D-106 Tyrosine Sulfation in the Second Variable Domain (V2) of gp120 Regulates HIV-1 Sensitivity to Neutralization

The native HIV-1 envelope spike adopts a cryptic conformation that protects conserved neutralization epitopes from antibody recognition. We recently documented the presence of sulfated tyrosines within the second variable domain (V2) of gp120, which contribute to stabilizing the intramolecular interaction between V2 and V3, shifting the conformational equilibrium of the envelope toward the closed trimeric state. To elucidate the functional relevance of V2 sulfation, we investigated the effects of modulating tyrosine sulfation on HIV-1 neutralization by a wide panel of monoclonal and polyclonal antibodies of well-defined specificity. Data obtained with different HIV-1 Envs demonstrated a striking dichotomous effect. Increasing the efficiency of tyrosine sulfation by overexpression of the sulfotransferase TPST2 resulted in reduced binding and neutralization by soluble CD4 and several mAbs to the CD4- and coreceptor-binding sites. However, opposite effects were seen on glycan-dependent V2 epitopes recognized by trimer-preferring antibodies such as PG9, PG16, VRC26.03, and PGT145, which showed increased binding and neutralization upon TPST2 overexpression. Likewise, polyclonal patient sera with defined neutralization fingerprints exhibited a similar discrepant behavior, with a group of CD4-like sera showing reduced neutralization upon TPST2 overexpression and a group of PG9-like sera showing the reciprocal pattern. These data suggest that V2 tyrosine sulfation acts as a neutralization switch that HIV-1 can exploit to address the escape dilemma between different families of broadly neutralizing antibodies.