Role of macrophage protection in the development of murine AIDS

Macrophages play a key role in AIDS pathogenesis and thus controlling infec tivity and viral replication in these cells is a key issue in any antiretro viral therapy. In the present study, using a murine model of AIDS, we evalu ated new therapeutic approaches specifically designed for the protection of macrophages. Based on previous observations, we took advantage of the uniq ue ability of autologous erythrocytes to deliver drugs selectively to macro phages. The antiviral drugs selected were a new homodimer of AZT (AZTp(2)AZ T) and reduced glutathione (GSH). The addition of an oral drug for the prot ection of lymphocytes (i.e., AZT) was also investigated. C57BL/6 mice infec ted with the retroviral complex LP-BM5 were treated with GSH-loaded erythro cytes, GSH-loaded erythrocytes plus oral AZT, or GSH/AZTp(2)AZT-loaded eryt hrocytes plus oral AZT. The treatments including AZT and erythrocytes loade d with GSH alone or with GSH plus AZTp(2)AZT provided similar results and w ere most effective in inhibiting the progression of MAIDS; they reduced spl enomegaly, lymphadenopathy, and hypergammaglobulinemia by about 70%, 90% an d 83%, respectively, when compared with infected animals at 10 weeks postin fection. Evaluation of BM5d proviral DNA content in infected organs reveale d that both treatments were able to almost completely protect most infected animals. They were also able to normalize the blood lymphocyte phenotype a nd to restore the responses of T and B cells to mitogens significantly. Tre atment with GSH-loaded erythrocytes alone did not provide significant resul ts 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 retrovi ral infection and moreover prove that erythrocytes, by selectively protecti ng these cells, strongly affect MAIDS progression. Furthermore, the combina tion of GSH- or GSH/AZTp(2)AZT-loaded erythrocytes with an oral nucleoside analogue (AZT) for the protection of lymphocytes provides additive response s in all the parameters investigated.