Gut barrier structure, mucosal immunity and intestinal microbiota in the pathogenesis and treatment of HIV infection.

Camilla Tincati,Daniel C. Douek,Giulia Marchetti

doi:10.1186/s12981-016-0103-1

Abstract

Over the past 10 years, extensive work has been carried out in the field of microbial translocation in HIV infection, ranging from studies on its clinical significance to investigations on its pathogenic features. In the present work, we review the most recent findings on this phenomenon, focusing on the predictive role of microbial translocation in HIV-related morbidity and mortality, the mechanisms by which it arises and potential therapeutic approaches. From a clinical perspective, current work has shown that markers of microbial translocation may be useful in predicting clinical events in untreated HIV infection, while conflicting data exist on their role in cART-experienced subjects, possibly due to the inclusion of extremely varied patient populations in cohort studies. Results from studies addressing the pathogenesis of microbial translocation have improved our knowledge of the damage of the gastrointestinal epithelial barrier occurring in HIV infection. However, the extent to which mucosal impairment translates directly to increased gastrointestinal permeability remains an open issue. In this respect, novel work has established a role for IL-17 and IL-22-secreting T cell populations in limiting microbial translocation and systemic T-cell activation/inflammation, thus representing a possible target of immune-therapeutic interventions shown to be promising in the animal model. Further, recent reports have not only confirmed the presence of a dysbiotic intestinal community in the course of HIV infection but have also shown that it may be linked to mucosal damage, microbial translocation and peripheral immune activation. Importantly, technical advances have also shed light on the metabolic activity of gut microbes, highlighting the need for novel therapeutic approaches to correct the function, as well as the composition, of the gastrointestinal microbiota.

Highlights

A decade ago, microbial translocation was described as an underlying cause of T-cell activation in human immunodeficiency virus (HIV) infection
Our group showed that pre-combination antiretroviral therapy (cART) levels of high sensitivity C reactive protein (CRP), but not soluble CD14 (sCD14), LPS or endotoxin core antibodies (EndoCAb) predicted clinical events in a large cohort of treated HIV-infected subjects [13] and suggest, together with other literature evidence, that the occurrence of non-acquired immune deficiency syndrome (AIDS) conditions may be only in part related to gut damage and microbial translocation (Table 1)
Since its discovery approximately a decade ago as a cause of T-cell activation in HIV infection, microbial translocation has been investigated as a mechanism underlying increased morbidity and mortality in this setting

Summary

Introduction

A decade ago, microbial translocation was described as an underlying cause of T-cell activation in HIV infection. Following the discovery of microbial translocation as a mechanism for immune activation [4,5,6], different groups assessed the role of circulating bacterial components in predicting the outcome of HIV infection In this respect, plasma levels of sCD14 and lipopolysaccharide (LPS) were first described as independent predictors of mortality [7] and disease progression [8] in chronicallyinfected individuals; similar results were recently found in the setting of spontaneous control of HIV viremia [9] (Table 1). One study demonstrated that measures of LPS-induced innate immune activation (sCD14), gut epithelial barrier dysfunction (I-FABP; zonulin-1), coagulation (D-dimer) and inflammation (hs CRP, sTNFRI) were able to predict mortality in individuals on cART [10] (Table 1) In accordance with these findings, high levels of similar markers prior to the initiation of antiretrovirals were shown to predict nonAIDS morbid events on stable treatment [11] (Table 1). Our group showed that pre-cART levels of CRP, but not sCD14, LPS or EndoCAb predicted clinical events in a large cohort of treated HIV-infected subjects [13] and suggest, together with other literature evidence, that the occurrence of non-AIDS conditions may be only in part related to gut damage and microbial translocation (Table 1)

Objectives

Conclusion