Naive B Cell Output in HIV-Infected and HIV-Uninfected Children.

Helen Payne,Joanna Lewis,Stuart Adams,Avy Violari,Patricia Hunter,Nigel Klein,Mark Cotton,Kimberly Gilmour,Gabriel Chain,Abdel Babiker,Diana Gibb,Natasha Luckhurst,Robin Callard

doi:10.1089/aid.2018.0170

Abstract

In this study, we aimed to quantify KREC (kappa-deleting recombination excision circle) levels and naive B cell output in healthy HIV-uninfected children, compared with HIV-infected South African children, before and after starting ART (antiretroviral therapy). Samples were acquired from a Child Wellness Clinic (n = 288 HIV-uninfected South African children, 2 weeks–12 years) and the Children with HIV Early Antiretroviral Therapy (CHER) trial (n = 153 HIV-infected South African children, 7 weeks–8 years). Naive B cell output was estimated using a mathematical model combining KREC levels to reflect B cell emigration into the circulation, flow cytometry measures of naive unswitched B cells to quantify total body naive B cells, and their rates of proliferation using the intracellular marker Ki67. Naive B cell output increases from birth to 1 year, followed by a decline and plateau into late childhood. HIV-infected children on or off ART had higher naive B cell outputs than their uninfected counterparts (p = .01 and p = .04). This is the first study to present reference ranges for measurements of KRECs and naive B cell output in healthy and HIV-infected children. Comparison between HIV-uninfected healthy children and HIV-infected children suggests that HIV may increase naive B cell output. Further work is required to fully understand the mechanisms involved and clinical value of measuring naive B cell output in children.

Highlights

In HIV-infected individuals, CD4 T cell loss results in profound immunodeficiency and susceptibility to infection[1]; loss of CD4 T cells can be partially reversed by antiretroviral therapy (ART)
The components of naive B cell output are presented in Supplementary Table S3 and demonstrated in Supplementary Figure S2 suggesting that all three components may be marginally higher in HIV-infected children on ART in the first 2 years of life compared with healthy HIV-uninfected children
Measurements of naive B cell output from children treated with ART for 96 weeks (ART-96W) were compared to healthy HIV-uninfected South African children from the Child Wellness Clinic’’ (CWC)

Summary

Introduction

In HIV-infected individuals, CD4 T cell loss results in profound immunodeficiency and susceptibility to infection[1]; loss of CD4 T cells can be partially reversed by antiretroviral therapy (ART). In adults this is largely due to peripheral proliferation of an existing T cell repertoire; in children the thymus plays a more prominent role in immune reconstitution with the generation of naive T cells.[2]. Naive B cells play key roles in the immune response to infection, largely through differentiation into antibody producing plasma cells and generation of memory B cells[6]; it has not been determined whether naive B cell output changes with HIV infection or even with age in the way that thymic output does

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Conclusion