Cross-reactivity between HIV-1 bnAbs and parasite glycans

Background: Many HIV-1 broadly neutralizing antibodies (bnAbs) isoated from HIV-1 infected donors directly engage, or are dependent upon, N-linked glycans on the HIV-1 envelope-trimer for neutralization. It can take many years for bnAbs to develop following HIV-1 infection making it a challenge to identify immunization strategies that will re-elicit these bnAbs through vaccination. Since other glycosylated pathogens, such as bacteria and parasites, can raise a strong anti-glycan antibody response, the question arises whether the development of glycan-dependent HIV-1 bnAbs could be guided by Abs targeting glycans on other pathogens. We therefore set out to study cross-reactivity of glycan-binding bnAbs with parasite glycans and prevalence of seroreactivity to parasite Schistosoma mansoni in the IAVI Protocol C cohort. Methods: To measure cross-reactivity of known glycan-binding bnAbs with non-self parasite-derived glycans, we used a synthetic parasite glycan microarray and a 'shotgun' parasite glycan microarray The mode of glycan binding was assessed using STD NMR. We further confirmed cross-reactivity with S. mansoni using confocal microscopy and immunohistochemical analysis. To understand the seroprevalence of this parasitic infection in HIV-1 infected individuals in S. mansoni endemic regions we screened plasma from the well-studied IAVI Protocol C cohort for seroreactivity to S. mansoni antigens by ELISA. Results: We observed cross-reactivity of glycan-specific bnAbs to self and non-self S. mansoni glycans and were able to further confirm cross-binding of bnAbs to S. mansoni glycoproteins by confocal microscopy and immunohistochemical analysis. STD NMR analysis demonstrated that bnAb PGT121 contacts both self and non-self components of a representative parasite glycan. We detected an overall 41% seroprevalence against S. mansoni in a subset of IAVI protocol C donors, with a higher occurrence in donors with medium and top plasma neutralization (88% vs. 63%). We further observed cross-reactivity of N332/V3 specific PCDN76 bnAb lineage, including the unmutated common ancestor, with S. mansoni. Conclusions: These findings suggest antibody responses against parasite glycoproteins are readily found in HIV-1 positive donors. The cross-reactivity with parasite glycoproteins, particularly of the unmutated common ancestor of a bnAb suggest a non-self-glycan response could direct the development of glycan reactive HIV-1 bnAbs. These observations will inform and aid HIV-1 immunogen design.
OA15.05LB I. Huettner (1); S. Krumm (1,2); E. Landais (3); K. Brzezicka (4); S. Serna (4); A.van Diepen (5); J. Angulo (6); F. Allan (7); A. Emery (7); N. Reichardt [...]