Lack of ADCC Breadth of Human Nonneutralizing Anti-HIV-1 Antibodies

Abstract

Anti-human immunodeficiency virus type 1 (HIV-1) nonneutralizing antibodies (nnAbs) capable of antibody-dependent cellular cytotoxicity (ADCC) have been identified as a protective immune correlate in the RV144 vaccine efficacy trial. Broadly neutralizing antibodies (bNAbs) also mediate ADCC in cell culture and rely on their Fc region for optimal efficacy in animal models. Here, we selected 9 monoclonal nnAbs and 5 potent bNAbs targeting various epitopes and conformations of the gp120/41 complex and analyzed the potency of the two types of antibodies to bind and eliminate HIV-1-infected cells in culture. Regardless of their neutralizing activity, most of the selected antibodies recognized and killed cells infected with two laboratory-adapted HIV-1 strains. Some nnAbs also bound bystander cells that may have captured viral proteins. However, in contrast to the bNAbs, the nnAbs bound poorly to reactivated infected cells from 8 HIV-positive individuals and did not mediate effective ADCC against these cells. The nnAbs also inefficiently recognize cells infected with 8 different transmitted-founder (T/F) isolates. The addition of a synthetic CD4 mimetic enhanced the binding and killing efficacy of some of the nnAbs in an epitope-dependent manner without reaching the levels achieved by the most potent bNAbs. Overall, our data reveal important qualitative and quantitative differences between nnAbs and bNAbs in their ADCC capacity and strongly suggest that the breadth of recognition of HIV-1 by nnAbs is narrow. Most of the anti-HIV antibodies generated by infected individuals do not display potent neutralizing activities. These nonneutralizing antibodies (nnAbs) with antibody-dependent cellular cytotoxicity (ADCC) have been identified as a protective immune correlate in the RV144 vaccine efficacy trial. However, in primate models, the nnAbs do not protect against simian-human immunodeficiency virus (SHIV) acquisition. Thus, the role of nnAbs with ADCC activity in protection from infection remains debatable. In contrast, broadly neutralizing antibodies (bNAbs) neutralize a large array of viral strains and mediate ADCC in cell culture. We analyzed the capacities of 9 nnAbs and 5 bNAbs to eliminate infected cells. We selected 18 HIV-1 strains, including virus reactivated from the reservoir of HIV-positive individuals and transmitted-founder isolates. We report that the nnAbs bind poorly to cells infected with primary HIV-1 strains and do not mediate potent ADCC. Overall, our data show that the breadth of recognition of HIV-1 by nnAbs is narrow.

Non-neutralizing Antibodies Alter the Course of HIV-1 Infection In Vivo

“…CD4 + T-cells were infected with HIV-1 YU2 or HIV-1 YU2(R456K) and stained with the nnAb A32,(Wyatt et al, 1995) which binds to gp120 that has been shed from infected cells and is bound to cell surface CD4 (Bruel et al, 2017; Richard et al, 2016), and the V3 crown targeting antibody 10–188 (Mouquet et al, 2011). As expected, uninfected bystander p24 − CD4 + T cells in cultures infected with HIV-1 YU2 showed high levels of A32 and 10–188 staining.…”

“…In vitro studies with laboratory-adapted, tier 1 HIV-1 strains showed that Env-specific nnAbs can direct ADCC/ADCVI (reviewed in (Ferrari et al, 2017)). However, little evidence exists to demonstrate Fc-mediated nnAb activity against primary HIV-1 isolates and transmitted/founder viruses (Bruel et al, 2017). Passive transfer experiments in macaques have associated nnAbs with reduced numbers of transmitted/founder variants and, in some cases, with lower acute viremia, but not with protection from infection (Burton et al, 2011; Mascola et al, 1999; Moog et al, 2014; Santra et al, 2015).…”

“…In contrast, nnAbs do not neutralize HIV-1 in vitro , and have variable activity in antibody dependent cellular cytotoxicity (ADCC) assays in vitro (Bruel et al, 2017; Chung et al, 2014; Holl et al, 2006; Kramski et al, 2013; Lewis, 2013). In the RV144 trial, induction of nnAbs capable of mediating ADCC in vitro was associated with decreased transmission risk (Haynes et al, 2012; Liao et al, 2013).…”

BST-2 Expression Modulates Small CD4-Mimetic Sensitization of HIV-1-Infected Cells to Antibody-Dependent Cellular Cytotoxicity

“…Statistical significance was tested using a paired t test or Wilcoxon matched-pair signed-rank test based on statistical normality (*, P Ͻ 0.05; **, P Ͻ 0.01, ***, P Ͻ 0.001; ****, P Ͻ 0.0001; ns, nonsignificant). (3,4,45,46). While the reasons for these differences are not fully understood, the angle of approach of the antibody toward Env might differentially expose the Fc region which must be engaged by the Fc␥ receptor in order to activate effector cells.…”

Adaptive NK cell responses in HIV/SIV infections: A roadmap to cell-based therapeutics?

“…41 Unsurprisingly, nonneutralizing HIV-1 antibodies have been shown to lack ADCC breadth. 42 Thus, it is becoming increasingly evident that the elimination of virus-infected cells may require nonneutralizing functions mediated through interaction with Fc receptors, particularly those on NK cells. 43 Data from a clinical trial with bNAb antibody cocktails showed very modest results with only 2 of 8 participants showing moderate delays in viral rebound.…”