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Immune activation and Inflammation in the GIT
Immune activation and inflammation, during HIV-1 infection involves several mechanisms related to viral replication either directly or indirectly [227]. The gastrointestinal mucosa is located at the interface between a sterile internal and a microbially contaminated external environment. It serves the conflicting needs of nutrient absorption and host defense, functions that require intimate contact with the external environment [199; 228]. As a result, the GIT has evolved a thin polarized epithelium and a large surface area characterized by mucosal folds, villi and microvilli. In the small intestine of healthy persons, antigen exposure comes primarily from the diet, whereas in the ileum and colon the antigenic load is further enhanced by an abundant and complex array of commensal microbes [229]. The organization of the epithelial barrier with its tight junctions helps reduce the risk of luminal antigens entering the mucosa (including commensal and pathogenic microbes), but it does not completely prevent this process [229-231]. Some food proteins and non-pathogenic commensal bacteria enter the mucosa through breaks in the tight junctions, possibly at the villus tip where epithelial cells are shed, a process that is relatively limited in healthy individuals [232]. The task of mounting an effective immune response to invading pathogens while remaining relatively unresponsive to commensal microbes and food antigens poses a daunting challenge to the GIT. As a result, the gut mucosa has evolved an elaborate system to protect its host from infectious agents. This system consists of two anatomically separated but functionally linked components of the common mucosal immune system [228]. An afferent component, which contains elements involved in the initiation of the immune response including antigen presentation and lymphocyte proliferation, and an efferent component containing elements directly involved in antibody production and CTL responses. Structurally, the afferent system consists of distinct lymphoid follicles overlaid by an epithelial membrane containing M cells. These cells transcytose particulate antigens to antigen-presenting macrophages located at the basal surface of the epithelium [233; 234]. Macrophages are the first phagocytic cells to interact with microorganisms that have entered the intestinal mucosa. Intestinal macrophages have avid phagocytic and bactericidal activities that protect the host from pathogenic organisms and they regulate the immune response to commensal bacteria. Antigen-presenting DC survey the microenvironment by extending processes between gut epithelial cells. They sample both commensal and pathogenic microbes for subsequent transport and presentation to B and T lymphocytes in the spleen and lymph nodes [235; 236]. Cells of the efferent compartment are diffusely scattered throughout the epithelium and lamina propria of the intestine. In addition to CTL, IFN-γ-producing lymphoctyes and IgG/IgAsecreting plasma cells, antibody-dependent cytotoxicity may also play an important role in the adaptive immune response [228; 237-239]. Together, this defense system consisting of the innate immune system, the epithelial barrier and its associated mucous layer and the adaptive immune system, can effectively prevent or restrict the entry and propagation of commensal and pathogenic organisms, including HIV-1 [240].
Recently, in North America, there has been a dramatic increase in inflammatory bowel disease in the absence of overt microbial infection [229]. This finding suggests that some, as yet unknown factor, is perturbing the balance between the normal microflora of the gut and host immunity. It will be important to determine whether this change is due to the use of antibiotics and a treatment-associated reduction in commensal flora. It has been suggested that, under normal homeostatic conditions, the anti-inflammatory responses induced by commensal flora protect the intestinal epithelium from pathogenic insults [241; 242].
This relationship, however, appears to extremely delicate and anything that perturbs either immune or epithelial homeostasis can lead to inflammation and life-long inflammatory conditions such as Crohn’s disease and ulcerative colitis. Patients afflicted by this disease suffer from chronic diarrhea, weight loss and fatigue, in addition to other potential complications such as skin ulcers, arthritis and bile-duct inflammation [243].
HIV-1-associated enteropathy is a poorly-defined clinical condition in which chronic diarrhea, malabsorption and wasting occurs in the absence of a detectable enteric pathogen [228; 244]. Whether this condition is due to subclinical enteric infections, chronic inflammation or direct effects of HIV-1 on the epithelium of the GIT remain to be established. Although there is little evidence that HIV-1 infects enterocytes, various histological studies have reported that the intestinal mucosa of HIV-1-infected persons is characterized by chronic inflammation, villous atrophy, crypt hyperplasia, nuclear enlargement and apoptosis. It has also been reported that jejunal enterocytes have an over-developed smooth endoplasmic reticulum and decreased levels of mitochondria [245-247]. In vitro studies, performed on duodenal biopsies have shown that HIV-1-infected patients with diarrhea have decreased transepithelial resistance when compared to patients without diarrhea [248]. At the molecular level, the binding of gp120 to receptors on the basal surface of epithelial cells has been shown to cause decreased acetylation of tubulin, microtubular depolymerization and cytoskeletal rearrangements, changes that result in increased intestinal permeability, increased levels of intracellular calcium and diarrhea [249]. Other studies have reported that HIV-1 infection is associated with degenerative changes in the enteric nerves and in the vasculature of the lamina propria [250; 251] and that the protease inhibitors, saquinavir, ritonavir and nelfinavir (but not indinavir) cause damage the epithelial barrier [252]. Studies showing massive depletion of CD4+ T cells in the GALT during the first few weeks of infection have suggested that this loss in helper T cell function together with the damage caused to the epithelium may alter the antimicrobial properties of the gut allowing for the increased translocation of luminal microbes and microbial products [175; 179].
CHAPTER 1 LITERATURE REVIEW
CHAPTER2 CLINICAL PATHOLOGY OF THE KIDNEYS IN BABESIOSIS2 MATERIALS AND METHODS
CHAPTER 3 DIFFERENTIAL DISTRIBUTION AND EVOLUTION OF HIV-1 RNA VARIANTS IN THE GASTROINTESTINAL TRACT OF ANTIRETROVIRAL NAÏVE AFRICAN AIDS PATIENTS WITH DIARRHEA AND (OR) WEIGHT LOSS
CHAPTER 4 DIFFERENCES IN HIV-1 REPLICATION AND IMMUNE ACTIVATION IN THE THERAPEUTIC RESPONSE OF HIV-1 IN THE SMALL vs. LARGE INTESTINE
CHAPTER 5 CONCLUSIONS AND PERSPECTIVES FOR ENHANCED THERAPEUTIC STRATEGIES AND THE PREVENTION OF DISEASE PROGRESSION
