Fab-dimerized glycan-reactive antibodies neutralize HIV and are prevalent in humans and rhesus macaques

Summary The HIV-1 envelope (Env) is comprised by mass of over 50% glycans. A goal of HIV-1 vaccine development is the induction of Env glycan-reactive broadly neutralizing antibodies (bnAbs). The 2G12 bnAb recognizes an Env glycan cluster using a unique variable heavy (V H ) domain-swapped conformation that results in fragment antigen-binding (Fab) dimerization. Here we describe Fab-dimerized glycan (FDG)-reactive antibodies without V H -swapped domains from simian-human immunodeficiency virus (SHIV)-infected macaques that neutralized heterologous HIV-1 isolates. FDG precursors were boosted by vaccination in macaques, and were present in HIV-1-naïve humans with an average estimated frequency of one per 340,000 B cells. These data demonstrate frequent HIV-1 Env glycan-reactive bnAb B cell precursors in macaques and humans and reveal a novel strategy for their induction by vaccination. Highlights Discovery of Fab-dimerized HIV-1 glycan-reactive antibodies with a non-domain-swapped architecture Fab-dimerized antibodies neutralize heterologous HIV-1 isolates. Antibodies with this architecture can be elicited by vaccination in macaques. Fab-dimerized antibodies are found in HIV-1 naïve humans.