Distinct Immunoglobulin Fc Glycosylation Patterns Are Associated with Disease Nonprogression and Broadly Neutralizing Antibody Responses in Children with HIV Infection.

M Muenchhoff,Henrik Kløverpris,Philip J R Goulder,Simone Richardson,Galit Alter,Alasdair Leslie,J Roider,Anne-Sophie Dugast,Thumbi Ndung’U,Penny Moore,A W Chung,Helene F Rosenberg

doi:10.1128/msphere.00880-20

Abstract

A prophylactic HIV vaccine would ideally induce protective immunity prior to sexual debut. Children develop broadly neutralizing antibody (bnAb) responses faster and at higher frequencies than adults, but little is known about the underlying mechanisms or the potential role of Fc-mediated effector functions in disease progression. We therefore performed systems immunology, with immunoglobulin profiling, on HIV-infected children with progressive and nonprogressive disease. Pediatric nonprogressors (PNPs) showed distinct immunoglobulin profiles with an increased ability to elicit potent Fc-mediated natural killer (NK)-cell effector functions. In contrast to previous reports in adults, both groups of children showed high levels of gp120-specific IgG Fc glycan sialylation compared to bulk IgG. Importantly, higher levels of Fc glycan sialylation were associated with increased bnAb breadth, providing the first evidence that Fc sialylation may drive affinity maturation of HIV-specific antibodies in children, a mechanism that could be exploited for vaccination strategies.IMPORTANCE To protect future generations against HIV, a vaccine will need to induce immunity by the time of sexual debut and hence requires immunization during childhood. Current strategies for a prophylactic HIV vaccine include the induction of a broadly neutralizing antibody response and the recruitment of potent effector functions of immune cells via the constant antibody Fc region. In this study, we show that nonprogressing HIV-infected children mounted antibody responses against HIV that were able to mediate potent Fc effector functions, which may contribute to the control of HIV replication. Children who had specific glycan structures on the Fc portion of antibodies against HIV were able to neutralize a broader range of HIV variants, providing evidence of a potential role of Fc glycovariation in the development of bnAbs against HIV. These findings complement our knowledge of the distinct immune landscape in early life that could be exploited in the development of vaccine strategies.

Highlights

IMPORTANCE To protect future generations against HIV, a vaccine will need to induce immunity by the time of sexual debut and requires immunization during childhood
To determine if disease nonprogression in vertical HIV infection is associated with distinct HIV-specific IgG levels, we profiled IgG responses to recombinant HIV-1 consensus C p24, gp41, gp120, and gp140 antigens in HIV-infected pediatric nonprogressors (PNPs) in comparison to progressors or antiretroviral therapy (ART)-treated children
Limited HIV-specific CD4 T-cell activity in PNPs. To address if these differences in IgG levels were correlated with HIV-specific CD4 T-cell activity, we examined T-cell responses upon stimulation with peptide pools covering all HIV-1 consensus subtype C proteins using intracellular cytokine staining against interferon gamma (IFN-g), tumor necrosis factor alpha (TNF-a), and interleukin-2 (IL-2)

Summary

Introduction

IMPORTANCE To protect future generations against HIV, a vaccine will need to induce immunity by the time of sexual debut and requires immunization during childhood. There is a subgroup of vertically HIV-infected pediatric nonprogressors (PNPs) who maintain normal-for-age CD4 counts despite ongoing viral replication at high rates in the absence of antiretroviral therapy (ART) [2] This “nonprogressing” phenotype in children is characterized by low levels of immune activation that are maintained by active tolerogenic mechanisms, including increased regulatory Tcell activity and homeostatic signaling [3]. Efforts to investigate the immunological mechanism that underlies this phenomenon indicate that T follicular helper (Tfh) cells, a subgroup of CD4 T cells specialized to provide help to B cells in antibody affinity maturation and class switching, may play an important role [6] They primarily exert their function within germinal centers of secondary lymphoid tissue, various antigen-experienced subsets of CD4 T cells expressing the follicular homing marker CXCR5 can be identified in circulation [7]. Progressors; HIV2, HIV negative; PNP, pediatric nonprogressor; VL, viral load; cp/ml, HIV RNA copies per milliliter of plasma; ND, not determined

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