SUPPRESSION OF HIV-1 INFECTION IN LINOMIDE-TREATED SCID-HU-PBL MICE

Background: Proinflammatory cytokine overproduction, as well as synthe sis of the inducible form of nitric oxide synthase (iNOS), are known t o play a major role in HIV-1-triggered disease. AIDS patients show inc reased serum tumour necrosis factor (TNF)-alpha and interferon (IFN)-g amma levels, which synergize with HIV-1-produced nitric oxide (NO) to augment viral replication. Linomide has strong immunomodulatory effect s in animals and humans, yielding promising clinical benefits in sever al pathological disorders including septic shock and autoimmune diseas e, processes largely mediated by overproduction of these cytokines. In peripheral T cells, linomide also prevents apoptosis triggered by a v ariety of stimuli, including superantigens, dexamethasone and vaccinia virus. Design and methods: Linomide inhibits production of proinflamm atory cytokines such as TNF-alpha, interleukin-1 beta and IFN-gamma, a s well as iNOS synthesis. The SCID-hu-PBL mouse model was used to anal yse the effect of linomide on HIV-1 infection. T-cell frequency was ch aracterized in reconstituted animals, and the frequency of infected mi ce and viral load of infected animals were studied. Results: Linomide promotes an increase in human CD4+ T-cell counts in the peritoneal cav ity of HIV-1-infected, linomide-treated mice. Linomide also prevents h uman TNF-alpha and IFN-gamma production, as well as iNOS expression an d affects the viral load, promoting potent suppression of HIV-1 infect ivity as detected in peritoneal cavity and spleen. Conclusions: The co mbination of linomide's properties, namely, blockage of proinflammator y cytokine and NO production, as well as prevention of apoptosis, is o f paramount interest, making linomide a potential candidate for combat ing HIV-1 infection or preventing some of its associated pathological manifestations. (C) 1998 Lippincott-Raven Publishers.