The mechanism of action of diethyldithiocarbamate (DTC) in the murine LP-BM5 retrovirus-induced immune deficiency syndrome (Murine AIDS).

Abstract

Acquired Immune Deficiency Syndrome (AIDS), caused by HIV-1 and HIV-2, is a pandemic which continues to have devastating consequences to those who are infected. HIV-1 infection results in hypergammaglobulinemia, lymphadenopathy, splenomegaly and severe immune suppression. Anti-viral agents have been approved and are widely used to treat HIV-1 infection. These agents inhibit viral replication but do not enhance or restore the immune system. Diethyldithiocarbamate (DTC), an immunomodulatory drug, is an effective therapy for HIV-1 infection. In clinical trials, DTC treated patients had fewer opportunistic infections, improved CD4+ T lymphocyte counts, and decreased lymphadenopathy. The mechanism of action of DTC in AIDS is unknown. The LP-BM5 retrovirus mixture causes murine retrovirus-induced acquired immune deficiency syndrome (Murine AIDS). This animal model has striking similarities to human AIDS, including hypergammaglobulinemia, lymphadenopathy, splenomegaly, and severe immune suppression. Anti-viral agents used to treat HIV-1 are effective in LP-BM5. In addition, DTC is an effective therapy for Murine AIDS. DTC treatment reduced hypergammaglobulinemia, inhibited lymphadenopathy and splenomegaly, and prolonged survival. The mechanisms of action of DTC in Murine AIDS is unknown. The results of this project demonstrate that DTC treatment inhibits the hyperproliferation of B lymphocytes seen in Murine AIDS. DTC treatment results in decreased IL-10 production by splenocytes during Murine AIDS. Cytotoxic T lymphocyte (CTL) and natural killer cell (NK) were not enhanced by DTC treatment. Supernatants obtained from splenocytes of virus-infected animals reduced mitogen responses (PHA and LPS) of splenocytes obtained from normal animals. Supernatants obtained from DTC-treated, virus-infected animals did not reduce mitogen responses of normal splenocytes. The soluble suppressive factor produced by LP-BMS virus-infected splenocytes has not been identified. Hydrogen peroxide release by peritoneal macrophages is increased during Murine AIDS. DTC treatment reduced hydrogen peroxide release by macrophages during Murine AIDS. Cytotoxicity to L-929 cells, a TNF-α sensitive cell line, was not effected by DTC treatment. In addition, DTC treatment did not enhance cytostatic activities of macrophages during Murine AIDS.