Unlocking HIV-1 Env: implications for antibody attack

Abstract

Collective evidence supporting a role of Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) in controlling HIV-1 transmission and disease progression emerged in the last few years. Non-neutralizing antibodies (nnAbs) recognizing conserved CD4-induced epitopes on Env and able to mediate potent ADCC against HIV-1-infected cells exposing Env in its CD4-bound conformation have been shown to be present in some RV144 vaccinees and most HIV-1-infected individuals. HIV-1 evolved sophisticated strategies to decrease exposure of this Env conformation by downregulating CD4 and by limiting the overall amount of cell-surface Env. In this review, we will summarize our contribution to this rapidly evolving field, discuss how structural properties of HIV-1 Env might have contributed to the modest efficacy of the RV144 trial and how we recently used this knowledge to develop new strategies aimed at sensitizing HIV-1-infected cells to ADCC mediated by easy to elicit nnAbs.

Keywords: ADCC; BST-2; CD4; CD4-mimetics; Env; HIV-1; Nef; RV144; Vpu; gp120.

Fig. 1

Unlocking HIV-1 Env for antibody attack. ADCC-mediating Abs present in some RV144 vaccinees and sera from HIV-1-infected individuals preferentially recognize Env in its CD4-bound conformation (Env in the unbound conformation is shown in red and in the CD4-bound conformation is shown in purple). To limit the exposure of Env CD4i epitopes, HIV-1 has evolved protective mechanisms to counteract the host restriction factor BST-2 through Vpu-mediated downregulation. It also downregulates CD4 via Nef and Vpu activities (a Nef and Vpu accessory proteins are shown in black). Deletion of Vpu and Nef results in accumulation of Env-CD4 complexes at the cell-surface, enhancing the susceptibility of HIV-1-infected cells to ADCC (b). Flanking the Phe43 cavity, the identity of residue 375 modulates the transition of Env to the CD4-bound conformation. The presence of a small amino acid such as serine (S375) at this position keeps Env in its unbound “closed” conformation (a), thus preventing the exposure of CD4i ADCC-mediating epitopes. The presence of a larger residue within the Phe43 cavity, such as the naturally-occurring histidine at position 375 (H375) in CRF01_AE strains, shifts Env conformation to a state closer to the CD4-bound state, enhancing susceptibility of infected cells to ADCC mediated by HIV+ sera and easy-to-elicit antibodies (c). Small CD4-mimetics (CD4mc) sensitize HIV-1-infected cells to ADCC mediated by HIV+ sera by forcing Env to sample its CD4-bound conformation. Type I IFNs (IFNα is shown in green and IFNβ in brown) or IL-27 (shown in yellow) treatment, through upregulation of BST-2, boosts the ability of CD4mc to sensitize HIV-1-infected cells to ADCC by increasing the amounts of Env able to interact with CD4mc at the cell surface (d)