Effective Postexposure Treatment of Retrovirus-Induced Disease with Immunostimulatory DNA Containing CpG Motifs

Abstract

Therapeutic strategies for the treatment of acute retroviral infections have relied mainly on antiviral drugs. In this study we used the Friend virus model system to demonstrate that enhancement of the immune system can also have dramatic therapeutic effects. Since resistance to Friend virus-induced leukemia in mice is associated with T helper cell type 1 (Th1) immune responses, we enhanced these responses in susceptible mice by treatment with synthetic oligodeoxynucleotides containing unmethylated CpG motifs (CpG-ODN). Treatments begun at 4 days postinfection increased recovery from 6% in the control group to 74% in the CpG-treated group. CpG-mediated recovery was associated with a significant reduction of viral loads in the blood and spleens of treated mice compared to those of control animals. The treatment promoted Th1-type cytokine production by splenocytes of Friend virus-infected mice and augmented Friend virus-specific cytotoxic T-cell responses, but no influence on the virus-specific neutralizing antibody response was observed. Friend virusspecific CD8 ؉ T cells were critical for effective treatment with CpG-ODN, since in vivo depletion of these cells from treated mice prevented their recovery. Our results demonstrate that CpG-ODN therapy can significantly enhance virus-specific cellular immune responses and prevent retrovirus-induced disease. These findings may have implications for antiviral therapy in general.

CpG Oligodeoxynucleotides Protect Newborn Mice from a Lethal Challenge with the Neurotropic Tacaribe Arenavirus

“…In addition, recent studies show that systemic administration of CpG ODN improved recovery of mice infected with the Friend leukemia virus and senescent mice infected with the influenza virus (12,44). Protection in all cases was linked to induction of a Th1 response.…”

Preinfection Treatment of Resistant Mice with CpG Oligodeoxynucleotides Renders Them Susceptible to Friend Retrovirus-Induced Leukemia

“…Thus, a CpG-ODN treatment could potentially lead to enhanced virulence in several different viral infections when applied at the wrong time point pre-or postinfection. With this information at hand researchers and clinicians should carefully evaluate the antiviral potential of CpG-ODN that has recently been described for two different model virus infections (20,22). If used under the right conditions, CpG-ODN should be a powerful substance for antiviral therapy in the future.…”

“…Intraperitoneal injections of 15 nmol (95 g) of CpG-ODN or control ODN without the CpG motif were administered on days Ϫ12 and Ϫ4 and at Ϫ1 h with respect to infection (arrows). The same or a comparable dose of CpG-ODN has been used in other experimental therapies of infectious diseases and has never been documented to be toxic for mice (7,20,24). Phosphothioate-modified single-stranded ODN were used in our experiments (MWG-Biotech AG, Ebersberg, Germany).…”

“…The treatment of mice with synthetic oligodeoxynucleotides containing unmethylated CpG motifs (CpG-ODN) has been shown to have curative effects in allergy models (26), experimental cancer models (1), and infectious diseases (20,22,27). In particular, the ability of CpG-ODN to promote Th1-type responses and activate several cell populations of the immune system has been associated with the therapeutic effect of CpG-ODN in these models (17).…”

“…These were the same dose of CpG-ODN and the same frequency of injections that were used previously for the successful postexposure treatment of FV infection (20). After CpG-ODN inoculation mice were injected intravenously on day 0 with 3,000 spleen focus-forming units of pathogenic FV complex (2).…”