Targeting HIV-1 Envelope Glycoprotein Trimers to B Cells by Using APRIL Improves Antibody Responses

Abstract

An HIV-1 vaccine remains elusive, in part because various factors limit the quantity and quality of the antibodies raised against the viral envelope glycoprotein complex (Env). We hypothesized that targeting Env vaccines directly to B cells, by fusing them to molecules that bind and activate these cells, would improve Env-specific antibody responses. Therefore, we fused trimeric Env gp140 to A PRoliferation-Inducing Ligand (APRIL), B-cell Activating Factor (BAFF), and CD40 Ligand (CD40L). The Env-APRIL, Env-BAFF, and Env-CD40L gp140 trimers all enhanced the expression of activation-induced cytidine deaminase (AID), the enzyme responsible for inducing somatic hypermutation, antibody affinity maturation, and antibody class switching. They also triggered IgM, IgG, and IgA secretion from human B cells in vitro. The Env-APRIL trimers induced higher anti-Env antibody responses in rabbits, including neutralizing antibodies against tier 1 viruses. The enhanced Env-specific responses were not associated with a general increase in total plasma antibody concentrations, indicating that the effect of APRIL was specific for Env. All the rabbit sera raised against gp140 trimers, irrespective of the presence of CD40L, BAFF, or APRIL, recognized trimeric Env efficiently, whereas sera raised against gp120 monomers did not. The levels of trimer-binding and virus-neutralizing antibodies were strongly correlated, suggesting that gp140 trimers are superior to gp120 monomers as immunogens. Targeting and activating B cells with a trimeric HIV-1 Env-APRIL fusion protein may therefore improve the induction of humoral immunity against HIV-1.

DNA Vaccine Molecular Adjuvants SP-D-BAFF and SP-D-APRIL Enhance Anti-gp120 Immune Response and Increase HIV-1 Neutralizing Antibody Titers

“…When given in soluble form, the BAFF, APRIL, and CD40L adjuvants can enhance IL-4 and IL-5 secretion by CD4 T cells but are unable to induce a significant increase in humoral responses. Direct targeting of B cells with soluble single trimers of CD40L, BAFF, and APRIL fused to HIV-1 gp120 in DNA prime-protein boost vaccination of rabbits enhanced neutralizing antibody titers (33). In contrast to that study and previous data from our lab (34), we show here that the combination of IL-12 with APRIL or BAFF multitrimers, but not CD40L multitrimers, enhanced tier 1 and tier 2 neutralization.…”

“…Some researchers have reported some success with BAFF, and particularly with APRIL (33). When given in soluble form, the BAFF, APRIL, and CD40L adjuvants can enhance IL-4 and IL-5 secretion by CD4 T cells but are unable to induce a significant increase in humoral responses.…”

“…A prior study using BAFF and APRIL trimers as adjuvants in rabbits showed improved antibody response; however, only tier 1 viruses could be neutralized (33). These observations led us to hypothesize that soluble multitrimers of BAFF and APRIL, as opposed to single trimers, would induce optimal immune activation of B cells and enhance the overall immune response.…”

Cloning, Expression and Purification of a Novel Multi-epitopic HIV-1 Vaccine Candidate: A Preliminary Study on Immunoreactivity

“…In addition, the results showed that our candidate vaccine injected with Alum, Freund's and Montanide adjuvants could induce specific IgM production. These results are in agreement with other studies indicating that polyepitope vaccines can induce vaccine specific IgM which is essential for controlling viral infections [29][30][31]. Moreover, all three adjuvants could induce different levels of humoral and cellular immune responses that indicate the effect of adjuvants on the vaccine immunogenicity.…”

Untitled

“…HLA class I molecules bind to endogenous antigenic epitopes and present them to CD8+ T lymphocytes, while HLA class II molecules present antigenic peptides to CD4+ T lymphocytes 30 .…”