HIV-specific Fc effector function early in infection predicts the development of broadly neutralizing antibodies.

Simone I Richardson,Harini Natarajan,Nonhlanhla N Mkhize,Margaret E Ackerman,Salim Abdool Karim,Nigel Garrett,Lynn Morris,Galit Alter,Amy W Chung,Batsirai Mabvakure,Penny L Moore,Daniel C Douek

doi:10.1371/journal.ppat.1006987

Abstract

While the induction of broadly neutralizing antibodies (bNAbs) is a major goal of HIV vaccination strategies, there is mounting evidence to suggest that antibodies with Fc effector function also contribute to protection against HIV infection. Here we investigated Fc effector functionality of HIV-specific IgG plasma antibodies over 3 years of infection in 23 individuals, 13 of whom developed bNAbs. Antibody-dependent cellular phagocytosis (ADCP), complement deposition (ADCD), cellular cytotoxicity (ADCC) and cellular trogocytosis (ADCT) were detected in almost all individuals with levels of activity increasing over time. At 6 months post-infection, individuals with bNAbs had significantly higher levels of ADCD and ADCT that correlated with antibody binding to C1q and FcγRIIa respectively. In addition, antibodies from individuals with bNAbs showed more IgG subclass diversity to multiple HIV antigens which also correlated with Fc polyfunctionality. Germinal center activity represented by CXCL13 levels and expression of activation-induced cytidine deaminase (AID) was found to be associated with neutralization breadth, Fc polyfunctionality and IgG subclass diversity. Overall, multivariate analysis by random forest classification was able to group bNAb individuals with 85% sensitivity and 80% specificity based on the properties of their antibody Fc early in HIV infection. Thus, the Fc effector function profile predicted the development of neutralization breadth in this cohort, suggesting that intrinsic immune factors within the germinal center provide a mechanistic link between the Fc and Fab of HIV-specific antibodies.

Highlights

Antibodies form a link between the adaptive and innate immune systems and serve as a correlate of protection for many viral vaccines
CAPRISA is funded by the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes for Health (NIH), and U.S Department of Health and Human Services
We aimed to determine whether individuals with HIV-1 specific broadly neutralizing antibodies (bNAbs) showed differences in Fc effector functions and what the kinetics of these responses were relative to the development of neutralization breadth

Summary

Introduction

Antibodies form a link between the adaptive and innate immune systems and serve as a correlate of protection for many viral vaccines They mediate diverse functions through the use of the Fab portion to bind specific antigens and the Fc portion that interacts with cellular receptors to effect a variety of additional non-neutralizing activities [1]. Maturation of antibodies occurs in the germinal center where they undergo somatic hypermutation to generate high affinity neutralizing antibodies, as well as class-switch recombination to select constant regions that determine the scope of Fc effector functions Both processes are dependent on the enzyme activation-induced cytidine deaminase (AID) as well as the cytokine milieu within the germinal center, suggesting that the Fab and Fc maturation processes of antigen-specific antibodies may be jointly regulated [9,10,11]. Far less is known about the corresponding Fc effector response and IgG subclass usage in individuals who develop neutralization breadth

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