Incorporation of Ebola glycoprotein into HIV particles facilitates dendritic cell and macrophage targeting and enhances HIV-specific immune responses

Abstract

The development of an effective vaccine against HIV infection remains a global priority. Dendritic cell (DC)-based HIV immunotherapeutic vaccine is a promising approach which aims at optimizing the HIV-specific immune response using primed DCs to promote and enhance both the cellular and humoral arms of immunity. Since the Ebola virus envelope glycoprotein (EboGP) has strong DC-targeting ability, we investigated whether EboGP is able to direct HIV particles towards DCs efficiently and promote potent HIV-specific immune responses. Our results indicate that the incorporation of EboGP into non-replicating virus-like particles (VLPs) enhances their ability to target human monocyte-derived dendritic cells (MDDCs) and monocyte-derived macrophages (MDMs). Also, a mucin-like domain deleted EboGP (EboGPΔM) can further enhanced the MDDCs and MDMs-targeting ability. Furthermore, we investigated the effect of EboGP on HIV immunogenicity in mice, and the results revealed a significantly stronger HIV-specific humoral immune response when immunized with EboGP-pseudotyped HIV VLPs compared with those immunized with HIV VLPs. Splenocytes harvested from mice immunized with EboGP-pseudotyped HIV VLPs secreted increased levels of macrophage inflammatory proteins-1α (MIP-1α) and IL-4 upon stimulation with HIV Env and/or Gag peptides compared with those harvested from mice immunized with HIV VLPs. Collectively, this study provides evidence for the first time that the incorporation of EboGP in HIV VLPs can facilitate DC and macrophage targeting and induce more potent immune responses against HIV.

Dendritic Cells/Macrophages-Targeting Feature of Ebola Glycoprotein and its Potential as Immunological Facilitator for Antiviral Vaccine Approach

“…Another study also checked for the impact of EBOV GP without MLD (EBOV GP ΔMLD) on the stimulation of anti-GP and neutralizing antibodies; this study revealed that EBOV GP ΔMLD elicits more anti-EBOV GP antibody than EBOV GP VLP, with moderate stimulation of neutralizing antibodies [107], indicating that MLD is dispensable for EBOV attachment. Our study also showed that the removal of MLD from EBOV facilitates the cell entry efficiently more than the wild type; however, EBOV GP wild-type stimulated NFκB than EBOV GP with deleted MLD [115]. Moreover, in the development of drugs for EBOV, EBOV GP is an important target to be considered.…”

“…Also, Venezuelan Equine Encephalitis (VEE), virus-like replicon particles with the replacement of VEE virus structural genes by EBOV GP or NP, has been demonstrated to have full protection against Ebola virus challenge [171]. Interestingly, our recent study showed that the incorporation of EBOV GP into the HIV VLP induces a more effective immune response against HIV-1 [115]. We showed that the presence of EBOV GP enhances the ability of the HIV VLP to target MDMs and MDDCs.…”

“…Also, we revealed that EBOV GP-pseudotyped HIV VLP induces a significantly stronger humoral immune response than that of HIV VLP alone. Furthermore, macrophages inflammatory cytokines (MIP-1α) is significantly induced in the spleen by EBOV GP-pseudotyped HIV VLP more than HIV VLPs [115]. The heterogenic induction of immune responses by EBOV GP suggests that the immunogenicity of EBOV GP is not only beneficial in the development of a vaccine for EBOV, but can also be used to develop a vaccine for some other infectious diseases.…”

“…The receptors on DCs for GP 1 include DC-SIGN [110], L-SIGN, LSECtin [111], hMGLs [112,113], and NPC-1 [114]. Although N-glycosylation sites are present on the MLD, MLD is dispensable, and its absence contributes to more efficient cell entry of EBOV GP [115]. ( B ) Schematic diagram showing the incorporation of EBOV GP with a different pathogen antigen into VLPs [115].…”

“…Although N-glycosylation sites are present on the MLD, MLD is dispensable, and its absence contributes to more efficient cell entry of EBOV GP [115]. ( B ) Schematic diagram showing the incorporation of EBOV GP with a different pathogen antigen into VLPs [115]. ( C ) Schematic structure of vesicular stomatitis virus (VSV) with deleted glycoprotein and having EBOV GP with different pathogen antigen in the deleted G domain of VSV [116].…”