Modulating APOBEC expression enhances DNA vaccine immunogenicity

Author(s)

Almeida, Rafael Ribeiro ^{[1, 2]} ; Raposo, Rui Andre Saraiva ^[3] ; Coirada, Fernanda Caroline ^[1] ; da Silva, Jamile Ramos ^[4] ; de Souza Ferreira, Luis Carlos ^[4] ; Kalil, Jorge ^{[5, 1, 2]} ; Nixon, Douglas F. ^[3] ; Cunha-Neto, Edecio ^{[5, 1, 2]}

Affiliation

^[1] Univ Sao Paulo, Sch Med, Lab Clin Immunol & Allergy LIM60, Div Clin Immunol & Allergy, Dept Med, Sao Paulo - Brazil

^[2] Inst Invest Immunol INCT, Sao Paulo - Brazil

^[3] George Washington Univ, Dept microbiol Immunol & Trop Med, Washington, DC - USA

^[4] Univ Sao Paulo, Inst Biomed Sci, Dept Microbiol, Sao Paulo - Brazil

^[5] Univ Sao Paulo, Sch Med, Heart Inst InCor, Sao Paulo - Brazil

• Document type: Journal article
• Source: Immunology and Cell Biology; v. 93, n. 10, p. 868-876, NOV 2015.
• Web of Science Citations: 3

Abstract

DNA vaccines have failed to induce satisfactory immune responses in humans. Several mechanisms of double-stranded DNA (dsDNA) sensing have been described, and modulate DNA vaccine immunogenicity at many levels. We hypothesized that the immunogenicity of DNA vaccines in humans is suppressed by APOBEC (apolipoprotein B (APOB) mRNA-editing, catalytic polypeptide)-mediated plasmid degradation. We showed that plasmid sensing via STING (stimulator of interferon (IFN) genes) and TBK-1 (TANK-binding kinase 1) leads to IFN-beta induction, which results in APOBEC3A mRNA upregulation through a mechanism involving protein kinase C signaling. We also showed that murine APOBEC2 expression in HEK293T cells led to a 10-fold reduction in intracellular plasmid levels and plasmid-encoded mRNA, and a 2.6-fold reduction in GFP-expressing cells. A bicistronic DNA vaccine expressing an immunogen and an APOBEC2-specific shRNA efficiently silenced APOBEC2 both in vitro and in vivo, increasing the frequency of induced IFN-gamma-secreting T cells. Our study brings new insights into the intracellular machinery involved in dsDNA sensing and how to modulate it to improve DNA vaccine immunogenicity in humans. (AU)

• FAPESP's process: 08/57881-0 - Institute for Investigation in Immunology
• Grantee: Jorge Elias Kalil Filho
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 06/50096-0 - Characterization of Human Immunodeficiency Virus type 1 (HIV-1) in a cohort of recently infected persons from the State of São Paulo by full genome sequencing
• Grantee: Sabri Saeed Mohammed Ahmed Al-Sanabani
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 04/15856-9 - Prospective analysis of the virological and immunological characteristics in individuals with recent HIV-1 infection in the cities of São Paulo and Santos
• Grantee: Ricardo Sobhie Diaz
• Support Opportunities: Research Projects - Thematic Grants