One step from eden igg3/19/2023 Strikingly, HIV-1 elite controllers develop strong high-affinity IgA responses ( Nabi et al., 2017), and cross-clade IgA-mediated seroneutralization has been found in long-term survivors ( Planque et al., 2010). IgA antibodies are indeed thought to play an important role at mucosal sites for reducing viral infection and spread ( Lopez et al., 2018), despite potential decreased efficacy compared with IgGs ( Astronomo et al., 2016 Cheeseman et al., 2017 Tay et al., 2016). Yet, nonneutralizing IgAs induced by RV144 vaccination may possess important antiviral properties for blocking mucosal transmission ( Wills et al., 2018). IgAs have been proposed to negatively modulate Fc-effector functions of IgG antibodies in viremic subjects and RV144 vaccinees ( Ruiz et al., 2016 Tomaras et al., 2013). However, the contribution of naturally induced and vaccine-induced anti-gp160 IgA antibodies is poorly understood and still debated ( Lopez et al., 2018). First-generation bNAb 2G12 ( Trkola et al., 1996) and members of the PGT135-PGT137 family ( Walker et al., 2011) recognized alternative epitopes within the N332-supersite ( Daniels and Saunders, 2019).Īll bNAbs identified belonged to the IgG class until recently, when genuine IgA bNAbs targeting the V3 loop crown (M4008_N1) and the V5-V2 loop corridor (M1214_N1) were described ( Jia et al., 2020). The majority of N332-supersite bNAbs target distinct subepitopes comprising the N332 glycan, various neighboring glycans, and the 324GDIR 327 peptide at the base of the V3 loop ( Daniels and Saunders, 2019). Despite strain variations, the cluster of glycans centered on N332/N334 generally includes the potential N-glycosylation sites (PNGSs) at position N295, N301, N386, and N392 ( Behrens et al., 2016 Pritchard et al., 2015). Epitopes on the N-glycan–associated V3 loop, referred as the N332 supersite or the high-mannose patch, are of particular interest for vaccine design since they are frequently targeted by various classes of bNAbs ( Daniels and Saunders, 2019), which may not require prolonged maturation pathways to be generated ( MacLeod et al., 2016). bNAbs target a handful of vulnerability sites on the HIV-1 surface envelope glycoprotein 160 (gp160): the CD4 binding site (CD4bs), the N-glycan-associated V3 loop and V1/V2 loops, the gp120 “silent face,” the N-glycan-associated gp120/gp41 bridging region, the membrane proximal external region, and the fusion peptide on gp41 ( McCoy, 2018). Yet, to elicit bNAbs by vaccination remains a challenge ( Stephenson et al., 2020 Victora and Mouquet, 2018). Hence, bNAbs hold great promise for HIV-1 treatment and prevention by vaccination or passive immunoprophylaxis ( Klein et al., 2013). Apart from neutralization, Fc-dependent effector functions of bNAbs contribute to eliminating infected cells in vivo ( Bournazos et al., 2014 Bruel et al., 2016 Lu et al., 2016) and boosting autologous cellular and humoral immune responses in recipients ( Niessl et al., 2020 Schoofs et al., 2019). Over the past decade, hundreds of bNAbs have been isolated, some of which can protect nonhuman primates from infection ( Nishimura and Martin, 2017) and decrease viremia in infected humans ( Caskey et al., 2019). HIV-1 broadly neutralizing antibodies (bNAbs) develop in rare infected humans, termed Elite neutralizers, as a result of a complex co-evolution process with diversifying viruses ( Doria-Rose and Landais, 2019 Victora and Mouquet, 2018). Hence, multiple B cell lineages of IgG and IgA bNAbs focused on a unique HIV-1 site of vulnerability can codevelop in HIV-1 viremic controllers. Binding and cryo-EM structural analyses showed that antibodies from the two other lineages interact mostly with glycans N332 and N386. The 2.8-Å resolution cryo-EM structure of 7-269-BG505 SOSIP.664 complex showed a similar pose as 2G12, on an epitope mainly composed of sugar residues comprising the N332 and N295 glycans. bNAbs in all three lineages targeted the N332 glycan supersite. 7-269 bNAb in the IgA-only lineage displayed the highest neutralizing capacity despite limited somatic mutation, and delayed viral rebound in humanized mice. Here, we characterized IgA and IgG bNAbs of three distinct B cell lineages in a viremic controller, two of which comprised only IgG + or IgA + blood memory B cells the third combined both IgG and IgA clonal variants. Decrypting the B cell ontogeny of HIV-1 broadly neutralizing antibodies (bNAbs) is paramount for vaccine design.
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