The Yin and Yang of ADCC-Mediating Antibodies

Antibodies mediating antibody-dependent cellular cytotoxicity et al., 2014) and that the CD4 mimetic sensitized infected cells to (ADCC) have been of increasing interest since their identification as a protective immune correlate in the RV144 clinical vaccine efficacy trial (Haynes et al., 2012). Earlier studies associated these non-neutralizing antibodies with protection against HIV infection and disease progression in both humans and non-human primates (for review see VargasInchaustegui and Robert-Guroff, 2013). Therefore it is somewhat surprising to find them now linked to HIV pathogenesis. HIV disease progression is marked by a gradual loss of CD4 T cells during which a small proportion of HIV-infected CD4 T cells and a much larger proportion of uninfected “bystander” CD4 T cells are killed. While numerous mechanisms have been described for infected cell killing, the mechanism of bystander killing has remained controversial. In this issue, Richard et al. (2016) attribute bystander killing largely to antibodies mediating ADCC. They further suggest that a small CD4 mimetic developed by the Sodroski group might be used to alter this pathogenic mechanism for therapeutic benefit. How can the conflicting findings regarding ADCC antibodies be explained? And what caveats should be considered in using CD4 mimetics? As reported by Richard et al. in this issue of EBioMedicine, the external envelope of HIV is labile and continually sheds the gp120 component which then binds the primary viral receptor, CD4, on bystander uninfected T cells. A subsequent conformational change opens the co-receptor binding site exposing an epitope recognized by cluster A antibodies, including theprototypic ADCC-mediatingmonoclonal antibody, A32. Killing of the bystander CD4 T cells follows. Concurrently, the virus subverts killing of infected cells by down-regulating CD4, inhibiting tetherin, and internalizing Env (as cited in von Bredow et al., 2015). Consequently, less Env is expressed on the infected-cell surface, less CD4 is available to complexwith gp120, and less expression of Env in the open conformation occurs. Thus ADCC killing of the infected cell is diminished in favor of bystander killing. CD4 mimetics were previously shown to interact with the viral envelope, inducing conformational changes, exposing the co-receptor binding site, and rendering the virus susceptible to neutralization by CD4-induced antibodies (Madani et al., 2008; Madani et al., 2014). The Finzi laboratory also previously reported that gp120/CD4 binding within the same infected cell led to exposure of ADCC epitopes (Veillette