CTLA-4 Blockade, during HIV Virus-Like Particles Immunization, Alters HIV-Specific B-Cell Responses

Abstract

Studies have shown that blockade of CTLA-4 promoted the expansion of germinal center B-cells in viral infection or immunization with model antigens. Few studies have evaluated the immunological consequences of CTLA-4 blockade during immunization against relevant vaccine candidates. Here, we investigated the effects of CTLA-4 blockade on HIV virus-like particles (VLPs) vaccination in a C57BL/6J mouse model. We found that CTLA-4 blockade during HIV VLP immunization resulted in increased CD4+ T-cell activation, promoted the expansion of HIV envelope (Env)-specific follicular helper T cell (Tfh) cells, and significantly increased HIV Gag- and Env-specific IgG with higher avidity and antibody-dependent cellular cytotoxicity (ADCC) capabilities. Furthermore, after only a single immunization, CTLA-4 blockade accelerated T-cell dependent IgG class switching and the induction of significantly high serum levels of the B-cell survival factor, A proliferation-inducing ligand (APRIL). Although no significant increase in neutralizing antibodies was observed, increased levels of class-switched Env- and Gag-specific IgG are indicative of increased polyclonal B-cell activation, which demonstrated the ability to mediate and enhance ADCC in this study. Altogether, our findings show that CTLA-4 blockade can increase the levels of HIV antigen-specific B-cell and antigen-specific Tfh cell activity and impact humoral immune responses when combined with a clinically relevant HIV VLP-based vaccine.

So Pathogenic or So What?—A Brief Overview of SIV Pathogenesis with an Emphasis on Cure Research

“…CTLA-4 blockade in ART-treated RMs increased T-cell activation and viremia, but did not augment responses to vaccination, nor increase SIV-specific responses [601]. This is contrary to a mouse study which demonstrated increased HIV-specific B-cell and T follicular helper responses with CTLA-4 blockade combined with HIV virus-like particle vaccination [602]. Thus, the evidence points towards a potential usage for CTLA-4 blockade as an immune boosting agent when combined with an LRA, as standalone CTLA-4 blockade does not potently reactivate virus.…”

Nanoparticle-Delivered HIV Peptides to Dendritic Cells a Promising Approach to Generate a Therapeutic Vaccine

“…Both G4-70/30 PAMAM and β-cyclodextrin derivative AMC6 polycationic nanoparticles were able to bind and deliver the antigenic peptide to DCs. We have chosen an antigenic peptide derived from the gag p24 protein since this protein have been shown to be antigenic in several vaccine preparation attempts [ 14 ]. We failed in a previous work to induce a robust antigenic response using as delivery agent a cationic phosphorous dendrimer [ 13 ].…”

“…We explored this approach using a cationic phosphorous dendrimer which failed to induce an efficient antigenic response [ 13 ]. Since gag-derived peptides (including p24-derived peptides) have potential antigenic activity [ 14 ], we decided to explore whether other NPs with different chemical structure were able to deliver the peptide in such a way that it would produce a significant antigenic response. This was the rationale to perform the present experiments since we think that NPs can be very helpful tools to potentiate the antigenic presentation and so contribute to elicit a potent immune response.…”

Immune checkpoint blockade in HIV

“…Finally, a murine study indicated a potential adjuvant role of anti-CTLA-4 as CTLA-4 blockade during HIV immunization in mice led to increased CD4+ T-cell activation, expansion of HIV specific follicular helper T-cell (Tfh) cells, altered HIV specific B-cell responses and significantly increased anti-HIV antibodies with higher avidity and antibody-dependent-cellular cytotoxicity (ADCC) capabilities. 44 …”

“…In animal models, ICB during vaccination improved protective efficacy 36 and increased levels of anti-HIV antibodies with higher antibody-dependent cellular cytotoxicity capabilities. 44 …”