GSH plus
AZTp2AZT provided similar results and were most effective in inhibiting the progression of
MAIDS; they reduced
splenomegaly,
lymphadenopathy, and
hypergammaglobulinemia by about 70%, 90% and 83%, respectively, when compared with infected animals
at 10 weeks postinfection. Evaluation of BM5d proviral
DNA content in infected organs revealed that both treatments were able to almost completely protect most infected animals. They were also able to normalize the blood lymphocyte phenotype and to restore the responses of T and B cells to
mitogens significantly. Treatment with GSH-loaded erythrocytes alone did not provide significant results for most parameters investigated, but a marked reduction in proviral
DNA content was obtained in infected organs, including the brain. The results reported in this paper confirm the important role of macrophages in retroviral
infection and moreover prove that erythrocytes, by selectively protecting these cells, strongly affect
MAIDS progression. Furthermore, the combination of GSH- or GSH/
AZTp2AZT-loaded erythrocytes with an oral
nucleoside analogue (AZT) for the protection of lymphocytes provides additive responses in all the parameters investigated.