Incorporation of CD40 ligand into SHIV virus-like particles (VLP) enhances SHIV-VLP-induced dendritic cell activation and boosts immune responses against HIV

Abstract

Engagement of CD40 with CD40L induces dendritic cell (DC) maturation and activation, thereby promoting immune responses. The objective of this study was to investigate whether immunization with chimeric CD40L/SHIV virus-like particles (CD40L/SHIV-VLP) could enhance immune responses to SIV Gag and HIV Env proteins by directly activating DCs. We found that CD83, CD40, and CD86 were significantly up-regulated and significantly increased cytokines production were observed after hCD40L/SHIV-VLP treatment in human CD14+ monocyte-derived DCs as compared to SHIV-VLP treatment. Mice immunized with mCD40L/SHIV-VLP showed more than a two-fold increase in HIV Env-specific IgG antibody production, an increase in SIV Gag and HIV Env-specific IFN-γ and IL-4 producing cells, and an increase in HIV Env-specific cytotoxic activity compared to that in SHIV-VLP immunized mice. Furthermore, multifunctional CD4+ Th1 cells, which simultaneously produce IFN-γ, IL-2 and TNF-α triple cytokines, and CD8+ T-cells, which produce IFN-γ were elevated in the mCD40L/SHIV-VLP immunized group. These data demonstrate that chimeric CD40L/SHIV-VLP potently induce DC activation and enhance the magnitude of both humoral and cellular immune responses to the SIV Gag and HIV Env proteins in the mouse model. Therefore, incorporation of CD40L into VLP may represent a novel strategy to develop effective HIV vaccines.

Incorporation of GM-CSF or CD40L Enhances the Immunogenicity of Hantaan Virus-Like Particles

“…Our findings also demonstrate that CD40L incorporation into HTNV VLPs produces strong primary CD4 + Th1 and CD8+ T cell responses. Other studies that incorporated CD40L into VLPs to enhance immunogenicity reported similar results (Skountzou et al, 2007; Zhang et al, 2010). The incorporation of CD40L into HTNV VLPs also increased the titers of GP- and NP-specific antibodies and the neutralization antibody.…”

“…The binding of CD40L to CD40 modulates cellular immune responses by inducing the expression of costimulatory molecules that reside on antigen-presenting cells (APCs). Because of the upregulation of costimulatory molecules, APCs are activated, CD4 + T cell responses are augmented by increased cytokine production, and CD4 + -dependent naive CD8 + T cells are activated in vivo (Skountzou et al, 2007; Lin et al, 2009; Zhang et al, 2010). …”

Protein transfer-mediated surface engineering to adjuvantate virus-like nanoparticles for enhanced anti-viral immune responses

“…To enhance VLP immunogenicity for stronger cross-protection, VLPs have been genetically modified using the recombinant baculovirus (rBV) system to express immunostimulatory molecules (ISMs), such as membrane-bound cytokines, GM-CSF, CD40L, and flagellin, on the VLP surface (12–14). Another approach to introduce proteins onto VLPs is by pseudotyping, which involves fusing peptides or proteins-of-interest and viral proteins together on the VLPs (15, 16).…”

Protein based therapeutic delivery agents: Contemporary developments and challenges

“…Virus-like particles (VLPs) have been employed for immunotherapy owing to the similarities with viruses [77] and have been reported to deliver several immunoregulatory proteins such as C-C motif chemokine ligand 19 (CCL19) [242], interleukin 2 (IL-2) [242], and cluster of differentiation 40 ligand (CD40L) [243, 244]. The small hepatitis B surface antigen, HBsAg(S), which is the small envelop protein of the hepatitis B virus, has been engineered to be flanked by CCL19 at the N-terminus and IL-2 along with an antigen derivative (from human papillomavirus 16 transforming protein E7, HPV16 E7) at the C-terminus in order to enhance the immunogenicity [242].…”