Schistosoma mansoni treatment reduces HIV entry into cervical CD4+\xa0T cells and induces IFN-I pathways

Sergey Yegorov,Andrea K Boggild,Rupert Kaul,Egbert Tannich,Sara V Good,Ronald M Galiwango,Bernard S Bagaya,Vineet Joag,Noah Kiwanuka,Juliet Mpendo

doi:10.1038/s41467-019-09900-9

Abstract

Schistosoma mansoni (Sm) infection has been linked with an increased risk of HIV acquisition in women. Therefore, defining the mechanism(s) by which Sm alters HIV susceptibility might lead to new HIV prevention strategies. Here, we analyze the impact of standard Sm therapy in HIV-uninfected Sm+ Ugandan adult women on genital HIV susceptibility and mucosal and systemic immunology. Schistosomiasis treatment induces a profound reduction of HIV entry into cervical and blood CD4+ T cells that is sustained for up to two months, despite transient systemic and mucosal immune activation and elevated genital IL-1α levels. Genital IFN-α2a levels are also elevated post-treatment, and IFN-α2a blocks HIV entry into primary CD4+ T cells ex vivo. Transcriptomic analysis of blood mononuclear cells post-Sm treatment shows IFN-I pathway up-regulation and partial reversal of Sm-dysregulated interferon signaling. These findings indicate that Sm therapy may reduce HIV susceptibility for women with Sm infection, potentially through de-repression of IFN-I pathways.

Highlights

Schistosoma mansoni (Sm) infection has been linked with an increased risk of human immunodeficiency virus (HIV) acquisition in women
The diagnosis of schistosomiasis was made based on the urine circulating cathodic antigen (CCA) test, and 36 consenting, Sminfected women were provided with a standard dose of oral praziquantel for Sm treatment at Visit 1 (V1); of these, two participants were subsequently excluded due to infection by Chlamydia trachomatis and/or Neisseria gonorrhoeae (Fig. 1a)
The present study demonstrated that standard praziquantel treatment of Sm-infected HIV-negative women resulted in over two- fold reduction of ex vivo HIV entry into cervical- and bloodderived CD4+ T cells

Summary

Introduction

Schistosoma mansoni (Sm) infection has been linked with an increased risk of HIV acquisition in women. Transcriptomic analysis of blood mononuclear cells post-Sm treatment shows IFN-I pathway up-regulation and partial reversal of Sm-dysregulated interferon signaling These findings indicate that Sm therapy may reduce HIV susceptibility for women with Sm infection, potentially through de-repression of IFN-I pathways. While one potential mechanism for enhanced HIV susceptibility is the impairment of systemic antiviral defenses by helminthic immunomodulation, it is plausible that Sm egg-induced inflammation of the gut mucosa activates common mucosal homing pathways[14] with enhanced CD4+ T cell trafficking to genital sites of HIV exposure through expression of the mucosa-homing integrin α4β7. We demonstrate that Sm clearance substantially reduces cervical CD4+ T cell susceptibility, and boosts both mucosal and systemic IFN-I antiviral responses These findings help to elucidate the impact of Sm infection and its treatment on antiviral immunity and HIV acquisition, and may point the way to novel strategies to reduce HIV transmission in the region

Methods

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Conclusion