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Inflammation and gut permeability.


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 [28,29]. In addition, recently reported findings from studies in SIV-infected monkeys suggest that the underlying mechanism of regenerative enteropathy in early infection is SIV-induced massive gut epithelial cell apoptosis [7].


During acute HIV/SIV infection, increased production of pro-inflammatory cytokines such as IFN-[gamma], tumour necrosis factor (TNF)-[alpha] and IL-1[beta] by the dendritic cells and macrophages has been observed in the intestine of HIV-infected humans [30-32] and colon of SIV-infected primates [33]. This could also exacerbate mucosal damage by activating factors such as myosin light chain kinase (MLCK) [34,35] (Figure 1). GI mucosal barrier integrity is maintained by junctional complexes between epithelial cells including tight junctions, desmosomes and adherens junctions [36-38]. MLCK is thought to contribute to the damage of the GI epithelial barrier in other GI diseases such as inflammatory bowel disease [39] by selectively phosphorylating myosin II regulatory light chains, resulting in perijunctional actin-myosin contraction and redistribution of tight junction proteins, and leading to changes in the integrity of the mucosal barrier [40]. The role of MLCK in HIV-related enteropathy is not fully known.

Another hypothesis is that microRNAs have a potential role in the pathogenesis of HIV-associated intestinal barrier disruption [35].MicroRNAs are small, single-stranded RNA molecules that regulate the expression of complementary messenger RNA [41]. MicroRNA-212 is thought to downregulate zonula occludens-1 (ZO-1) protein, a major component of the tight junctions that regulate intestinal permeability. Findings from a recent study showed increased expression of miR-212 in the GI mucosa of patients with alcohol-related liver disease. In this study, overexpression of miR-212 was associated with intestinal hyperpermeability [42,43]. However, there are no data from studies specifically examining this theory in HIV-infected humans.


Irrespective of the mechanism of intestinal epithelial disruption, a more permeable GI mucosa allows entry of bacteria and their products into the peripheral blood. Increased levels of microbial translocation plasma markers such as plasma lipopolysaccharide (LPS) and plasma 16S rDNA have been observed in HIV-infected individuals and their source is thought to be the GI tract following GI mucosal damage by HIV infection [44-46]. In these studies, raised levels of microbial translocation markers were found to be correlated with indices of innate and adaptive immune activation. It is postulated that some of the translocated microbial products bind to Toll-like receptor 4 (TLR4) receptors expressed on immune cells, such as dendritic cells and macrophages, and lead to their activation. This results in localised cytokine production and activation of other immune cells such as CD4+ T cells that can also serve as substrates for HIV/SIV infection [35].

In support of this hypothesis, findings from a study investigating IL-6 signal transduction in the colon and jejunum of chronically SIV-infected rhesus macaques showed constitutive activation of the signal transducer and activator of transcription 3 (STAT3) and dysregulation of the IL-6-STAT3 signal transduction pathway [47]. These data suggest a possible link between SIV infection and GI inflammation that could also play a role in enhancing SIV viral replication [47,48]. In addition, there may be links between the STAT3 pathway and Th17 cells that are thought to play a role in enterocyte homeostasis [49]. Moreover, findings from a recent study suggest that CCAAT-enhancer-binding protein [beta] (C/EBP [beta]), known to be activated in response to IL-6 and other pro-inflammatory cytokine signalling in the GI tract, may also facilitate SIV replication [50].


It is also interesting to note that plasma LPS levels in nonpathogenic SIV infections of sooty mangabeys and African green monkeys were found to be normal [46]. However, as in HIV-infected humans and SIV-infected macaques, rapid and massive loss of intestinal CD4+CCR5+ T cells was observed in studies of SIV infection in these non-human primate hosts [51,52]. In addition, these hosts do not progress to AIDS despite high levels of HIV-1 RNA. SIV infection of sooty mangabeys and African green monkeys is also not typically associated with microbial translocation and immune activation [53] indicating that mucosal integrity is maintained. There is no preferential loss of Th17 cells in SIV-infected sooty mangabeys and healthy frequencies of Th17 cells are maintained in the GI tract and blood [25].


Effective antiretroviral therapy reduces plasma HIV-RNA to undetectable levels and results in increases in CD4+ T cells in peripheral blood [54]. Ongoing HIV replication has been observed in the GI mucosa of HIV-infected patients receiving antiretroviral therapy despite suppression of viral replication in peripheral blood [55,56]. Although some data suggest an almost complete restoration of mucosal CD4+ T cells [57,58] on combination antiretroviral therapy, there is contrasting data in which no mucosal CD4+ T cell reconstitution was observed despite prolonged treatment during acute HIV infection [55,56]. The underlying mechanisms for poor CD4+ T cell reconstitution in the gut are not fully understood but are thought to be, in part, a result of fibrotic collagen deposition that occurs early in HIV infection [59]. Findings from a study of colonic biopsies of HIV-infected individuals initiating combination antiretroviral therapy at the time of acute infection showed that early initiation of therapy did not reverse immunological abnormalities in gut-associated lymphoid tissue [60]. Recent data show that suppressive combination antiretroviral therapy abrogates HIV-induced intestinal barrier defects and villous atrophy in HIV-infected individuals, suggesting that intestinal barrier impairment depends on active viral replication [61].


HIV infection is associated with inflammation and increased permeability of the intestinal epithelium. This disruption of the epithelial barrier occurs throughout the entire course of HIV infection. It also takes place independent of opportunistic infections, especially early on in the course of HIV infection, thereby reflecting the impact of the infection on the integrity of the GI mucosa. Loss of the integrity of the GI epithelial barrier leads to enhanced translocation of luminal antigens such as LPS across the intestinal epithelium, which in turn may elicit chronic activation of the immune system, a known main driving force for progressive HIV infection [62,63]. This suggests a central role of intestinal epithelial barrier function in HIV disease progression. Understanding the molecular mechanisms involved in HIV-associated epithelial barrier disruption may be important in informing novel approaches in therapeutic and vaccine development. None the less, a major problem for this theory is the paucity of data supporting a causal relationship between microbial translocation and morbidity and mortality in HIV disease.


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Correspondence to: Helen Byakwaga, National Centre in HIV Epidemiology and Clinical Research University of New South Wales, Level 2, 376 Victoria Street Darlinghurst NSW 2010, Australia Email:

Helen Byakwaga, Christoph Boesecke and Sean Emery

National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Australia
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Title Annotation:LEADING ARTICLE
Author:Byakwaga, Helen; Boesecke, Christoph; Emery, Sean
Publication:Journal of HIV Therapy
Article Type:Report
Geographic Code:8AUST
Date:Nov 1, 2009
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