Plasma IL-5 but Not CXCL13 Correlates With Neutralization Breadth in HIV-Infected Children.

Julia Roider,J Zachary Porterfield,Emily Adland,Alasdair Leslie,Andreas Groll,Henrik Kløverpris,Maximilian Muenchhoff,Thumbi Ndung'U,Penny L Moore,Paul Ogongo,Lynn Morris,Philip J R Goulder

doi:10.3389/fimmu.2019.01497

Abstract

Children may be the optimal target for HIV vaccine development as they generate substantially more frequent and more potent broadly HIV neutralizing antibodies (bnAbs) than adults. Development of a biomarker that correlates with neutralization breadth in this group could function as a powerful tool to facilitate the development of an HIV vaccine. Previously, we observed that this preferential ability in HIV-infected children over adults to generate bnAbs is associated with an enrichment of circulating follicular helper T-cells (TFH) with an effector phenotype, and the presence of IL-21 secreting HIV-specific TFH within lymphoid tissue germinal centers (GC). In adults, bnAbs development has been linked with high plasma levels of CXCL13, a chemoattractant for CXCR5-expressing TFH cells to the lymph node GC. We sought to test this relationship in HIV-infected children, but found no association between neutralization breadth and plasma levels of CXCL13, or with the Th2 cytokines IL-4 and IL-13, or the TFH associated factor Activin A. However, we did find an unexpected association between plasma IL-5 levels and bnAb development in these children. Importantly, although CXCL13 correlated with total circulating TFH cells, it was not associated with effector TFH. Additionally, raised CXCL13 expression was associated with a lower CD4 percentage, higher viral load and a loss of immune function, implying it is associated with progressive disease rather than HIV-specific GC activity in these subjects. Taken together, our data suggests that IL-5 should be evaluated further as a candidate plasma biomarker for HIV neutralization breadth and for monitoring vaccine responses in the pediatric age group.

Highlights

Recent HIV vaccine development strategies have highlighted the unique potential contribution that can be made by the study of the immune responses to HIV infection in children [1]
A protective HIV vaccine will most likely require the generation of broadly HIV neutralizing antibodies (bnAbs) and this depends on an both an effective Germinal centers (GC) response and T-follicular helper cells (TFH) activity
Since direct monitoring of the GC response in future pediatric vaccine trials is not feasible due to lack of routine access to tissue, a plasma marker of the GC response, TFH activity, and neutralization breadth would be of great value

Summary

Introduction

Recent HIV vaccine development strategies have highlighted the unique potential contribution that can be made by the study of the immune responses to HIV infection in children [1]. In response to the same gp120 vaccine, infants produced higher magnitude anti-V1V2 antibodies than adults [2]. There is growing evidence that children are better at eliciting HIVspecific antibody responses than adults and develop broad and potent neutralizing antibodies as early as 2 years of life [3, 4]. Germinal centers (GC) of secondary lymphoid organs are the primary site where a humoral immune response develops, but are challenging to directly monitor in vaccine trials due to a lack of routine access to lymphoid tissue. As an alternative various studies of plasma markers of germinal center activity have been conducted in adults to seek for correlates to GC activity [8,9,10]

Methods

Results

Conclusion