Alteration of cytokine levels in murine retrovirus infection: modulation by combination therapy

Immunoregulatory cytokines may regulate the resistance or susceptibility of a host to retroviral infection. These cytokines may be therapeutically mod ulated to prevent or limit the progression of infection. The non-progressio n to AIDS of some HIV+ patients has been related to a strong type 1 cytokin e response (IL-2, IL-12, and IFN gamma). For this reason, we investigated t he ability of combination therapeutics to modulate cytokines in vivo toward s a type 1 cytokine response in a murine retroviral infection using Friend leukemia virus (FLV). BALB/c mice were infected with FLV and treated with e ither 3'-azido-3'-deoxythymidine (AZT), the immunomodulator methionine enke phalin (MENK), or a combination of both AZT and MENK starting 3 d post infe ction. Splenocytes were harvested on days 1, 3, 7, 14, 21 and 28 post treat ment initiation and cultured with 1 mu g/ml concanavalin A (ConA) for 24 h. Supernatants were examined for IL-2, IL-4, IL-10, IL-12, acid IFN gamma cy tokine production using cytokine specific ELISAs. The levels of type 2 cyto kines were not significantly changed by any treatment group over the course of the disease. However, although decreased in all infected animals, type 1 cytokines were partially maintained by the combination treatment through day 21. RT-PCR for cytokine specific mRNA confirmed these results, with exp ression of the type 1 cytokines, especially IFN gamma, being maintained thr ough day 21. Establishment of a treatment regime that can maintain protecti ve cytokine activities against disease progression may prove applicable to other retroviral infections. (C) 1999 International Society for Immunopharm acology. Published by Elsevier Science Ltd. All rights reserved.