Human PD1-based mosaic Gag-p41 DNA vaccines for inducing potent and broad HIV-specific immune responses

Abstract

Human immunodeficiency virus type 1 (HIV-1) is one of the most devastating infectious microbes that commonly involves diverse HIV-1 subtypes even in a single geographical location (e.g. China). Unfortunately, there has yet to be an effective HIV vaccine due to the severe diversity of the viral genome. Therefore, a new strategy to design antigens through in silico algorithms that can match and maximize the sequences of natural HIV-1 subtypes can potentially be broadly reactive for vaccine protection. In addition to this approach, previous finding showed that when soluble programmed death-1 (sPD1) was fused with HIV-1 Gag-p24 to target DCs, the vaccine was able to enhance antigen presentation and induced potent cellular immunity in murine model. Utilizing these two strategies, novel DNA vaccines incorporating sPD1 and generically derived Consensus Env-gp120 and Mosaic Gag-p41-fusion antigens were designed based on the major circulating HIV-1 subtypes (B/B’, C/CB’ and 01_AE) in China to overcome the HIV diversity and to enhance the immunogenicity. The data showed that Consensus Env-gp120 could induce neutralizing antibodies (NAbs) against a tier 1 pseudovirus in small-animal models. Meanwhile, the immunogenicity profiles of sPD1 fused together with two Mosaic Gag-p41 antigens (achieving the epitope coverage about 97% of all three HIV-1 subtypes) were determined using ELISA, ELISpot, ICS and Tetramer assays from samples of vaccinated mice. Interestingly, the sPD1-mosaic p41 fusion DNA vaccine was broadly reactive and was able to induce potently durable and protective Gag-specific T cell immunity, as well as produced fast acting TEM activation and long-lasting TCM responses. To test whether the efficacy of huPD1-mosaic p41 was translatable in non-human primates, Chinese rhesus macaques were vaccinated, and results showed that broad and potent Gag-specific T cell immunity was rapidly induced. In addition, they were also able to generate HIV-specific TEM and TCM response, as well as immunoprevalent 〖CD8〗^+ and 〖CD4〗^+ T cell specific-epitopes that are associated to HIV control. Samples from naturally infected Chinese HIV^+ individuals were applied to characterize the antigenicity of the huPD1-mosaic p41 immunogen, and the findings showed that robust T cell responses specific for Mosaic p41 immunogens were detected in untreated HIV^+ patients compared to treated patients ex vivo. Taken together, this huPD1-mosaic p41 fusion DNA vaccine could enhance HIV-specific T cell responses against the three major subtypes in China in mice and rhesus macaques, and these Mosaic peptides can be recognize by the T cells from HIV^+ infected individuals. These findings indicate that the huPD1-mosaic p41 DNA vaccine may have prophylactic and therapeutic characteristics, and could be an advantageous HIV/AIDS vaccine.