41 research outputs found
Cross-reactivity of glycan-reactive HIV-1 broadly neutralizing antibodies with parasite glycans
The HIV-1 Envelope glycoprotein (Env) is the sole target for broadly neutralizing antibodies (bnAbs). Env is heavily glycosylated with host-derived N-glycans, and many bnAbs bind to, or are dependent upon, Env glycans for neutralization. Although glycan-binding bnAbs are frequently detected in HIV-infected individuals, attempts to elicit them have been unsuccessful because of the poor immunogenicity of Env N-glycans. Here, we report cross-reactivity of glycan-binding bnAbs with self- and non-self N-glycans and glycoprotein antigens from different life-stages of Schistosoma mansoni. Using the IAVI Protocol C HIV infection cohort, we examine the relationship between S. mansoni seropositivity and development of bnAbs targeting glycan-dependent epitopes. We show that the unmutated common ancestor of the N332/V3-specific bnAb lineage PCDN76, isolated from an HIV-infected donor with S. mansoni seropositivity, binds to S. mansoni cercariae while lacking reactivity to gp120. Overall, these results present a strategy for elicitation of glycan-reactive bnAbs which could be exploited in HIV-1 vaccine development.This project has received funding from the European Union’s Horizon 2020
Research and Innovation program under grant agreement 681137 (to K.J.D.
and I.H.), the Medical Research Council (MRC) (to K.J.D. [MR/K024426/1]),
The Rosetrees Trust (to K.J.D. [M686]) and Fondation Dormeur, Vaduz (to
K.J.D). This research was funded or supported by the National Institute for
Health Research Biomedical Research Centre based at Guy’s and St Thomas’
NHS Foundation Trust and King’s College London and/or the NIHR Clinical
Research Facility. The views expressed are those of the authors and not
necessarily those of the National Health Service (NHS), the National Institute
for Health Research (NIHR), or the Department of Health. N.R. acknowledges
funding from Ministry of Science and Education grants CTQ2017-90039-R,
RTC-2017-6126-1, and CTQ2011-27874 (fellowship to K.B.) and the Maria
de Maeztu Units of Excellence Program from the Spanish State Research
Agency (grant MDM-2017-0720). F.A. was funded by the Wellcome Trust
(104958/Z/14/Z). J.A. was supported by the Spanish Ministry of Science, Innovation
and Universities through the grant PID2019-109395GB-I00. J.A. and
S.M. acknowledge support of BBSRC (grant BB/P010660/1). T.H. and S.W.
were funded by Biotechnology and Biological Sciences Research Council
(BBSRC) Norwich Research Park Doctoral Training Grant BB/M011216/1. IAVI’s
work is made possible by generous support from many donors, including
the Bill & Melinda Gates Foundation, the Ministry of Foreign Affairs of Denmark,
Irish Aid, the Ministry of Finance of Japan in partnership with The World Bank,
the Ministry of Foreign Affairs of the Netherlands, the Norwegian Agency for
Development Cooperation, the United Kingdom Department for International
Development (DFID), and the United States Agency for International Development.
The full list of IAVI donors is available at www.iavi.org.
Brendan McAtarsney and Jonathan Hare from the IAVI Human Immunology
Lab (HIL) for coordinating the samples transfers and shipments.
Monica Agromayor and the KCL Nikon Centre for assistance and advice on
confocal microscopy. NMRI strain Schistosoma mansoni-infected Biomphalaria
glabrata snails were provided by the NIAID Schistosomiasis
Resource Center, Rockville, USA.Peer reviewe
Cross-reactivity of glycan-reactive HIV-1 broadly neutralizing antibodies with parasite glycans
The HIV-1 Envelope glycoprotein (Env) is the sole target for broadly neutralizing antibodies (bnAbs). Env is heavily glycosylated with host-derived N-glycans, and many bnAbs bind to, or are dependent upon, Env glycans for neutralization. Although glycan-binding bnAbs are frequently detected in HIV-infected individuals, attempts to elicit them have been unsuccessful because of the poor immunogenicity of Env N-glycans. Here, we report cross-reactivity of glycan-binding bnAbs with self- and non-self N-glycans and glycoprotein antigens from different life-stages of Schistosoma mansoni. Using the IAVI Protocol C HIV infection cohort, we examine the relationship between S. mansoni seropositivity and development of bnAbs targeting glycan-dependent epitopes. We show that the unmutated common ancestor of the N332/V3-specific bnAb lineage PCDN76, isolated from an HIV-infected donor with S. mansoni seropositivity, binds to S. mansoni cercariae while lacking reactivity to gp120. Overall, these results present a strategy for elicitation of glycan-reactive bnAbs which could be exploited in HIV-1 vaccine development