Efficacy and mechanism of PD1-based DNA vaccines in enhancing HIV-1 Gag-specific immunity

Abstract

Human immunodeficiency virus type 1 (HIV-1) has caused more than 70 million infections worldwide since its discovery, with half of the infected already died by the end of 2011 as a result of HIV-progression to acquired immunodeficiency syndrome (AIDS). Highly active antiretroviral therapy (HAART) is capable to extend the lifespan of HIV patients but economic burden and emergence of resistant HIV strains pose immediate problems in the care of HIV patients. Furthermore, HAART cannot clear virus. Therefore, tremendous efforts have tried to develop an effective HIV vaccine in the last thirty years but only partial efficacy (31%) was achieved in the recent Thai RV144 clinical trial. Hence, new vaccine and understanding the mechanism are required now and in the future. In this study, two novel DNA vaccine strategies that utilized programmed death-1 (PD-1) or its isoform to improve immunogenicity of DNA vaccine for HIV-1 Gag p24 by acting on dendritic cells are described. The molecule PD-1 delivers negative regulatory signals to T cells through interacting with its ligands PD-L1 and PD-L2, while blocking this signal could functionally rescue the “exhausted” T cells during chronic infection such as HIV-1. The first DNA vaccine involves the fusion between HIV-1 Gag p24 antigen and soluble PD1 for effective targeting to DCs while improving antigen uptake and DC maturation, which in turn elicited consistently high frequencies of HIV-1 Gag-specific, broadly reactive, polyfunctional, long-lived and cytotoxic CD8+ T cells, in addition to robust anti-Gag antibody titers in mouse. The mechanism behind the action of this vaccine (sPD1-p24fc) is based on engagement of cross-presentation to CD8+ T cells, and induction of Th1 cytokines. The second DNA vaccine utilized a novel isoform of human PD1 (Δ42PD1) that contains a 42-nucleotide in-frame deletion located at exon 2 domain discovered in healthy PBMC donors. Interestingly, Δ42PD1 does not engage PD-L1/PD-L2 but its recombinant form could induce pro-inflammatory cytokines. When Δ42PD1 was used as an intramolecular adjuvant to develop a fusion DNA vaccine with HIV-1 Gag p24 antigen (sΔ42PD1-p24fc), enhanced DC uptake was also observed. When mice was vaccinated with this vaccine, significantly enhanced anti-p24 IgG1/IgG2a antibody, p24-specific T cells responses with functionally improved proliferative and cytolytic capacities were also identified. Importantly, both of these vaccines enhanced antigen-specific immunity and provided protection against pathogenic viral challenge as well as tumor growth in mice. Overall, the induction of high frequency of durable and protective Gag-specific T cell immunity, especially CD8+ T cell immunity using these two vaccines have important implications for vaccine development and immunotherapy against HIV-1 and other pathogens.