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

Deborah Heydenburg Fuller,Cristy Stagnar,Michael Murphey-Corb,Peter Ertl,Fiona C Cook,Premeela Rajakumar,Eric J Yager,Brendon Wahlberg,Rachel Taber,Joel R Haynes,Angela M Amedee,Amithi Narendran,John Tite,Jenny W Che,Heather Michael,Julia Nyaundi

doi:10.1371/journal.pone.0033715

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.

Highlights

Antiretroviral drugs exert considerable control of HIV infection, they do not eliminate virus in the tissues or fully restore virus-specific immunity and interruption of therapy usually results in viral rebound [1,2,3]
We hypothesized that a vaccine capable of enhancing these responses in the gut associated lymphoid tissues (GALT) would be critical for effective immunotherapy because it would target the primary site of virus production
Highly active antiretroviral therapy (HAART) does not result in a cure and if drug treatment is interrupted, virus rebound usually occurs within weeks

Summary

Introduction

Antiretroviral drugs exert considerable control of HIV infection, they do not eliminate virus in the tissues or fully restore virus-specific immunity and interruption of therapy usually results in viral rebound [1,2,3]. Studies employing therapeutic immunization with peptidepulsed dendritic cells or PBMC [5,6], viral vectored vaccines [7], or DNA vaccines [8,9] support this concept in that therapeutic vaccination with these approaches has been shown to enhance virus-specific T cell responses, reduce viral set-point after withdrawing drugs, and slow or prevent disease progression in SIV-infected macaques. Some of these approaches had some immunological impact and virological benefit in chronically HIV1 infected patients [10,11,12]. Therapeutic vaccines that stimulate mucosal immune responses in the gut could provide a means to more effectively target and control viral replication in this reservoir but to date the impact of a therapeutic vaccine on virus in the gut or other tissue reservoirs has not been investigated

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