OA01.05
Background: Immunization with recombinant HIV-1 Env elicits antibodies targeting epitopes on variable regions of Env that display narrow breadth of neutralization (nNAbs), but fails to elicit antibodies targeting conserved epitopes that display broad neutralizing activity (bnAbs). This is thought to be in part due to the immunodominance of the variable regions of Env, as well as the inability of recombinant Env to activate naive B cells that give rise to bNAbs. We recently engineered an Env capable of activating B cells expressing germline-reverted (gl) BCRs of VRC01-class bNAbs and herein compare the ability of this Env to stimulate B cells expressing glVRC01-class BCRs and B cells expressing glnNAb BCRs
Methods: We developed novel assays to monitor the concurrent activation of B cells expressing glVRC01 class BCRs and glnNAb BCRs in response to various Envs, and assays to assess Env uptake by these B cell lines.
Results: Unlike B cells expressing glVRC01 class BCRs, several Envs bound to, activated, and were internalized by B cells expressing glnNAb BCRs targeting both the CD4-BS and V3, indicating that nNAb eptiopes are more readily presented on Env than bNAb epitopes. A direct comparison of the magnitude of B cell activation responses, showed that an Env specifically engineered to engage glVRC01 class B cells, preferentially activates B cells expressing glnNAb BCRs, and that the latter internalize this Env more efficiently than glVRC01 class B cells. Importantly, we demonstrate that the removal of V1 V2 and V3 from Env improves B cell activation and antigen uptake through glVRC01 class BCRs relative to CD4-BS and V3 directed nNAb BCRs.
Conclusions: Our results provide experimental evidence that explains why immunization with recombinant Env results in the production of nNAbs instead of VRC01 class bNAbs. However, we demonstrate that it is possible to engineer an Env-based immunogen that eliminates or reduces the immunodominance of nNAb epitopes and favors the maturation process of VRC01 class bNAbs.
