title: Therapeutic DNA vaccine induces broad T cell responses in the gut and sustained protection from viral rebound and AIDS in SIV-infected rhesus macaques.
abstract: 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.
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America. fullerdh@u.washington.edu
authors.forename: Deborah Heydenburg
authors.initials: DH
authors.lastname: Fuller
authors.forename: Premeela
authors.initials: P
authors.lastname: Rajakumar
authors.forename: Jenny W
authors.initials: JW
authors.lastname: Che
authors.forename: Amithi
authors.initials: A
authors.lastname: Narendran
authors.forename: Julia
authors.initials: J
authors.lastname: Nyaundi
authors.forename: Heather
authors.initials: H
authors.lastname: Michael
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Yager
authors.forename: Cristy
authors.initials: C
authors.lastname: Stagnar
authors.forename: Brendon
authors.initials: B
authors.lastname: Wahlberg
authors.forename: Rachel
authors.initials: R
authors.lastname: Taber
authors.forename: Joel R
authors.initials: JR
authors.lastname: Haynes
authors.forename: Fiona C
authors.initials: FC
authors.lastname: Cook
authors.forename: Peter
authors.initials: P
authors.lastname: Ertl
authors.forename: John
authors.initials: J
authors.lastname: Tite
authors.forename: Angela M
authors.initials: AM
authors.lastname: Amedee
authors.forename: Michael
authors.initials: M
authors.lastname: Murphey-Corb
mesh_terms: D016915:AIDS Vaccines / Q000494:pharmacology*; D000163:Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000517:prevention & control*; D000818:Animals; D007114:Immunization / Q000379:methods; D007371:Interferon-gamma / Q000276:immunology; D008253:Macaca mulatta; D018449:SAIDS Vaccines / Q000494:pharmacology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000517:prevention & control*; D019444:Vaccines, DNA / Q000382:microbiology*
chemical_list: D016915:AIDS Vaccines; D018449:SAIDS Vaccines; D019444:Vaccines, DNA; D007371:Interferon-gamma