8 Br-cAMP enhances both humoral and cell-mediated immune responses inducedby an HIV-1 DNA vaccine

From a series of preclinical studies and animal experiments, we have been a ble 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 (C MV promoter) is known to be responsive to an elevation in the level of intr acellular cAMP, we hypothesized that use of cAMP analogue (8-Bromo adenosin e 3'5'-cyclic monophosphate, 8 Br-cAMP) would increase the level of transge ne expression supported by the CMV, and enhance the ability of DNA vaccines to evoke an immune response against the transgene product in vivo. To eval uate this hypothesis, immune responses against HIV-1 envelope protein, gp16 0, an immunogenic HIV-1 component expressed under the control of the CMV pr omoter, were evaluated in BALB/c mice with or without stimulation by 8 Br-c AMP. 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 wh ich route was used, the combination increased the serum lgG antibody (Ab) t iter, 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 (slgA). Moreover, it induce d increased production of interferon-gamma with reduction in IL-4 synthesis , and decreased the ratio of serum IgG1/lgG2a. 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 indu ction 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 adju vant effect of 8 Br-cAMP may be due to the activation of the CMV promoter i n the DNA vaccine. The virus challenge experiment in a mouse influenza mode l also proved our hypothesis.