Development of antibody-dependent cell cytotoxicity function in HIV-1 antibodies.

Laura E Doepker,Sonja Danon,Elias Harkins,Megan M Stumpf,Amrit Dhar,Meghan E Garrett,Frederick A Matsen,Duncan K Ralph,Zak Yaffe,James A Williams,Walter Jaoko,Cassia Wagner,Kelly K Lee,Julie M Overbaugh,Kishor Mandaliya,Dana Arenz

doi:10.7554/elife.63444

Abstract

A prerequisite for the design of an HIV vaccine that elicits protective antibodies is understanding the developmental pathways that result in desirable antibody features. The development of antibodies that mediate antibody-dependent cellular cytotoxicity (ADCC) is particularly relevant because such antibodies have been associated with HIV protection in humans. We reconstructed the developmental pathways of six human HIV-specific ADCC antibodies using longitudinal antibody sequencing data. Most of the inferred naive antibodies did not mediate detectable ADCC. Gain of antigen binding and ADCC function typically required mutations in complementarity determining regions of one or both chains. Enhancement of ADCC potency often required additional mutations in framework regions. Antigen binding affinity and ADCC activity were correlated, but affinity alone was not sufficient to predict ADCC potency. Thus, elicitation of broadly active ADCC antibodies may require mutations that enable high-affinity antigen recognition along with mutations that optimize factors contributing to functional ADCC activity.

Highlights

A major concept underlying HIV vaccine research is that we can learn from the processes that lead to potent antibody responses in natural infection to inform immunogen design
We previously reported the isolation of six monoclonal antibodies, each with potent antibody-dependent cell cytotoxicity (ADCC) activity, from a sample collected 914 days post-infection (D914) from a clade A-infected Kenyan woman (Williams et al, 2015; Williams et al, 2019)
Renewed interest in ADCC-capable antibodies as important to HIV vaccine responses has highlighted the need for a better understanding of their natural development (Forthal and Finzi, 2018)

Summary

Introduction

A major concept underlying HIV vaccine research is that we can learn from the processes that lead to potent antibody responses in natural infection to inform immunogen design. Over the course of an HIV infection, an immune cell goes through genetic changes that tweak the 3D structure of the antibodies it manufactures This process can improve the antibodies’ ability to fight off the virus, but it was still unclear how it would shape antibody-dependent cellular cytotoxicity. The data are less convincing for sterilizing protection by HIV-specific non-neutralizing antibodies that mediate antibody-dependent cell cytotoxicity (ADCC) in the same experimental animal models (Fouts et al, 2015), where the functional interactions of antibodies are harder to test due to species differences (Bournazos et al, 2017) They have been implicated in protection from HIV-infection in humans in several settings. Productive replicate- Estimated sequencing merged deduplicated coverage within sampled sequences blood PBMCs†

Results

Discussion

Materials and methods

Data and code availability

Funding Funder National Institutes of Health