Gut epithelial barrier dysfunction in human immunodeficiency virus-hepatitis C virus coinfected patients: Influence on innate and acquired immunity

Abstract

Even in cases where viral replication has been controlled by antiretroviral therapy for long periods of time, human immunodeficiency virus (HIV)-infected patients have several non-acquired immunodeficiency syndrome (AIDS) related co-morbidities, including liver disease, cardiovascular disease and neurocognitive decline, which have a clear impact on survival. It has been considered that persistent innate and acquired immune activation contributes to the pathogenesis of these non-AIDS related diseases. Immune activation has been related with several conditions, remarkably with the bacterial translocation related with the intestinal barrier damage by the HIV or by hepatitis C virus (HCV)-related liver cirrhosis. Consequently, increased morbidity and mortality must be expected in HIV-HCV coinfected patients. Disrupted gut barrier lead to an increased passage of microbial products and to an activation of the mucosal immune system and secretion of inflammatory mediators, which in turn might increase barrier dysfunction. In the present review, the intestinal barrier structure, measures of intestinal barrier dysfunction and the modifications of them in HIV monoinfection and in HIV-HCV coinfection will be considered. Both pathogenesis and the consequences for the progression of liver disease secondary to gut microbial fragment leakage and immune activation will be assessed.

Keywords: Acquired immunity; Gut barrier; Hepatitis C virus infection; Human immunodeficiency virus infection; Innate immunity.

Figure 1

Effect of bacterial translocation on innate and acquired immune activation in human immunodeficiency virus-infected patients. In the gastrointestinal tract, human immunodeficiency virus (HIV) infection induces a Th17 CD4+ T helper cells depletion and a damage of intestinal epithelium as a consequence of the HIV exposure itself or by immune-induced enterocyte damage. The consequence of the alteration in gut barrier is the bacterial translocation. Increased plasma concentrations of several markers indicative of pathological bacterial translocation [lipopolysaccharide (LPS), bacterial DNA] have been detected in these patients. These molecules induce a monocyte and lymphocyte activation implicated in the increased morbidity and mortality from non-acquired immunodeficiency syndrome (AIDS) defining causes (neurocognitive impairment, cardiovascular diseases, etc.) and in the poor immune recovery. IL: Interleukin; sCD14: Soluble CD14.

Figure 2

Increased fibrogenesis rate in human immunodeficiency virus-hepatitis C virus coinfected patients. In human immunodeficiency virus (HIV)-hepatitis C virus (HCV) coinfection, translocated bacterial products contribute to liver disease progression by binding to specific pathogen recognition receptors in Kupffer cells. Activated Kupffer cells secrete proinflammatory cytokines and transforming growth factor β1. Activated stellate cells, stimulated by transforming growth factor β1, produce a matrix rich in type 1 collagen, increasing the effect of HCV on hepatic fibrosis.