Therapeutic DNA vaccine induces broad T cell responses in the gut and sustained protection from viral rebound and AIDS in SIV-infected rhesus macaques

• Published in: PloS one 2012-03, Vol.7 (3), p.e33715
• Main Authors: Fuller, Deborah Heydenburg, Rajakumar, Premeela, Che, Jenny W, Narendran, Amithi, Nyaundi, Julia, Michael, Heather, Yager, Eric J, Stagnar, Cristy, Wahlberg, Brendon, Taber, Rachel, Haynes, Joel R, Cook, Fiona C, Ertl, Peter, Tite, John, Amedee, Angela M, Murphey-Corb, Michael
• Format: Article
• Language: English
• Subjects: Acquired immune deficiency syndrome; Acquired Immunodeficiency Syndrome - immunology; Acquired Immunodeficiency Syndrome - prevention & control; AIDS; AIDS (Disease); AIDS vaccines; AIDS Vaccines - pharmacology; Analysis; Animals; Antiretroviral agents; Antiretroviral drugs; Antiretroviral therapy; Biology; Blood; CD8 antigen; Chronic infection; Control; Deoxyribonucleic acid; Development and progression; Disease control; DNA; DNA vaccines; Drug dependence; Drugs; E coli; Gag protein; Health aspects; Highly active antiretroviral therapy; HIV; Human immunodeficiency virus; Immune response; Immunization; Immunization - methods; Immunosuppressive agents; Immunotherapy; Infection; Interferon; Interferon-gamma - immunology; Lymphocytes; Lymphocytes T; Macaca mulatta; Medical research; Medicine; Mucosal immunity; Nef protein; Plasmids; SAIDS Vaccines - pharmacology; Simian Acquired Immunodeficiency Syndrome - immunology; Simian Acquired Immunodeficiency Syndrome - prevention & control; Simian immunodeficiency virus; Studies; T cells; Therapy; Tissues; Tumor necrosis factor-α; Vaccines; Vaccines, DNA - microbiology; Viruses; γ-Interferon
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0033715

Immunotherapies that induce durable immune control of chronic HIV infection may eliminate the need for life-long dependence on drugs. We investigated a DNA vaccine formulated with a novel genetic adjuvant that stimulates immune responses in the blood and gut for the ability to improve therapy in rhesus macaques chronically infected with SIV. Using the SIV-macaque model for AIDS, we show that epidermal co-delivery of plasmids expressing SIV Gag, RT, Nef and Env, and the mucosal adjuvant, heat-labile E. coli enterotoxin (LT), during antiretroviral therapy (ART) induced a substantial 2-4-log fold reduction in mean virus burden in both the gut and blood when compared to unvaccinated controls and provided durable protection from viral rebound and disease progression after the drug was discontinued. This effect was associated with significant increases in IFN-γ T cell responses in both the blood and gut and SIV-specific CD8+ T cells with dual TNF-α and cytolytic effector functions in the blood. Importantly, a broader specificity in the T cell response seen in the gut, but not the blood, significantly correlated with a reduction in virus production in mucosal tissues and a lower virus burden in plasma. We conclude that immunizing with vaccines that induce immune responses in mucosal gut tissue could reduce residual viral reservoirs during drug therapy and improve long-term treatment of HIV infection in humans.