From a series of preclinical studies and animal experiments, we have been able to demonstrate that
DNA vaccines are a promising tool in strategies for protecting hosts from a variety of
infectious diseases. Since the promoter activity of the human cytomegalovirus immediate-early promoter/ enhancer (CMV promoter) is known to be responsive to an elevation in the level of intracellular cAMP, we hypothesized that use of cAMP analogue (8-Bromo
adenosine 3'5'-cyclic monophosphate, 8 Br-cAMP) would increase the level of transgene expression supported by the CMV, and enhance the ability of
DNA vaccines to evoke an immune response against the transgene product in vivo. To evaluate this hypothesis, immune responses against
HIV-1 envelope protein, gp160, an immunogenic HIV-1 component expressed under the control of the CMV promoter, were evaluated in BALB/c mice with or without stimulation by 8 Br-cAMP.
DNA vaccine with 8 Br-cAMP was intramuscularly (i.m.) or intranasally (i.n.) administered to BALB/c mice twice on days 0 and 14. Regardless of which route was used, the combination increased the serum
IgG antibody (Ab) titer, HIV-1-specific cytotoxic T lymphocyte (CTL) activity and the delayed-type
hypersensitivity (DTH) response, compared with the effect of using the
vaccine alone. When administered via the i.n. route, the combination also remarkably increased the titer of
secretory IgA (
sIgA). Moreover, it induced increased production of
interferon-gamma with reduction in
IL-4 synthesis, and decreased the ratio of serum
IgG1/
IgG2a. However, these enhancements were not observed when 8 Br-cAMP was coadministered with
peptide vaccine or
protein antigen. These data suggest that 8 Br-cAMP is able to enhance both humoral and cellular immune responses induced by the
DNA vaccine. The induction of T helper type 1 (Th1) immunity against HIV-1 was also enhanced by coadministration of 8 Br-cAMP. A CAT assay study demonstrated that the adjuvant effect of 8 Br-cAMP may be due to the activation of the CMV promoter in the
DNA vaccine. The virus challenge experiment in a mouse
influenza model also proved our hypothesis.