HIV-1 vaccine strategies and viral interaction with dendritic cells

Abstract

Both the tremendous diversity of HIV-1 and viral reservoirs are major challenges for the development of an effective HIV-1 vaccine. The mosaic antigen provides the potential for vaccine design that aims at global protection. In addition, studies to date have indicated that Gag-specific CD8+ T cells serve as host dominant immune surveillance for HIV-1 control. Therefore, mosaic antigen HIV-1 Gag allows antigenic breadth for vaccine-induced cellular immune response against a wider spectrum of viral strains. Moreover, a heterologous prime/boost regimen has been shown to be able to induce stronger immune responses. Here, we found that priming with DNA vaccine, followed by boosting with the live replication-competent modified vaccinia TianTan (MVTT) vector-based vaccine, both of which are combined with the mosaic antigen, could induce greater and broader protective immune responses. Our findings corroborate the promise of the mosaic approach and the two acceptably safe vectors to enhance anti-HIV immunity. Dendritic cell (DC)-targeted vaccine strategy is well appreciated to enhance immune response. Thus we determined the efficacy of soluble rhesus macaque programmed death-1 (RhPD1) fused with SIVmac239 Gag-p27 in murine and monkey models. We found this DNA vaccine allowed an effective dendritic cell targeting. Compared with RhPD1 fused to the full-length Gag, our new vaccine induced significantly greater immune responses, and provided a better protection against both vaccinia virus expressing SIV Gag and simian-human immunodeficiency virus (SHIV) challenge. Interestingly, we identified a new T cell epitope from SIV Gag-p27, which is highly homologous to the Gag293 epitope recognized by CD4+ T cells of HIV elite controllers. Our study indicates the potential ability of PD1-based DNA vaccine to induce superior T cell immunity for HIV control. Meanwhile, our studies have shown that a novel isoform of human PD1 (Δ42PD1)- based vaccine could also elicit pronounced immune response by acting on dendritic cells. To investigate further the mechanism behind the action of the vaccine, we proposed to determine the role of Δ42PD1 in regulating dendritic cells-mediated HIV transmission and adaptive immune responses. We found that immature monocytederived DCs (MDDCs) expressed the highest level of Δ42PD1 compared with monocyte and mature MDDCs. Interestingly, some Δ42PD1 co-localized with GFPtagged vesicular stomatitis virus glycoprotein (VSV-g)-pseudotyped HIV particles and MHC class II (MHC-II) at the virological synapses of MDDC-T cell contact sites. In addition, some 42PD1+ vesicles moved along the dendrites and interacted with autologous CD4+ T cells. These vesicles perhaps oriented HIV infection of the T cells or were secreted as exosomes for immune regulation. Therefore, Δ42PD1 may play an important role in regulating HIV-1 transmission as well as antigen presentation. Understanding how Δ42PD1 is involved in these processes would provide novel targets to control HIV infection. Overall, our findings demonstrate the superiority of the mosaic approach and heterologous DNA prime/MVTT boost regimen, which have implications to develop an effective HIV-1 vaccine. Meanwhile, we demonstrate the efficacy improvement of PD1-based vaccination in rhesus macaque model. Furthermore, we delineate the effect of Δ42PD1 on viral interaction with DC, which may represent a promising immune mechanism underlying HIV-1 pathogenesis.