Type I, N332-glycan-dependent and Type II, N332-glycan-independent V3-glycan antibodies against HIV-1

The V3-glycan supersite is a recurrent target of HIV-1 broadly neutralizing antibodies (bNAbs) and a major focus of vaccine and therapeutic development. Classical V3-glycan bNAbs engage the epitope through contacts with the glycan at position N332 of the HIV envelope. This review summarizes new findings demonstrating that V3-glycan epitope recognition is not restricted to N332-glycan-dependent antibodies and provides clarification about the new classification of V3-glycan antibodies.

A new class of N332-glycan-independent V3-glycan antibodies has been identified. Two new human bNAbs, EPTC112 and 007, target the V3-glycan epitope in an N332-glycan-independent manner and exhibit complementary neutralization activity to classical N332-glycan-dependent bNAbs. In addition, WIN332, the first immunogen rationally designed to elicit N332-glycan-independent V3-glycan antibodies, has induced this antibody class in macaques. These findings have prompted the proposal of a revised classification and nomenclature for V3-glycan antibodies, in which canonical N332-glycan-dependent antibodies are designated as Type I, whereas the newly identified N332-glycan-independent antibodies are designated as Type II.

The identification of Type II V3-glycan bNAbs demonstrates that broad neutralization can be achieved through previously unrecognized modes of Env recognition. Coupled with the ability of WIN332 to induce this antibody class, these findings expand the landscape for antibody discovery, therapeutic development, and vaccine design.