Retinaldehyde dehydrogenase 2 as a molecular adjuvant for enhancement of mucosal immunity during DNA vaccination.
In order for vaccines to induce efficacious immune responses against mucosally transmitted pathogens, such as HIV-1, activated lymphocytes must efficiently migrate to and enter targeted mucosal sites. We have previously shown that all-trans retinoic acid (ATRA) can be used as a vaccine adjuvant to enhance mucosal CD8+T cell responses during vaccination and improve protection against mucosal viral challenge. However, the ATRA formulation is incompatible with most recombinant vaccines, and the teratogenic potential of ATRA at high doses limits its usage in many clinical settings. We hypothesized that increasing in vivo production of retinoic acid (RA) during vaccination with a DNA vector expressing retinaldehyde dehydrogenase 2 (RALDH2), the rate-limiting enzyme in RA biosynthesis, could similarly provide enhanced programming of mucosal homing to T cell responses while avoiding teratogenic effects. Administration of a RALDH2- expressing plasmid during immunization with a HIVgag DNA vaccine resulted in increased systemic and mucosal CD8+T cell numbers with an increase in both effector and central memory T cells. Moreover, mice that received RALDH2 plasmid during DNA vaccination were more resistant to intravaginal challenge with a recombinant vaccinia virus expressing the same HIVgag antigen (VACVgag). Thus, RALDH2 can be used as an alternative adjuvant to ATRA during DNA vaccination leading to an increase in both systemic and mucosal T cell immunity and better protection from viral infection at mucosal sites.
Biodesign Center for Infectious Diseases and Vaccinology, Biodesign Institute, Arizona State University, Tempe, AZ 85287-5401, United States; School of Life Sciences, Arizona State University, Tempe, AZ 85287-4501, United States; Simon A. Levin Mathematical, Computational and Modeling Sciences Center, Arizona State University, Tempe, AZ 85287-3901, United States.
Susan A
SA
Holechek
Biodesign Center for Infectious Diseases and Vaccinology, Biodesign Institute, Arizona State University, Tempe, AZ 85287-5401, United States; School of Life Sciences, Arizona State University, Tempe, AZ 85287-4501, United States.
Megan S
MS
McAfee
Biodesign Center for Infectious Diseases and Vaccinology, Biodesign Institute, Arizona State University, Tempe, AZ 85287-5401, United States; School of Life Sciences, Arizona State University, Tempe, AZ 85287-4501, United States.
Lizbeth M
LM
Nieves
Biodesign Center for Infectious Diseases and Vaccinology, Biodesign Institute, Arizona State University, Tempe, AZ 85287-5401, United States; School of Life Sciences, Arizona State University, Tempe, AZ 85287-4501, United States.
Vanessa P
VP
Guzman
Biodesign Center for Infectious Diseases and Vaccinology, Biodesign Institute, Arizona State University, Tempe, AZ 85287-5401, United States; School of Life Sciences, Arizona State University, Tempe, AZ 85287-4501, United States.
Kavita
K
Manhas
Profectus BioSciences, Inc., Baltimore, MD 21224, United States.
Timothy
T
Fouts
Profectus BioSciences, Inc., Baltimore, MD 21224, United States.
Kenneth
K
Bagley
Biodesign Center for Infectious Diseases and Vaccinology, Biodesign Institute, Arizona State University, Tempe, AZ 85287-5401, United States; School of Life Sciences, Arizona State University, Tempe, AZ 85287-4501, United States. Electronic address: Joseph.Blattman@asu.edu.
Joseph N
JN
Blattman
D016915:AIDS Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D000276:Adjuvants, Immunologic; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D054298:Human Immunodeficiency Virus Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D018928:Immunity, Mucosal; D007114:Immunization / Q000379:methods; D007156:Immunologic Memory; D051379:Mice; D010957:Plasmids; D050697:Retinal Dehydrogenase / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D014212:Tretinoin / Q000276:immunology / Q000378:metabolism; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology*; D014615:Vaccinia / Q000276:immunology / Q000517:prevention & control; D014616:Vaccinia virus / Q000235:genetics
D016915:AIDS Vaccines; D000276:Adjuvants, Immunologic; D054298:Human Immunodeficiency Virus Proteins; D019444:Vaccines, DNA; D014212:Tretinoin; D000080924:Aldehyde Dehydrogenase 1 Family; C545372:ALDH1A2 protein, human; D050697:Retinal Dehydrogenase
HIV DNA vaccine; Mucosal protection; RALDH2 adjuvant; Retinoic acid
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