Role of macrophage protection in the development of murine AIDS.
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.
Fraternale
A
A
Institute of Biological Chemistry Giorgio Fornaini, University of Urbino, Italy.
Tonelli
A
A
Casabianca
A
A
Vallanti
G
G
Chiarantini
L
L
Schiavano
G F
GF
Benatti
U
U
De Flora
A
A
Magnani
M
M
D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000821:virology; D016516:CD4-CD8 Ratio / Q000187:drug effects; D004279:DNA, Viral / Q000032:analysis; D054306:Dideoxynucleotides; D018450:Disease Progression; D004337:Drug Carriers; D004359:Drug Therapy, Combination; D004912:Erythrocytes; D005260:Female; D005978:Glutathione / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D007668:Kidney / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000821:virology; D008221:Lymphoid Tissue / Q000187:drug effects / Q000276:immunology / Q000473:pathology / Q000821:virology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000821:virology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008934:Mitogens / Q000494:pharmacology; D016183:Murine Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology / Q000821:virology; D013942:Thymine Nucleotides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D015215:Zidovudine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use / Q000031:analogs & derivatives
D019380:Anti-HIV Agents; D004279:DNA, Viral; D054306:Dideoxynucleotides; D004337:Drug Carriers; D008934:Mitogens; D013942:Thymine Nucleotides; C098899:azidothymidine homodinucleotide; D015215:Zidovudine; D005978:Glutathione