Abstract
A major advantage of virus-like particle (VLP) vaccines against HIV is their structural identity to wild-type viruses, ensuring that antigen-specific B-cells encounter the envelope protein in its natural conformation. For the induction of affinity-matured antibodies, the B-cells must also obtain help from T-cells that are restricted by linear epitopes. Using B- and T-cell transgenic mouse models, we compared the efficacy of modified HIV-VLPs delivered by subcutaneous and intravenous immunization to stimulate primary B- and T-cell proliferative responses in different lymphoid organs. VLPs containing an influenza virus hemagglutinin epitope within the HIV-Gag protein induced comparable primary cognate T-cell proliferative responses in the draining lymph node and the spleen, irrespective of the delivery route. In contrast, after subcutaneous immunization with HIV-Gag VLPs containing hen egg lysozyme (HEL) on their surface, the proliferative response of transgenic HEL-specific B-cells was restricted to the draining lymph nodes, while intravenous VLP immunization primarily induced a B-cell proliferative response in the spleen. In vitro co-culture experiments further revealed that the presentation of VLP-associated surface antigens by dendritic cells to cognate B-cells is inefficient. This is consistent with a direct triggering of the B-cell proliferative response by the VLPs and suggests that HIV VLPs may indeed be suitable to directly promote the expansion of B-cells specific for conformational epitopes that are unique to functionally-active Env spikes on the virion. Further investigations are warranted to explore potential differences in the quality and protective potency of HIV-specific antibody responses induced by the two routes.
Highlights
High variability, the inaccessibility of functionally-important conserved epitopes and the conformational instability of the HIV Env protein constitute major hurdles for the development ofEnv-based vaccines inducing broadly-protective antibody responses
We recently demonstrated that the T-helper cell function for the Env protein after immunization with HIV-virus-like particles (VLP) is not restricted to Env-specific
It was shown that HIV-VLPs produced in yeast were internalized by human dendritic cells (DCs), leading to the activation of Gag-specific T-cells in HIV-infected individuals, but not in healthy donors [20]
Summary
The inaccessibility of functionally-important conserved epitopes and the conformational instability of the HIV Env protein constitute major hurdles for the development ofEnv-based vaccines inducing broadly-protective antibody responses (reviewed in [1]). The Env protein can be incorporated into the VLP in a membrane-embedded form in its natural conformation. This conformation may facilitate the induction of antibodies against conformation-dependent epitopes that are unique to the trimeric Env spikes on the virion and may avoid distractive antibody responses to epitopes present only on the shed monomer. VLPs may enter lymphoid follicles by diffusion via gaps in the floor of the subcapsular sinuses They may be actively transported into lymphoid organs by subcapsular sinus macrophages or migratory DCs (reviewed in [6,7,8])
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