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The disease induced by the Friend virus complex (FV) in F1 hybrid mice containing the Rfv-3r/s genotype in the presence of H-2a/a was used to evaluate a variety of immunomodulating substances. In these genetically defined mice, the FV disease results in splenomegaly, early production of high titers of cell-associated and plasma virus, high levels of splenic viral RNA, increased hematocrit, and eventual death. As the disease progresses, reduced levels of infectious virus correlate with development of specific antibody; reduction in T cell populations, increase in B cells, and decrease in T-cell function also occur. The following immunomodulators were evaluated, listed in the order of their ability to inhibit the FV disease: imexon > MVE-2 > human recombinant IFN-alpha A/D > AS101 > ampligen > AM-3 = oxamisole > ImuVert > bropirimine. In fact, bropirimine, used with certain treatment regimens, appeared to enhance the FV disease. These data suggest that certain immunomodulators may have potential value in the treatment of HIV disease, but also indicate that caution should be exercised in their clinical use.

Since many of the severe cytomeqalovlrus infections in humans occur in individuals im,[fiunosuppressed by the human immunodeficiency virus, we developed an analogous murine model for studying this disease. BALB/c mice infected with the Friend retrovirus complex (FV)were immunosuppressed (i.e., exhibited reduced spleen-cell mitogenic responses and natural killer cell activity) by 21 days after FV inoculation. Challenge with murine cytomegalovirus (MCMV) at that time led to mortality at doses generally non-lethal to normal mice. Superinfection of FV-infected mice with MCMV reduced spleen cell FV infectious centres and splenomegaly, and extended the lives of mice surviving the MCMV infection. Once-daily ganciclovir treatments of 12.5, 25, and 50mg kg-1 given to duallyinfected mice for 5 days starting 24h after MCMV inoculation resulted in 90-100% survival at 14 days (relative to MCMV inoculation) compared to 15% survival in the placebo group. By 70 days, survival in the drug-treated and placebo groups were' Q-5%, these deaths being attributed to FV disease. Ganciclovir treatments reduced MCMV titres in spleen, liver, and kidney during treatment (day 4 of the infection), but lung and salivary gland titres rose between days 7 and 13 in surviving animals. Improved concanavalin A-induced mitogenic responses were noted on day 4 in mice treated with 25 and 50 mg kg-1. These results indicate that the FV/MCMV dual infection in mice can be used as a model for evaluating antiviral agents. Because of the complex nature of the interaction between FV and MCMV, the model may be more Received

The anti-Friend leukemia virus (FLV) effects of interferon-alpha-A/D (IFN-alpha) and 2',3'-didehydro-2',3'-dideoxythymidine (stavudine) used alone and in combination were examined in Mus dunni cells using a checkerboard-type experiment design. Strong antiviral synergy and a suggested cytotoxic synergy were seen. In two experiments to evaluate the effect of combining therapy with IFN-alpha and stavudine against FLV disease in the hybrid mouse strain (B10.A x A.By)F1, which is a strong producer of cytotoxic T cells, the drug combination resulted in better inhibition of FLV disease than did either drug used alone. Combination therapy inhibited splenomegaly, splenic virus infectious centers, plasma virus, and the virus-induced increase in hematocrit to a greater degree than did either drug alone. These data indicate that combination therapy with stavudine and IFN-alpha is effective in the treatment of murine retrovirus infections and may be of value in the treatment of human AIDS.

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