HIV infection and the gastrointestinal tract

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Abstract
Gastrointestinal mucosa and other mucous membranes occupy a unique anatomical niche: the interface between a sterile, internal environment and a contaminated, external environment. There is a polarity in epithelia that is different from all other tissues, in which one side of the epithelial cell faces ‘self’, whereas the other side faces ‘non-self’. Epithelial cells require intimate contact with the external environment in order to carry out their primary functions, e.g. nutrient absorption in the intestine, gas exchange in the lungs, etc. The need for such contact with the external environment makes mucous membranes inherently vulnerable to infectious organisms, because of the lack of a strong physical barrier. The problem is compounded by a large surface area that characterizes most mucous membranes. For example, in the intestine, adaptations such as mucosal folds, villi and microvilli lead to a 600-fold increase in surface area beyond that present in a simple tube. An elaborate system has evolved to protect the gastrointestinal tract from pathogens, which is part of a common mucosal immune system. The afferent and efferent limbs of the mucosal immune system are anatomically separate, but intermingled. The afferent limb represents the cell populations and structures involved in the production of an immune response, e.g. antigen presentation and lymphoproliferation, whereas the efferent limb involves the cell populations and structures directly involved in the immune response, e.g. antibody producing and cytotoxic mononuclear cells. The afferent system includes discrete lymphoid follicles (Fig. 1), which are overlaid by a follicle-associated epithelium, including microfold, or M cells. M cells are specially adapted epithelial cells, without long microvilli or overlying mucus, which promote the transcellular transit of particulate antigens to antigen-presenting macrophages that lie immediately beneath the cells, and then to mucosal lymphoid follicles (Fig. 2). Further maturation of cells occurs during migration through mesenteric lymphoid follicles and the systemic circulation, via the thoracic duct. After further maturation in the spleen and elsewhere, lymphoid cells return to the intestinal mucosa. The lymphoid cells in the efferent compartments, the epithelial layer, and the lamina propria are scattered diffusely throughout the intestine, in keeping with the defensive function along the length of the intestine. Differences in subpopulations of lymphoid cells, and in immune functions, are found in the epithelial layer and in the lamina propria. Mucosal immunity has many homologies to systemic immunity, and several distinctions. Although many consider the intestinal mucosa to be physiologically inflamed, it is quite uninflamed, despite microbial provocation. Secretory immunoglobulins and the process of immune exclusion from the internal environment, as well as the lack of complement activation by IgA, reflect the non-inflammatory tone of the intestines. Importantly, inflammation impairs mucosal function by several mechanisms. Intestinal mucosa has long been known to be a target for HIV and related viruses, based upon the route of exposure and other aspects of mucosal immunology (Fig. 3). The aim of this review is to document the progress in the field of HIV infection in the gastrointestinal tract over the past few years. Whereas new information is partly recapitulation of earlier work, discussion will concentrate on recently published studies. Early conceptions of HIV transmission were that it occurred through mucosal trauma or other breaches in the physical barriers of the genital epithelium or perineal skin. However, infection also occurs after atraumatic inoculation of mucous membranes.

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