Distinct systemic microbiome and microbial translocation are associated with plasma level of anti-CD4 autoantibody in HIV infection

Wanli Xu,Sonya L Heath,Kendra Maas,Zhiqiang Qin,Zhenwu Luo,Xiaomei Cong,Zhuang Wan,Wei Jiang,Alexander V Alekseyenko,Lisa Martin,Binhua Ling

doi:10.1038/s41598-018-31116-y

Abstract

Microbial signals have been linked to autoantibody induction. Recently, we found that purified anti-CD4 autoantibodies from the plasma of chronic HIV-1-infected patients under viral-suppressed antiretroviral therapy (ART) play a pathologic role in poor CD4+ T cell recovery. The purpose of the study was to investigate the association of systemic microbiome and anti-CD4 autoantibody production in HIV. Plasma microbiome from 12 healthy controls and 22 HIV-infected subjects under viral-suppressed ART were analyzed by MiSeq sequencing. Plasma level of autoantibodies and microbial translocation (LPS, total bacterial 16S rDNA, soluble CD14, and LPS binding protein) were analyzed by ELISA, limulus amebocyte assay, and qPCR. We found that plasma level of anti-CD4 IgGs but not anti-CD8 IgGs was increased in HIV+ subjects compared to healthy controls. HIV+ subjects with plasma anti-CD4 IgG > 50 ng/mL (high) had reduced microbial diversity compared to HIV+ subjects with anti-CD4 IgG ≤ 50 ng/mL (low). Moreover, plasma anti-CD4 IgG level was associated with elevated microbial translocation and reduced microbial diversity in HIV+ subjects. The Alphaproteobacteria class was significantly enriched in HIV+ subjects with low anti-CD4 IgG compared to patients with high anti-CD4 IgG even after controlling for false discovery rate (FDR). The microbial components were different from the phylum to genus level in HIV+ subjects with high anti-CD4 IgGs compared to the other two groups, but these differences were not significant after controlling for FDR. These results suggest that systemic microbial translocation and microbiome may associate with anti-CD4 autoantibody production in ART-treated HIV disease.

Highlights

Chronic inflammation or immune dysfunction has been a critical issue in human immunodeficiency virus (HIV) disease even in patients under viral suppressive antiretroviral therapy (ART)
We investigated the mechanism of anti-CD4 autoantibody production in well-controlled ART-treated HIV infection
We found that the plasma level of autoreactive anti-CD8 IgG was similar in controls and HIV+ subjects, but the level of anti-CD4 IgG increased in the HIV+ subjects compared to controls (Fig. 1A,B), suggesting that B cell function is still abnormal even after long-term ART treatment and successful viral suppression

Summary

Introduction

Chronic inflammation or immune dysfunction has been a critical issue in human immunodeficiency virus (HIV) disease even in patients under viral suppressive antiretroviral therapy (ART). Another study from Moir’s group reported that purified B cells from HIV-infected patients had reduced antigen-presenting function compared to B cells from healthy controls when co-culturing with purified T cells from the same healthy donors[29] These results suggest B cell intrinsic dysfunction in HIV disease. Differences in fecal microbiome in HIV-infected patients versus healthy controls are associated with systemic inflammation[32] Microbial products such as TLR ligands can induce autoantibody production and may play a pathogenic role in autoimmune diseases[36,37,38]. After long-term repeated stimulation by low concentrations of TLR ligands (compared to one dose and high concentration as vaccine adjuvants) and other microbial products released from the gut[24,25,26,39], B cells may be polyclonally activated as reflected by increased total IgM and IgG26,40

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