New treatment protocol including lympholytic and antiretroviral drugs to inhibit murine AIDS.
Highly active antiretroviral therapy (HAART), although very efficient in reducing viral load to undetectable levels within 2 weeks, does not eradicate HIV-1 infection and after the suspension of therapy, HIV RNA rebounds to pretherapy levels. This limited efficacy is mainly due to the existence of viral reservoirs such as CD4+ T cells, macrophages, and dendritic cells in which the virus can remain latent. Elimination of these latent reservoirs would be a possible solution to this problem and various efforts are now being directed to this end. With this goal in mind, we investigated a lympholytic drug with known activity against lymphoproliferative malignancies, 2-fluoro-ara-AMP (fludarabine). The murine model of AIDS was used to evaluate the efficacy of alternating administration of fludarabine and azidothymidine (AZT). The aim of this experiment was to eliminate infected cells with fludarabine and protect noninfected cells with AZT. LP-BM5-infected mice were treated with two different therapeutic protocols: one group was treated with two alternating 3-week cycles of fludarabine and AZT (treatment A), whereas the other was treated with three alternating 2-week cycles of fludarabine and AZT (treatment B); both treatments lasted 12 weeks and the animals in the two groups received the same amount of drug. At different times of infection, disease-related findings (i.e., splenomegaly, lymphadenopathy, hypergammaglobulinemia, T-cell and B-cell spleen cell proliferative index, and phenotypes of peripheral blood lymphocytes) were analyzed and the content of proviral DNA in the lymph nodes was quantified. The results obtained show that treatment B was more effective in inhibiting disease progression than treatment A. In fact, all parameters investigated were almost within control values. These results were also confirmed by the quantification of proviral DNA content in the lymph nodes, which after 12 weeks of treatment A declined by approximately 50%, whereas treatment B decreased proviral DNA content by approximately 85% with respect to infected/untreated mice. The data obtained suggest that a therapeutic protocol including three cycles rather than two of a lympholytic drug and antiretroviral drugs is more advantageous. The efficacy of the treatment could likely increase if other drugs were used in addition to AZT and more cycles of fludarabine were added. This approach appears to be of potential interest in an HIV-1 eradication protocol.
Fraternale
A
A
Institute of Biological Chemistry Giorgio Fornaini, University of Urbino, Italy.
Tonelli
A
A
Casabianca
A
A
Chiarantini
L
L
Schiavano
G F
GF
Celeste
A G
AG
Magnani
M
M
D000818:Animals; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D004279:DNA, Viral / Q000032:analysis; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005434:Flow Cytometry; D051379:Mice; D016183:Murine Acquired Immunodeficiency Syndrome / Q000188:drug therapy*; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use; D019562:Viral Load; D015215:Zidovudine / Q000008:administration & dosage / Q000627:therapeutic use
D019380:Anti-HIV Agents; D000970:Antineoplastic Agents; D004279:DNA, Viral; D015215:Zidovudine; D014740:Vidarabine; C024352:fludarabine