8 Br-cAMP enhances both humoral and cell-mediated immune responses induced by an HIV-1 DNA vaccine.
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.
Arai
H
H
Department of Bacteriology, Yokohama City University School of Medicine, Yokohama, Japan.
Xin
K Q
KQ
Hamajima
K
K
Lu
Y
Y
Watabe
S
S
Takahashi
T
T
Toda
S
S
Okuda
K
K
Kudoh
I
I
Suzuki
M
M
Okuda
K
K
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000627:therapeutic use*; D000281:Administration, Intranasal; D000818:Animals; D003131:Combined Modality Therapy; D003587:Cytomegalovirus / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D019302:HIV Envelope Protein gp160 / Q000235:genetics*; D006968:Hypersensitivity, Delayed / Q000188:drug therapy* / Q000276:immunology; D007074:Immunoglobulin G / Q000032:analysis; D007273:Injections, Intramuscular; D051379:Mice; D008807:Mice, Inbred BALB C; D009976:Orthomyxoviridae Infections / Q000276:immunology; D011401:Promoter Regions, Genetic; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology; D019444:Vaccines, DNA / Q000627:therapeutic use*
D019302:HIV Envelope Protein gp160; D007074:Immunoglobulin G; D019444:Vaccines, DNA; D015124:8-Bromo Cyclic Adenosine Monophosphate