HIV-1 Envelope Recognition by Polyreactive and Cross-Reactive Intestinal B Cells

Abstract

Summary Mucosal immune responses to HIV-1 involve the recognition of the viral envelope glycoprotein (gp)160 by tissue-resident B cells and subsequent secretion of antibodies. To characterize the B cells “sensing” HIV-1 in the gut of infected individuals, we probed monoclonal antibodies produced from single intestinal B cells binding to recombinant gp140 trimers. A large fraction of mucosal B cell antibodies were polyreactive and showed only low affinity to HIV-1 envelope glycoproteins, particularly the gp41 moiety. A few high-affinity gp140 antibodies were isolated but lacked neutralizing, potent ADCC, and transcytosis-blocking capacities. Instead, they displayed cross-reactivity with defined self-antigens. Specifically, intestinal HIV-1 gp41 antibodies targeting the heptad repeat 2 region (HR2) cluster II cross-reacted with the p38α mitogen-activated protein kinase 14 (MAPK14). Hence, physiologic polyreactivity of intestinal B cells and molecular mimicry-based self-reactivity of HIV-1 antibodies are two independent phenomena, possibly diverting and/or impairing mucosal humoral immunity to HIV-1.

Biochemical patterns of antibody polyreactivity revealed through a bioinformatics-based analysis of CDR loops

“…This implies the existence of antibodies whose primary function is to act as polyreactive sentries in the gut, yet the downstream effects of polyreactive antibodies coating commensal bacteria is so far unclear. Similar polyreactive IgA and IgG mucosal antibodies were found in the gut of human immunodeficiency virus (HIV)-infected patients, but these antibodies either had low affinity to the virus or lacked neutralization capabilities ( Planchais et al, 2019 ). The benefit of singular antibody sequences with the ability to sample large portions of the commensal population may represent an improvement in efficiency of the homeostatic machinery of the gut.…”

T-bet+ Memory B Cells Link to Local Cross-Reactive IgG upon Human Rhinovirus Infection

“…Recent work identified monoclonal antibodies produced by B cells in the gastrointestinal tract that target the HIV1 envelope, but also cross-react with a number of intestinal proteins. Sequence and/or structural homology was proposed as the molecular basis for this phenomenon (Planchais et al, 2019). We propose that the BCR on the surface of dual-specific B cells recognizes an epitope on the external aspect of the capsid that is shared among different RV strains.…”

Polyreactive Broadly Neutralizing B cells Are Selected to Provide Defense against Pandemic Threat Influenza Viruses

“…Notably, the context and antigen can change the role and characteristics of polyreactive mAbs. HIV-binding polyreactive mAbs are low affinity and non-neutralizing and derive from intestinal B cells ( Planchais et al., 2019 ; Liao et al., 2011 ). However, HIV-binding polyreactive mAbs can become potently neutralizing against HIV through affinity maturation ( Liao et al., 2011 ; Prigent et al., 2018 ).…”