Inflammation and gut permeability.

AuthorByakwaga, Helen
PositionLEADING ARTICLE - Report


Early when HIV-1 was first defined as the infectious agent that causes AIDS, the importance of the gastrointestinal (GI) tract for viral progeny was noted [1]. In 1984, investigators observed that HIV-infected individuals had histological abnormalities in the GI mucosa along with lymphocyte depletion, and were also suffering from malabsorption [2]. Over the years, studies of simian immunodeficiency virus (SIV)-infected macaques and HIV-infected humans have provided substantial evidence that significant GI pathology results from progressive HIV-1 infection from the acute phase of the infection to advanced disease [2-9]. The changes in the structure and function of the GI tract associated with SIV/HIV infections have long been recognised, and their clinical implications and subsequent new therapeutic approaches are the subject of ongoing research. This article delineates the current knowledge about HIV-related gut permeability and inflammation.


The GI tract mucosal surface provides a unique structural and immunological barrier against various micro-organisms. However, in order to function normally, it requires not only an intact epithelium with cells joined by tight junctions but also coordinated function of a cooperative network made up of multiple cell types that occupy distinct anatomical positions [10]. Therefore, physical or functional disruption of the GI mucosal surface might be expected to have detrimental consequences. Although findings from studies of HIV-infected individuals suggest that HIV-associated breakdown of the intestinal epithelial barrier is a result of structural changes to the intestinal mucosa caused by intestinal immune dysfunction [11,12], the molecular basis of intestinal epithelial barrier damage is not fully elucidated.

HIV/SIV damage of the GI mucosa has been associated with enteropathy [3,4,9]. HIV-related enteropathy involves increased inflammation, increased intestinal permeability (up to five times higher than in non-HIV-infected individuals), diarrhoea, and malabsorption of bile acid and vitamin B12 [3,8,13]. It is important to note that enteropathy can occur at any point in the course of HIV infection, from the acute phase to advanced disease. During the chronic stages of infection, enteropathic manifestations of HIV infection are usually a result of concurrent fungal, viral, bacterial and protozoal infections. Histologically, the enteropathy involves inflammatory infiltrates of lymphocytes and damage to the GI epithelial layer including villous atrophy and blunting, along with crypt hyperplasia [3,5,14]. These changes have been associated with mucosal T cell activation both in vitro [15] and in vivo [16].


Up to 60% of mucosal memory CD4+ T cells become infected with SIV within days of infection at the time of peak viraemia. This results in rapid depletion of about 80% of these infected cells, also within days of infection [11,17]. It is claimed that up to 40% of the body's lymphocytes can be found in the GI mucosa [18] and consequently, CD4+ T cell depletion predominantly occurs here and then continues throughout the course of the disease [17,19-21].Most of the CD4+ T cells in the GI mucosal system are CCR5+ (an important T cell co-receptor facilitating viral entry) activated memory CD4+ T cells and therefore preferred targets for HIV infection [19,20].Moreover, recent reports suggest that the preference of HIV for the GI mucosal immune system may in part be due to HIV-1 selectively binding to a molecule that helps to direct T cells to the gut: the integrin [alpha]4[beta]7 molecule [22].

One subset of CD4+ T cells known as Th17 cells is of particular interest. These lymphocytes produce interleukin (IL)-17 and IL-22 (but not interferon [IFN]-[gamma] or IL-4) [23] and are thought to play a critical role in enterocyte homeostasis [11], induction of antimicrobial defensins and recruitment of neutrophils [24], all of which are important processes for maintenance of the mucosal barrier. Significant loss of Th17 cells has been observed in the GI tract of HIV-infected humans [25] and SIV-infected macaques [26]. In addition, Th17 cells are found to be even more profoundly depleted than CD4+CCR5+ T cells in the GI mucosa of SIV-infected rhesus macaques and HIV-infected individuals [26]. These data therefore suggest a possible direct association between CD4+ T cell destruction and intestinal mucosal dysfunction.

The network of connecting epithelial cells and the GI immune system is thought to be maintained through diffusible molecules such as cytokines, growth factors, locally derived hormones and products of arachidonic acid metabolism [27]. Therefore, it is likely to be disrupted by the sudden and substantial HIV-mediated destruction of activated effector memory, CCR5+ and Th17 CD4+ T cells. As a result, one would expect both a deficit of factors required for growth, maintenance and renewal of epithelial cells and subsequently increased epithelial cell apoptosis and death. Findings from gene-expression profiles of GI-tract biopsies in HIV-infected individuals show downregulation of genes associated with cell-cycle regulation, epithelial barrier maintenance and metabolic functions suggesting a potential association of this functional disruption with increased epithelial cell apoptosis...

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