Experimental colitis in SIV-uninfected rhesus macaques recapitulates important features of pathogenic SIV infection.

Xingpei Hao ,Peter L Choyke,Jacob D Estes,Jan Kristoff,Brandon F Keele,Luis D Giavedoni,Charles M Trubey,Srinivas S Rao,Jason M Brenchley,Carissa M Lucero,Gregory Q Del Prete,Ivona Pandrea,Nichole R Klatt,Jeffrey D Lifson,W Gregory Alvord,Jeremy Smedley,David R Morcock,Cristian Apetrei,Marcelino Bernardo ,Claire Deléage ,Barış Türkbey ,An Xu

doi:10.1038/ncomms9020

Abstract

Mucosal damage to the gastrointestinal (GI) tract with resulting microbial translocation is hypothesized to significantly contribute to the heightened and persistent chronic inflammation and immune activation characteristic to HIV infection. Here we employ a non-human primate model of chemically induced colitis in SIV-uninfected rhesus macaques that we developed using dextran sulfate sodium (DSS), to directly test this hypothesis. DSS treatment results in GI barrier damage with associated microbial translocation, inflammation and immune activation. The progression and severity of colitis are longitudinally monitored by a magnetic resonance imaging approach. DSS treatment of SIV-infected African green monkeys, a natural host species for SIV that does not manifest GI tract damage or chronic immune activation during infection, results in colitis with elevated levels of plasma SIV RNA, sCD14, LPS, CRP and mucosal CD4+ T-cell loss. Together these results support the hypothesis that GI tract damage leading to local and systemic microbial translocation, and associated immune activation, are important determinants of AIDS pathogenesis.

Highlights

Mucosal damage to the gastrointestinal (GI) tract with resulting microbial translocation is hypothesized to significantly contribute to the heightened and persistent chronic inflammation and immune activation characteristic to human immunodeficiency virus (HIV) infection
Because dextran sulfate sodium (DSS) is believed to be directly toxic to intestinal epithelial cells of the basal crypts and impair the integrity of the mucosal barrier, and because GI tract epithelial damage is a salient feature of pathogenic HIV/simian immunodeficiency virus (SIV) infections[5,23,24,25,26], we sought to develop a DSS-induced colitis model in non-human primate (NHP) as the first large animal model of experimentally induced inflammatory bowel disease (IBD) and to evaluate whether GI tract damage in the absence of lentiviral infection is sufficient to lead to microbial translocation, systemic inflammation, immune activation and disruption of the architecture of secondary lymphoid tissues, all pathologic hallmarks of pathogenic HIV/SIV infections
Direct evidence that GI tract damage leading to microbial translocation independent of lentiviral infection leads to systemic inflammation and immune activation, T-cell activation, has been lacking

Summary

Introduction

Mucosal damage to the gastrointestinal (GI) tract with resulting microbial translocation is hypothesized to significantly contribute to the heightened and persistent chronic inflammation and immune activation characteristic to HIV infection. DSS treatment of SIV-infected African green monkeys, a natural host species for SIV that does not manifest GI tract damage or chronic immune activation during infection, results in colitis with elevated levels of plasma SIV RNA, sCD14, LPS, CRP and mucosal CD4 þ T-cell loss. Together these results support the hypothesis that GI tract damage leading to local and systemic microbial translocation, and associated immune activation, are important determinants of AIDS pathogenesis. Previous work demonstrated that early damage to the GI epithelial barrier occurs during the late acute phase of infection, and once damage has taken place, bacterial constituents that translocate from the lumen of the GI tract perpetuate a state of inflammation resulting in sustained colitis, further exacerbating GI tract damage in SIVinfected RMs11

Methods

Results

Conclusion