Exposure to HIV-1 Directly Impairs Mucosal Epithelial Barrier Integrity Allowing Microbial Translocation

Introduction Top

The mucosa presents a primary barrier against a multitude of micro-organisms present on the mucosal surfaces of the human body [1]. The intestinal and upper reproductive tract are lined by a continuous monolayer of columnar epithelial cells that is responsible for maintaining the physical and functional barrier to harmful microorganisms, such as bacteria and their products, including bacterial toxins as well as commensal organisms [2][4]. The preservation of the barrier function is dependent on the intactness of apical plasma membrane on the epithelial cells as well as the intercellular tight junctions. The disruption of the tight junctions can cause increased permeability, leading to “leakiness” such that normally excluded molecules can cross the mucosal epithelium by paracellular permeation, and could lead to inflammatory conditions in the mucosa.

Various pathogenic organisms have developed strategies to either infect or traverse through the epithelial cells at mucosal surfaces, as part of the strategy to establish infection in the host. In fact, mucosal transmission account for majority of infections in humans [5]. Viruses such as rotavirus and astrovirus as well as bacteria such as enteropathogenic E. Coli and C. difficile are known to increase intestinal permeability by disrupting tight junctions, as part of their pathogenesis [6][9]. Increased permeability is also related to a number of other disease conditions that may or may not be related to infection by a pathogen. Crohn’s disease, a chronic inflammatory condition of the intestines is characterized by defective tight junction barrier functions, manifested by increased intestinal permeability, although the etiology of the disease is not clearly understood [10].

HIV-1 infection is initiated primarily on mucosal surfaces, through heterosexual or homosexual transmission [1],[11]. In fact, mucosal transmission accounts for greater than 90% of HIV infection [12],[13]. A number of clinical studies have reported intestinal barrier dysfunction, especially during chronic stage of HIV infection [14][19]. However, the pathophysiologic mechanism associated with compromised barrier function and whether HIV-1 plays a direct role in this is still unclear. Currently, epithelial barrier defect during HIV-1 infection is thought to be a consequence of mucosal T cell activation following infection, which could lead to increased production of inflammatory cytokines [19],[20]. The intestinal barrier dysfunction has also been implicated as the cause of systemic immune activation during chronic phase of HIV infection, although a recent study has raised the possibility that this may not be universal phenomenon [20],[21]. Studies that have demonstrated immune activation propose this to be the main driving force for progressive immune failure leading to the immunodeficiency stage [22][24]. In these studies, HIV disease progression was shown to correlate with increased circulating level of LPS, considered an indicator of microbial translocation, in chronic HIV-infected individuals [25]. Interestingly, immune activation was observed in both the chronic as well as acute phase of HIV infection [25]. The source of or mechanism whereby microbial products could cross the epithelial barrier leading to immune activation have not been elucidated thus far.

In the present study, we investigated the direct effects of HIV-1 exposure on intestinal and genital mucosal epithelia, where primary HIV-1 infection is frequently initiated. We show that in fact the impairment of epithelial barrier function can be a direct result of exposure to HIV-1. Using ex-vivo cultures of pure primary genital epithelium as well as an intestinal epithelial cell line, we show significantly decreased barrier functions and enhanced permeability that is not unique to the intestinal epithelium; similar increase in permeability was seen in the genital epithelium as well. Small amounts of both bacterial and viral translocation were seen following HIV-1 exposure. The mechanism appears to be mediated by increased production of inflammatory cytokines directly from the epithelial cells following exposure to HIV-1, including TNF-alpha, known to disrupt barrier functions. Further, we show that HIV-1 envelope protein gp120 was able to impair barrier functions in epithelial cells on its own. Neutralization of gp120 or exposure to HIV-1 lacking gp160 surface envelope glycoprotein did not have any effect on epithelial cells. These results provide strong evidence that exposure to HIV-1 may lead to impairment in barrier function of mucosal epithelium which could result both in translocation of HIV-1 and/or luminal bacteria that could serve as the source of immune activation during HIV-1 infection.



Author: GLBTQ Jamaica Moderator

Activist and concerned gay man in Jamaica with over 19 years experience in advocacy and HIV/AIDS prevention work, LGBT DJ since 1996.

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