Inhibition of murine AIDS by a new azidothymidine homodinucleotide.
A new antiretroviral drug (azidothymidine homodinucleotide, AZTp2AZT), designed for the protection of macrophages against retroviral infection, was evaluated in a murine retrovirus-induced immunodeficiency model of AIDS (MAIDS) alone and in combination with oral azidothymidine (AZT). C57BL/6 mice were infected with the retroviral complex LP-BM5 and treated for 3 months by weekly administrations of 15 nmol of AZTp2AZT encapsulated into autologous erythrocytes for macrophage protection. AZTp2AZT treatment was found to reduce lymphoadenopathy (48%), splenomegaly (26%), and BM5d proviral DNA content in lymph nodes, spleen, and brain of 37%, 40%, and 36%, respectively, compared with untreated animals. AZT administration in drinking water (0.25 mg/ml) was more effective than administration of AZTp2AZT encapsulated into erythrocytes in reducing lymphoadenopathy, splenomegaly, gammaglobulinemia, and proviral DNA content in lymph nodes, but it caused a reduction in erythrocyte count and hematocrit levels. Although combined treatments do not provide additive responses in the several parameters investigated, they were found to be much more effective in reducing the proviral DNA content in brain (67%) than were monotherapies. Furthermore, no apparent signs of hematotoxicity were observed. Thus, macrophage delivery of antiviral drugs may contribute to brain protection from retroviral infections by mechanisms other than those exerted by oral AZT administration.
Magnani
M
M
Institute of Biological Chemistry Giorgio Fornaini, University of Urbino, Italy.
Casabianca
A
A
Fraternale
A
A
Brandi
G
G
Chiarantini
L
L
Benatti
U
U
Scarfì
S
S
Millo
E
E
De Flora
A
A
D000818:Animals; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D001921:Brain / Q000821:virology; D004279:DNA, Viral / Q000032:analysis; D054306:Dideoxynucleotides; D004359:Drug Therapy, Combination; D005260:Female; D005434:Flow Cytometry; D007074:Immunoglobulin G / Q000097:blood; D007274:Injections, Intraperitoneal; D008198:Lymph Nodes / Q000821:virology; D008206:Lymphatic Diseases / Q000188:drug therapy; D008213:Lymphocyte Activation / Q000187:drug effects; D018655:Lymphocyte Count / Q000187:drug effects; D008264:Macrophages / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D016183:Murine Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D011355:Prodrugs / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D013154:Spleen / Q000821:virology; D013163:Splenomegaly / Q000188:drug therapy; D013942:Thymine Nucleotides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D015215:Zidovudine / Q000627:therapeutic use* / Q000031:analogs & derivatives
D019380:Anti-HIV Agents; D004279:DNA, Viral; D054306:Dideoxynucleotides; D007074:Immunoglobulin G; D011355:Prodrugs; D013942:Thymine Nucleotides; C098899:azidothymidine homodinucleotide; D015215:Zidovudine