Abstract
Though immune correlates for protection are still under investigation, potent cytotoxic T lymphocyte responses are desirable for an ideal HIV-1 vaccine. PD-1 blockade enhances SIV-specific CD8+ T cells. However, little information has been reported about how it affects the immunogenicity and protection of prophylactic SIV vaccines in nonhuman primates. Here, we show that PD-1 blockade during vaccination substantially improved protective efficacy in SIV challenged macaques. The PD-1 pathway was blocked using a monoclonal antibody specific to human PD-1. Administration of this antibody effectively augmented and sustained vaccine-induced SIV-specific T cell responses for more than 42 weeks after first immunization in rhesus monkeys, as compared with SIV vaccination only. Importantly, after intrarectally repeated low-dosage challenge with highly pathogenic SIVmac239, monkeys with PD-1 blockade during vaccination achieved full protection against incremental viral doses of up to 50,000 TICD50. These findings highlight the importance of PD-1 blockade during vaccination for the development of HIV vaccines.
Highlights
The pandemic of acquired immune deficiency syndrome (AIDS), which is caused by human immunodeficiency virus type 1 (HIV-1), continues to be a serious challenge for global public health
Results showed that genolimzumab competitively interacted with a fluorescent-labeled anti-CD279 antibody (Figures 1A,B), which is specific to recognizing PD-1 molecules on the surface of monkey cells
These findings demonstrated that genolimzumab was effectively bound to monkey PD-1, and this monoclonal antibody might be suitable for blockade of PD-1/PDL1 signal pathways in simian immunodeficiency virus (SIV)-infected or vaccinated monkeys
Summary
The pandemic of acquired immune deficiency syndrome (AIDS), which is caused by human immunodeficiency virus type 1 (HIV-1), continues to be a serious challenge for global public health. After termination of the highly anticipated STEP trial of Merck’s adenovirusvector HIV vaccine [4, 5], which was a major setback to the field of T cell-based HIV vaccine research, increasing findings in the era of post-STEP demonstrated that the generation of T cell-based HIV vaccine candidates should enhance the quantity and quality of CTL responses to confer superior protective efficacy [6,7,8]. A variety of vaccination regiments, including novel viral vector-based vaccines and heterologous prime/boost strategies, generated potent CTL responses and afforded significant protection against highly pathogenic SIV challenge in nonhuman primates, and several promising candidates are moving forward to preclinical and clinical trials [6, 9,10,11,12,13]. It is of great interest to develop strategies to further enhance the magnitude, breadth, and polyfunctionality of HIV vaccine-elicited CD8+ cytotoxic T lymphocyte immune responses.
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