The HIV-1 gp120 CD4-Bound Conformation Is Preferentially Targeted by Antibody-Dependent Cellular Cytotoxicity-Mediating Antibodies in Sera from HIV-1-Infected Individuals

Abstract

Recent studies have linked antibody Fc-mediated effector functions with protection or control of human immunodeficiency type 1 (HIV-1) and simian immunodeficiency (SIV) infections. Interestingly, the presence of antibodies with potent antibody-dependent cellular cytotoxicity (ADCC) activity in the Thai RV144 vaccine trial was suggested to correlate with decreased HIV-1 acquisition risk. These antibodies recently were found to recognize HIV envelope (Env) epitopes exposed upon Env-CD4 interaction. CD4 downregulation by Nef and Vpu, as well as Vpu-mediated BST-2 antagonism, were reported to modulate exposure of those CD4-induced HIV-1 Env epitopes and were proposed to play a role in reducing the susceptibility of infected cells to ADCC mediated by this class of antibodies. Here, we report the high prevalence of antibodies recognizing CD4-induced HIV-1 Env epitopes in sera from HIV-1-infected individuals, which correlated with their ability to mediate ADCC responses against HIV-1-infected cells, exposing these Env epitopes at the cell surface. Furthermore, our results indicate that Env variable regions V1, V2, V3, and V5 do not represent a major determinant for ADCC responses mediated by sera from HIV-1-infected individuals. Altogether, these findings suggest that HIV-1 tightly controls the exposure of certain Env epitopes at the surface of infected cells in order to prevent elimination by Fc-effector functions. IMPORTANCEHere, we identified a particular conformation of HIV-1 Env that is specifically targeted by ADCC-mediating antibodies present in sera from HIV-1-infected individuals. This observation suggests that HIV-1 developed sophisticated mechanisms to minimize the exposure of these epitopes at the surface of infected cells.

Influence of the Envelope gp120 Phe 43 Cavity on HIV-1 Sensitivity to Antibody-Dependent Cell-Mediated Cytotoxicity Responses

“…Interestingly, we observed that Env with a "filled" Phe 43 cavity (S375H and S375W mutants) were also recognized significantly better by HIV-positive (HIV ϩ ) sera than those with an "empty" Phe 43 cavity (S375) (Fig. 2M to O), thus supporting the notion that the CD4-bound conformation affects the recognition of Env by ADCC-mediating CD4i antibodies and antibodies within HIV ϩ sera (13).…”

“…In parallel, primary CD4 ϩ T cells were infected with SHIVs expressing clade C and D HIV-1 Env with the same substitutions in residue 375 (WT and S375H and S375W mutants). Since it is now well established that CD4 present on the cell surface affects Env conformation by forcing it to assume the CD4-bound conformation (13,14,21,22,35), we first evaluated the ability of all the IMCs to downregulate CD4. Figure 2 shows that all IMCs tested, independently of the residue present at position 375, efficiently downregulated CD4 from the cell surface ( Fig.…”

“…Accordingly, we recently reported that the transition of Env to the CD4-bound conformation is required for efficient interactions with ADCC-mediating antibodies (14). We reported that the replacement of serine 375 by a tryptophan residue (S375W) enhanced the exposure of epitopes recognized by anti-cluster A antibodies, known to mediate potent ADCC responses (13,14,18,(20)(21)(22)(23)(24)(25)(26). Thus, the transition of Env from the unbound to the CD4-bound conformation appears to be a prerequisite for the exposure of inner-domain ADCC epitopes.…”

“…It has been shown that HIV-1 minimizes the exposure of this ADCC-susceptible Env conformation using a highly sophisticated strategy to keep Env on the surface of infected cells in the unbound "closed" conformation. HIV-1 accomplishes this through its accessory proteins Nef and Vpu, which decrease the overall amounts of Env (via Vpu-mediated BST-2 downregulation) and CD4 at the cell surface (13)(14)(15)(16). In addition, decreased amounts of Env at the cell surface due to efficient internalization also help the virus to avoid ADCC responses (17).…”

“…Besides its potential involvement in viral replication, the CD4-bound conformation of HIV-1 Env represents a major target of antibodies (Abs) present in sera of HIV-1-infected individuals that mediate antibody-dependent cellular cytotoxicity (ADCC) (13). It has been shown that HIV-1 minimizes the exposure of this ADCC-susceptible Env conformation using a highly sophisticated strategy to keep Env on the surface of infected cells in the unbound "closed" conformation.…”