Tracking the Trajectory of Functional Humoral Immune Responses Following Acute HIV Infection.

Madeleine F Jennewein,Carolyn M Boudreau,Krista L Dong,Cassidy L Papia,Jennifer Mabuka,Margaret E Ackerman,Galit Alter,Thumbi Ndung'U

doi:10.3389/fimmu.2020.01744

Abstract

Increasing evidence points to a role for antibody-mediated effector functions in preventing and controlling HIV infection. However, less is known about how these antibody effector functions evolve following infection. Moreover, how the humoral immune response is naturally tuned to recruit the antiviral activity of the innate immune system, and the extent to which these functions aid in the control of infection, are poorly understood. Using plasma samples from 10 hyper-acute HIV-infected South African women, identified in Fiebig stage I (the FRESH cohort), systems serology was performed to evaluate the functional and biophysical properties of gp120-, gp41-, and p24- specific antibody responses during the first year of infection. Significant changes were observed in both the functional and biophysical characteristics of the humoral immune response following acute HIV infection. Antibody Fc-functionality increased over the course of infection, with increases in antibody-mediated phagocytosis, NK activation, and complement deposition occurring in an antigen-specific manner. Changes in both antibody subclass and antibody Fc-glycosylation drove the evolution of antibody effector activity, highlighting natural modifications in the humoral immune response that may enable the directed recruitment of the innate immune system to target and control HIV. Moreover, enhanced antibody functionality, particularly gp120-specific polyfunctionality, was tied to improvements in clinical course of infection, supporting a role for functional antibodies in viral control.

Highlights

Several lines of evidence suggest that the initial serum cellular and antibody responses to HIV infection shapes the course of disease [1]
Plasma samples from 1 month, 3, 9, and 12 months of infection were comprehensively profiled for their antibody response to infection, creating a detailed picture of the longitudinal development of non-neutralizing antibody responses including Antibody-Dependent Cellular Phagocytosis (ADCP), Antibody-Dependent Neutrophil Phagocytosis (ADNP), antibody dependent complement deposition (ADCD), and NK activation
While neutralizing antibodies were not detected in any of these women [54], functional responses and antibody biophysical profiles were all captured against gp120, gp41—for which responses emerge earliest [1]—and the internal gag antigen (p24), that are used diagnostically due to their early evolution and are associated with enhanced viral control [20,21,22,23]

Summary

Introduction

Several lines of evidence suggest that the initial serum cellular and antibody responses to HIV infection shapes the course of disease [1]. Primarily NK and T cells [2,3,4,5,6], have been linked to enhanced viral control, the establishment of a lower viral set-point, and slower progression to AIDS [1]. While strain-specific neutralizing antibodies and binding antibodies emerge within months of infection, the virus is quickly able to evade and escape from these responses [1, 7,8,9]. It takes several years of infection for broadly neutralizing antibodies to evolve [10]. While specific HLA class I alleles, essential for T cell mediated immunity, account for viral control in ∼15% of spontaneous controllers of HIV [18]; functional antibodies evolve in a larger fraction of “controllers” in an HLA-independent manner, potentially pointing to a globally relevant harness-able immune mechanism of viral control [19]

Methods

Results

Conclusion