4-imino-1-3-diazabicyclo(3.1.0)hexan-2-one and Acquired-Immunodeficiency-Syndrome

The Rauscher murine leukemia retrovirus system provides an in vivo model of the human acquired immune deficiency syndrome for testing the ability of antiviral agents and biological response modifiers (BRM) to suppress viremia and retroviral disease. In the present report we examined three agents in the Rauscher retrovirus model: imexon, Ampligen and poly[I,C]-LC. Imexon reduced splenomegaly, viremia, and serum reverse transcriptase levels even when treatment was not initiated until 7 days after virus infection. Imexon also significantly prolonged the survival of infected mice. Thus it proved to be an effective antiviral agent in this system, although imexon did not completely eliminate retroviral infection in treated mice. Poly[I,C]-LC and Ampligen had immunomodulatory effects. Both of these BRM augmented the cytolytic activity of splenic natural killer (NK) cells in infected animals when treatment was initiated 24 h after infection. Poly[I,C]-LC had antiretroviral activity when administered on this schedule. In order to examine the role of NK cell augmentation in the antiviral activity of poly[I,C]-LC, we attempted to deplete NK activity by treatment with rabbit antibody to asialo GM1, a ganglioside on the surface of murine NK cells. Combined treatment of infected mice with poly[I,C]-LC and anti-asialo GM1 decreased the antiviral activity of poly[I,C]-LC. This finding suggests that NK cells may be involved in the antiviral effect of this BRM.

Topics: Acquired Immunodeficiency Syndrome; Animals; Disease Models, Animal; Female; Hexanones; Immunologic Factors; Killer Cells, Natural; Leukemia, Experimental; Mice; Mice, Inbred BALB C; Rauscher Virus

Imexon (4-imino-1,4-diazobicyclo-3.1.0-hexan-2-one) was moderately effective in the treatment of a retroviral infection in a genetically defined murine model. The animal model consisted of a Friend virus complex (FV) infection in a hybrid mouse strain, (B10.A x A/WySn)F1, which has similarities with acquired immune deficiency syndrome (AIDS). Intraperitoneal imexon initiated 1 or 3 days after FV inoculation and continued through 13 days after inoculation significantly reduced splenomegaly, splenic cell-free virus titers and viral RNA. Viral infectious centers/10(6) splenocytes and FV titers in the plasma were reduced, though not to a statistically significant level. The effect of imexon on survival was not statistically significant which suggested that the antiviral effects were only transiently effective. Phytohemagglutinin-induced blastogenesis and percent of total T cells, T helper cells and T suppressor/cytotoxic cells in the spleens were increased, and the percentage of B cells decreased by imexon treatment of both FV-infected and uninfected mice. The splenic natural killer cell activity and interleukin-1 production were not markedly affected. Virus specific neutralizing antibody developed in both imexon- and placebo-treated FV-infected mice, although titers were lower in the imexon-treated animals.

Topics: Acquired Immunodeficiency Syndrome; Animals; Antineoplastic Agents; Antiviral Agents; Cell Count; Female; Friend murine leukemia virus; Hexanones; HIV-1; Leukemia, Experimental; Lymphocytes; Male; Mice; Mice, Inbred Strains; Models, Genetic; Phytohemagglutinins; RNA, Viral; Splenomegaly

Topics: Acquired Immunodeficiency Syndrome; Animals; Antiviral Agents; Disease Models, Animal; Female; Hexanones; Immunologic Factors; Ketones; Leukemia, Experimental; Mice; Mice, Inbred BALB C; Rauscher Virus; Retroviridae Infections; Reverse Transcriptase Inhibitors; Splenomegaly; Viremia