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Viral vector-based vaccines that induce protective CD8^sup +^ T cell immunity can prevent or control pathogenic SIV infections, but issues of preexisting immunity and safety have impeded their implementation in HIV-1. Here, we report the development of what we believe to be a novel antigen-targeting DNA vaccine strategy that exploits the binding of programmed death-1 (PD1) to its ligands expressed on dendritic cells (DCs) by fusing soluble PD1 with HIV-1 GAG p24 antigen. As compared with non-DC-targeting vaccines, intramuscular immunization via electroporation (EP) of the fusion DNA in mice elicited consistently high frequencies of GAG-specific, broadly reactive, polyfunctional, long-lived, and cytotoxic CD8^sup +^ T cells and robust anti-GAG antibody titers. Vaccination conferred remarkable protection against mucosal challenge with vaccinia GAG viruses. Soluble PD1-based vaccination potentiated CD8^sup +^ T cell responses by enhancing antigen binding and uptake in DCs and activation in the draining lymph node. It also increased IL-12-producing DCs and engaged antigen cross-presentation when compared with anti-DEC205 antibody-mediated DC targeting. The high frequency of durable and protective GAG-specific CD8^sup +^ T cell immunity induced by soluble PD1-based vaccination suggests that PD1-based DNA vaccines could potentially be used against HIV-1 and other pathogens.
Introduction
HIV-1 is one of the most devastating infectious agents existing worldwide for the past 30 years. Viral latency, high rates of mutation during viral replication, and emergence of drug-resistant strains are posing problems for highly active antiretroviral therapy (HAART) despite the ongoing development of newer drugs (1-3). An effective vaccine against HIV-1, therefore, remains a top priority in the fight against this pandemic virus. The induction of a high frequency of protective T cell immunity is a prerequisite for the successful control by a vaccine of intracellular pathogenic infections, and this has been well documented in the case of HIV-1 (4-7). Viral vector-based vaccines that induce such immunity can prevent or control pathogenic SIV infections, but issues of preexisting immunity and safety surround their implementation (8-10). DNA vaccines have shown a certain effectiveness, with a low level of toxicity in animal and human trials (11). However, conventional DNA vaccines with only the encoded antigen failed to mount a high frequency of effective CD8+ T cell immunity, even when delivered by in vivo electroporation (EP) (12, 13). Therefore, targeting DNA vaccines...