Antibody-mediated immune exclusion of HIV

Abstract

Purpose of review Although approximately 90% of all HIV transmissions in humans occur through mucosal contact, the induction of mucosal anti-HIV immune responses has remained understudied. Here we summarize data demonstrating the powerful protection that is achievable at mucosal frontlines through virus-specific mucosal IgA alone or combined with IgG. Recent findings Passive immunization with different monoclonal antibody (mAb) subclasses but identical epitope specificity (the conserved V3-loop crown of HIV gp120) has revealed that the dimeric IgA1 (dIgA1) form with its open hinge can prevent SHIV acquisition in rhesus macaques at a higher rate than dIgA2. Both dIgAs neutralized the challenge SHIV equally well. Protection was linked to better virion capture and inhibition of cell-free virus transcytosis by dIgA1. Synergistic interactions at the mucosal level between the IgG1 and dIgA2 versions of this mAb yielded complete protection. Active vaccine strategies designed to induce mucosal IgA and systemic/mucosal IgG have given promising data. Summary This review seeks to highlight the importance of mucosal IgAs in preventing virus acquisition. Passive immunization gave proof-of-concept for immune exclusion by mucosally administered monoclonal dIgAs. Unanswered questions remain regarding the interplay between mucosal IgA and other host immune defenses, including their induction with active immunization.

Mucosal IgA Responses: Damaged in Established HIV Infection—Yet, Effective Weapon against HIV Transmission

“…Passive immunization with mucosally administered, monoclonal dIgAs is depicted in Figure 2 A. Any significant prevention of SHIV acquisition would have to occur in the mucosal lumen by trapping infectious virion in large complexes to prevent mucosal transcytosis; this process is called immune exclusion ( 10 , 31 ). This information needs to be generated in order to assess the role of mucosal B cells and anti-HIV mucosal antibodies in preventing virus acquisition—key data for future vaccine design against a pathogen that is predominantly transmitted via mucosal routes.…”

Mucosal antibody responses to vaccines targeting SIV protease cleavage sites or full-length Gag and Env proteins in Mauritian cynomolgus macaques

“…In this study we examined mucosal antibodies induced by two different modalities of candidate HIV/SIV vaccines, a vaccine targeting short peptide sequences overlapping the 12 protease cleavage sites and a vaccine targeting full Gag and Env of SIVmac239. Since 90% of HIV transmissions occur through the mucosal route [ 68 ] and male to female sexual transmissions account for more than half of all HIV infections [ 53 ], it is important to test whether a candidate vaccine can induce mucosal immune responses to HIV/SIV antigens. Our study showed that both the PCS vaccine and Gag/Env vaccine can induce cervicovaginal mucosal IgG antibodies to SIV antigens, including PCSs, Gag and Env.…”

New GMP manufacturing processes to obtain thermostable HIV-1 gp41 virosomes under solid forms for various mucosal vaccination routes

“…There are also other gp41 epitopes that have induced antibodies with the ability to block HIV-1 transcytosis [47][48][49] and support the antibody-dependent cellular cytotoxicity activity 50,51 . Antibodies can also promote immunoglobulin-mediated mucus entrapment of virions 52,53 or other Fc-mediated antibody effector functions 54 , and synergies among IgG and IgA toward gp41 and/ or gp120 can offer better virus inhibition and protection 50,55 . The reported conserved epitopes on gp41 make this viral protein another very attractive antigen that could be included in prophylactic HIV-1 vaccines for establishing front-line defenses at the primary mucosal entry point used by HIV-1 to prevent virus transmission, local infection, and dissemination.…”