Non-neutralizing Antibodies Targeting the V1V2 Domain of HIV Exhibit Strong Antibody-Dependent Cell-mediated Cytotoxic Activity

Luzia M Mayr,Thomas Decoville,Christiane Moog,Géraldine Laumond,Sylvie Schmidt,Jéromine Klingler,Camille Ducloy,Susan Zolla-Pazner,Seiamak Bahram

doi:10.1038/s41598-017-12883-6

Abstract

The development of an effective vaccine against HIV-1 has proven to be challenging. Broadly neutralizing antibodies (bNAbs), whilst exhibiting neutralization breadth and potency, are elicited only in a small subset of infected individuals and have yet to be induced by vaccination. Case-control studies of RV144 identified an inverse correlation of HIV-1 infection risk with antibodies (Abs) to the V1V2 region of gp120 with high antibody-dependent cellular cytotoxicity (ADCC) activity. The neutralizing activity of Abs was not found to contribute to this protective outcome. Using primary effector and target cells and primary virus isolates, we studied the ADCC profile of different monoclonal Abs targeting the V1V2 loop of gp120 that had low or no neutralizing activity. We compared their ADCC activity to some bNAbs targeting different regions of gp120. We found that mAbs targeting the V1V2 domain induce up to 60% NK cell mediated lysis of HIV-1 infected PBMCs in a physiologically relevant ADCC model, highlighting the interest in inducing such Abs in future HIV vaccine trials. Our data also suggest that in addition to neutralization, lysis of infected cells by Abs can effectively participate in HIV protection, as suggested by the RV144 immune correlate analysis.

Highlights

The V1V2 domain is immunogenic and Abs targeting this region are induced in most HIV-1 infected patients[6]
antibody-dependent cellular cytotoxicity (ADCC) activity is characterized by the interaction of the Fc region of an immunoglobulin, bound via its Fab part to Env on infected cells, and to Fc receptors expressed on the surface of effector cells, such as NK cells
The ADCC assay that we perform uses primary CD4 T cells infected with HIV-1 isolates produced by primary Peripheral blood mononuclear cells (PBMCs) and autologous purified NK cells

Summary

Introduction

The V1V2 domain is immunogenic and Abs targeting this region are induced in most HIV-1 infected patients[6]. A set of mAbs, termed V2i mAbs, was isolated from HIV-1 clade B-infected patients and recognize a conformation-dependent epitope surrounding the α4β7 integrin binding site of the V1V2 domain[12,13,14,15] These V2i mAbs display numerous physiochemical similarities to the Abs elicited in RV144 such as weak neutralizing activity and overlapping epitope regions. ADCC activity is characterized by the interaction of the Fc region of an immunoglobulin, bound via its Fab part to Env on infected cells, and to Fc receptors expressed on the surface of effector cells, such as NK cells This triggers the release of cytotoxic granules containing perforin and granzymes, leading to the death of the antibody-bound infected target cell. These and additional studies have pointed towards ADCC as an important mechanism to target HIV-1 in vivo[28,29,30]

Methods

Results

Conclusion