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  • We also compared the protective

    2018-10-23

    We also compared the protective capacity of IgA2 mAb isoforms to their IgG1 counterparts following vaginal and rectal challenge. IgA2 can engage FcαR1 to mediate phagocytosis and ADCC via monocytes, Z DEVD FMK Supplier and neutrophils, and dimeric forms can aggregate HIV-1 virions (Woof and Russell, 2011) but Env-specific IgA2 cannot mediate transcytosis of infectious virions via FcRn. We observed no impact of any 7b2 mAb variants on vaginal explant infectivity, despite differences in their in vitro functional profiles. Both 7b2 and CH31 IgG1s mediate phagocytosis and capture virions, but CH31 IgG captures more infectious virions (Liu et al., 2014), neutralizes HIV-1, and protects better in vaginal and rectal transmission models. The inferior protection afforded by CH31 mIgA2 compared to CH31 IgG1 corresponded with a marked loss in neutralization potency. Interestingly, the CH31 dimeric IgA2 isoforms, which capture virions better than the mIgA2 and can also aggregate virions, protected against intrarectal challenge better than their neutralization potencies would have predicted. A similar observation was made in the ex vivo vaginal challenge model. These results suggest that infectious virion capture and aggregation activities may augment modest, but not absent, neutralizing ability. The protective capacity of other IgG and IgA isoforms of neutralizing mAbs has also been described. Unlike CH31, isotype switching to IgA2 improved 2F5 epitope binding, inhibition of transcytosis and maintained neutralization potency (Tudor et al., 2012). By contrast, monomeric and dimeric IgA1 variants showed inferior protection compared to 2F5 IgG in several models, including in vivo vaginal SHIV challenge (Klein et al., 2013b, Shen et al., 2010, Wolbank et al., 2003), despite the better virus aggregation abilities of 2F5 dIgA2. The compact versus flexible hinge region of IgA2 and IgA1, respectively, likely preserves the ability of the 2F5 Fv arms to protrude into the viral membrane, bind MPER and neutralize. Comparison of rectally instilled dIgA1, dIgA2, and IgG1 versions of the V3 mAb HGN194, with similar neutralizing potencies, showed that the dIgA1 provided the best protection against intrarectal SHIV challenge and protection correlated with virus capture and inhibition of virus transcytosis (Watkins et al., 2013). Interestingly, the combination of the dIgA2 and IgG1 delivered IV, synergized to provide complete protection, unlike each regimen on its own (Sholukh et al., 2015). Given the differences in structural architecture, FcR utilization and distribution of IgA Abs, the protective capability of this isotype in mucosal HIV-1 infection cannot be easily extrapolated by studying IgG mAbs, or a few mAb isotype variants. Dimeric IgA structures may enable additional antiviral functions but these gains may be at the expense of neutralization potency depending on the structural constraints associated with engaging a particular epitope. Antibody-mediated protection is the result of a complicated interplay between the Ab, HIV, the immune system and other host factors. As such, measurements of individual Ab-mediated effects on HIV-1, be it augmentation of virus trafficking or inhibition by ADCC, cannot recapitulate the overall impact of an Ab on preventing infection. Thus, we utilized two mucosal models of HIV-1 transmission and functionally modified mAb variants to identify relevant, protective Ab properties, with an emphasis on the first few days of infection. Our results extend previous findings suggesting that extra-neutralization functions may augment the protective efficacy of bnAbs, but these functions alone are insufficient against early stages of infection (Dugast et al., 2014, Burton et al., 2011, Hessell et al., 2009b, Sholukh et al., 2015, Hessell et al., 2007). These are important implications in light of recent NHP studies suggesting that HIV-1 may spread to distal sites within 24h of vaginal exposure, and that protection by bnAbs includes systemic clearance of these small, distal foci of infection, before plasma viral RNA is detectable (Barouch et al., 2016, Liu et al., 2016). Viral dissemination from the rectal mucosa may even be faster (McElrath et al., 2013, Miyake et al., 2006, Poles et al., 2001, Ribeiro Dos Santos et al., 2011), allowing less time to recruit effector cells from the periphery to contain the local infection.