Impact of HMGB1/TLR Ligand Complexes on HIV-1 Replication: Possible Role for Flagellin during HIV-1 Infection

Piotr Nowak,Anders Sönnerborg,Marius Troseid,Annica Lindkvist,Samir Abdurahman

doi:10.1155/2012/263836

Piotr Nowak, Anders Sönnerborg + Show 3 more

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https://doi.org/10.1155/2012/263836

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Abstract

Objective. We hypothesized that HMGB1 in complex with bacterial components, such as flagellin, CpG-ODN, and LPS, promotes HIV-1 replication. Furthermore, we studied the levels of antiflagellin antibodies during HIV-1-infection. Methods. Chronically HIV-1-infected U1 cells were stimulated with necrotic extract/recombinant HMGB1 in complex with TLR ligands or alone. HIV-1 replication was estimated by p24 antigen in culture supernatants 48–72 hours after stimulation. The presence of systemic anti-flagellin IgG was determined in 51 HIV-1-infected patients and 19 controls by immunoblotting or in-house ELISA. Results. Flagellin, LPS, and CpG-ODN induced stronger HIV-1 replication when incubated together with necrotic extract or recombinant HMGB1 than activation by any of the compounds alone. Moreover, the stimulatory effect of necrotic extract was inhibited by depletion of HMGB1. Elevated levels of anti-flagellin antibodies were present in plasma from HIV-1-infected patients and significantly decreased during 2 years of antiretroviral therapy. Conclusions. Our findings implicate a possible role of HGMB1-bacterial complexes, as a consequence of microbial translocation and cell necrosis, for immune activation in HIV-1 pathogenesis. We propose that flagellin is an important microbial product, that modulates viral replication and induces adaptive immune responses in vivo.

Highlights

Antiretroviral therapy (ART) suppresses efficiently the replication of human immunodeficiency virus type 1 (HIV-1) to undetectable levels with standard techniques in most treated patients, but there is still an ongoing low-grade replication in most or all patients [1]
Mounting evidence shows that high-mobility group binding 1 protein (HMGB1) does not act alone but forms stable potent proinflammatory complexes with other molecules, such as bacterial products or single stranded DNA [18,19,20, 28]
Since we have earlier shown that HMGB1 alone activates latent HIV-1 replication in vitro [12], we decided to expand our analysis to the effect of HGMB1 in complexes with bacterial products

Summary

Objective

We hypothesized that HMGB1 in complex with bacterial components, such as flagellin, CpG-ODN, and LPS, promotes HIV-1 replication. We studied the levels of antiflagellin antibodies during HIV-1-infection. HIV-1-infected U1 cells were stimulated with necrotic extract/recombinant HMGB1 in complex with TLR ligands or alone. The presence of systemic anti-flagellin IgG was determined in 51 HIV-1-infected patients and 19 controls by immunoblotting or in-house ELISA. LPS, and CpG-ODN induced stronger HIV-1 replication when incubated together with necrotic extract or recombinant HMGB1 than activation by any of the compounds alone. Elevated levels of anti-flagellin antibodies were present in plasma from HIV-1-infected patients and significantly decreased during 2 years of antiretroviral therapy. Our findings implicate a possible role of HGMB1bacterial complexes, as a consequence of microbial translocation and cell necrosis, for immune activation in HIV-1 pathogenesis. We propose that flagellin is an important microbial product, that modulates viral replication and induces adaptive immune responses in vivo

Introduction

Methods

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Results

Discussion