Antibody-Dependent Cellular Cytotoxicity (ADCC)-Mediating Antibodies Constrain Neutralizing Antibody Escape Pathway

Abstract

Both neutralization and antibody-dependent cellular cytotoxicity (ADCC) may be required for effective protection against HIV-1 infection. While there is extensive information on the targets of early neutralizing antibody (nAb) responses, much less is known about the targets of ADCC responses, which are more difficult to characterize. In four individuals recruited during acute HIV-infection, ADCC responses were detected 3-7 weeks prior to nAb responses. To determine the relative influence of ADCC and nAb responses on virus evolution, we performed an in-depth investigation of one individual (CAP63) who showed the highest nAb and ADCC responses. Both nAbs and ADCC antibodies targeted the V4 region of the Env, although there were some differences in epitope recognition. We identified accelerated viral evolution in this region concurrent with emergence of nAb activity, but not ADCC activity. Deep sequencing demonstrated that most nAb escape mutations were strongly selected for, however one nAb escape mutation that rendered the virus highly susceptible to autologous ADCC responses, was suppressed despite not affecting viral fitness. This escape mutation also rendered the virus more sensitive to autologous responses, as well as monoclonal antibodies targeting CD4-induced epitopes, compared to the wildtype virus. In conclusion, ADCC responses and nAbs in donor CAP63 recognized overlapping but unique epitopes in the V4 region, and while ADCC activity was present prior to nAbs, it did not drive viral evolution during this time. However, ADCC responses may select against nAb escape pathways that expose other common ADCC epitopes thereby restricting viral replication and expansion.

The development and kinetics of functional antibody-dependent cell-mediated cytotoxicity (ADCC) to SARS-CoV-2 spike protein

“…Our stable transfected cell line expressed S protein on its surface with good consistency that decreases assay variability. Some studies show that strong association between the ADCC response and antibody binding on the target antigen on the surface of infected cells ( Karlsson et al, 2018 ; Mielke et al, 2019 ; Smalls-Mantey et al, 2012 ). In order to explore that antibody binding to the S target cells was proportional to the amount of cell lysis.…”

Improved killing of HIV-infected cells using three neutralizing and non-neutralizing antibodies

“…Infected-cell antibody binding assay. The binding of mAbs to the cells was measured as described previously (84). Briefly, 2 × 10 5 cells per well were incubated with 1 μg/mL mAb for 2 hours at 37°C followed by surface staining with anti-CD4-PerCP-Cy5.5 for 20 minutes at room temperature.…”

Pre-existing infant antibody-dependent cellular cytotoxicity associates with reduced HIV-1 acquisition and lower morbidity

“…For instance, one previous study suggested that neutralization pressure renders viruses ADCC susceptible. 45 Animal models may yield conflicting results because in general, the challenge stocks only contain cell-free virus that have demonstrated neutralization susceptibility to the passively infused antibody.…”