Antibody-dependent cellular cytotoxicity in HIV infection

Abstract

: Interactions between the Fc segment of IgG and its receptors (FcγRs) found on cells such as natural killer cells, monocytes, macrophages and neutrophils can potentially mediate antiviral effects in the setting of HIV and related infections. We review the potential role of FcγR interactions in HIV, SIV and SHIV infections, with an emphasis on antibody-dependent cellular cytotoxicity (ADCC). Notably, these viruses employ various strategies, including CD4 down-regulation and BST-2/tetherin antagonism to limit the effect of ADCC. Although correlative data suggest that ADCC participates in both protection and control of established infection, there is little direct evidence in support of either role. Direct evidence does, however, implicate an FcγR-dependent function in augmenting the beneficial in vivo activity of neutralizing antibodies.

Figure 1.. HIV-1-infected cells are protected from ADCC responses.

To avoid exposing vulnerable CD4-induced epitopes, HIV-1 controls the level of cell surface CD4 through the action of Nef and Vpu and limits Env accumulation through Vpu-mediated BST-2/Tethering downmodulation (A). In the absence of Nef and/or Vpu, Env and CD4 can interact at the cell surface, thus sensitizing infected cells to ADCC mediated by CD4i Abs (B). An intrinsic property of HIV-1 Env is that its gp120 subunits sheds. This is due to the noncovalent association between gp41 and gp120. Shed gp120 interacts with the CD4 receptor present at the surface of uninfected bystander cells, thus resulting in the exposure of vulnerable epitopes leading to the sensitization of these cells to ADCC responses mediated by CD4i Abs (C).

Figure 2.. Impact of Env conformation on ADCC.

A small residue at position 375 in the Phe 43 cavity (shown in white) favors a closed (State 1) conformation. Larger hydrophobic residues at this position, such as histidine (H375), or mutations in restraining residues such as L193 shift Env to more open conformations. Env interactions with membrane-anchored CD4, due to Nef and/or Vpu deletion, stabilize State 3. This conformation is also sampled by monomeric gp120 bound to CD4, present at the surface of gp120-coated cells. Env conformational landscape modulates its opening and therefore the exposure of vulnerable epitopes recognized by ADCC-mediating CD4i Abs.