Antibody recognition of CD4-induced open HIV-1 Env trimers

Abstract

HIV-1 envelope (Env), a heterotrimer of gp120-gp41 subunits, mediates fusion of the viral and host cell membranes after interactions with the host receptor CD4 and a coreceptor. CD4 binding induces rearrangements in Env trimer, resulting in a CD4-induced (CD4i) open Env conformation. Structural studies of antibodies isolated from infected donors have defined antibody-Env interactions, with one class of antibodies specifically recognizing the CD4i open Env conformation. Here, we characterize a group of monoclonal antibodies isolated from HIV-1 infected donors (V2i mAbs) that display characteristics of CD4i antibodies. Binding experiments demonstrate that the V2i mAbs preferentially recognize CD4-bound open Env trimers. Structural characterizations of V2i mAb-Env-CD4 trimer complexes using single-particle cryo-electron microscopy show recognition by V2i mAbs using different angles of approach to the gp120 V1V2 domain and the β2/β3 strands on a CD4i open conformation Env with no direct interactions of the mAbs with CD4. We also characterize CG10, a CD4i antibody that was raised in mice immunized with a gp120-CD4 complex, complexed with Env trimer and CD4. CG10 exhibits similar characteristics to the V2i antibodies: i.e., recognition of the open Env conformation, but shows direct contacts to both CD4 and gp120. Structural comparisons of these and previously characterized CD4i antibody interactions with Env provide a suggested mechanism for how these antibodies are elicited during HIV-1 infection.

Asymmetric HIV-1 envelope trimers bound to one and two CD4 molecules are intermediates during membrane binding

“…The finding that these states are long-lived intermediates likely has consequences for antibody-mediated immune responses and vaccine immunogen design. Indeed, antibodies recognizing partially open conformational states, with the V1V2 loops of gp120 remaining at the apex of the trimer, have been identified 35,36 .…”

A germline-targeting chimpanzee SIV envelope glycoprotein elicits a new class of V2-apex directed cross-neutralizing antibodies

“…To examine whether the CAM13K and CAM13RRK Envs inherently adopt a more open conformation, we tested their sensitivity to conformation-sensitive V2i (697-D, 1393A) ( 61 ), V2p (CH58, CAP228-3D) ( 42, 62, 63 ), linear V3 (3074, 447-52D) ( 64, 65 ) and CD4i (17b, A32) ( 66, 67 ) antibodies as well as the V2-apex bNAb PG9 for control. These antibodies were selected because they recognize epitopes that are occluded in prefusion trimers and thus only neutralize viruses whose Envs are not completely closed.…”

“…One of these, termed V2p, includes both human and macaque antibodies that recognize the V2 loop in a helix-coil conformation and require a glutamic acid-aspartic acid (ED) LCDR2 motif for V2 peptide binding ( 42, 62, 63 ). The other class, designated V2i, recognizes conformational epitopes on gp120 ( 82 ) and has recently been shown to belong to the large family of CD4i antibodies ( 61 ). Our SCIV-derived antibodies lack the ED LCDR2 motif and bind the V2 domain in an occluded-open trimer.…”