Signal Peptide of HIV-1 Envelope Functions to Modulate Glycosylation Impacting Exposure of V1V2 Epitopes

HIV-1 envelope (Env) is a trimer of gp120-gp41 heterodimers, synthesized from a precursor gp160 that contains an ER signal peptide (SP) at its amino-terminus. Each trimer is swathed by ~90 N-linked glycans, comprising complex-type and oligomannose-type glycans, that play an important role in evasion of neutralization by antibodies. Here, we demonstrate that HIV-1 Env SP can impact the glycan processing at multiple N-linked glycosites, including the N156 and N160 located in V1V2 on the trimer apex. Env expressed with SP from heterologous HIV-1 isolates display altered exposure of V2i, V2p and V2q epitopes impacting Env antigenicity and virus neutralization by antibodies targeting distinct V1V2 configurations. These results reveal the importance of HIV-1 SP in partly shaping the Env glycan profile. Thus, SP should be cautiously selected in designing the Env-based vaccines.