HIV enteropathy and 'Slim disease': Historical and current perspectives.

OBJECTIVES: Chronic diarrhoea and severe wasting associated with HIV infection were first described in East African patients as slim disease (SD) in 1985. The main histological features are flattening of the villi (villous atrophy) and crypt hyperplasia (elongated crypts), i.e., HIV enteropathy (HIVE). Selective loss of mucosal clusters of differentiation 4 (CD4)+ T helper (Th)17+ lymphocytes is the immunological hallmark of HIVE. This review explores (i) the historical background of HIVE and SD, (ii) the relationship between gut mucosal CD4+ Th17+ and intestinal-resident intra-epithelial gamma delta (IRIE) T lymphocytes in pathogenesis of HIVE, (iii) the role of cytokines in regulation of intestinal epithelial proliferation, and (iv) the role of antiretroviral therapy in HIVE. METHODS: Recent studies have highlighted the role of IRIE T lymphocytes, mostly CD8+, in regulating gut epithelial regeneration. CD4+Th17+ and IRIE T cells are necessary to maintain intestinal barrier integrity and mucosal antimicrobial immune defence. However, the immunological cross-talk between such lymphocyte sub-sets culminating in HIVE is uncertain. We undertook a narrative literature review under the headings 'HIVE', 'SD', and 'Highly active antiretroviral therapy (HAART). Relevant studies were located using the electronic search engines Google Scholar and PubMed from 1984 to 2022. RESULTS: Depletion of Th17+ cells in the lamina propria, attributed to low-level viraemia, is accompanied by concomitant increase in the density of gut mucosal IRIE T lymphocytes in AIDS. The latter express a broad range of cytokines (interferon-gamma, tumor necrosis factor-alpha, interleukin-17) and chemokines e.g., keratinocyte growth factor, post exposure to HIV-infected cells. Keratinocyte growth factor induces epithelial proliferation mainly in the crypts, leading to functional immaturity of enterocytes, reduced gut absorptive surface area and malabsorption in animal experiments. Of note, the absence of IRIE T cells is associated with a reduction in epithelial cell turnover. Patients with HIVE receiving early HAART show enhanced expression of mucosal repair genes and improvement of gut symptoms. CONCLUSION: Multiple lines of enquiry suggest HIVE is directly related to HIV infection and is a consequence of perturbations in mucosal CD4+Th17+ and IRIE T lymphocytes. The pathological result is enterocyte immaturity and dysfunction. SD whose main features are malabsorption, diarrhoea and weight loss, is a severe clinical expression of HIVE. A better understanding of immuno-pathogenesis of HIVE opens a window of opportunity for the potential use of immunotherapy in HIV disease and other T cell-mediated enteropathies.

Marked Enteropathy in an Accelerated Macaque Model of AIDS.

Enteropathy in HIV infection is not eliminated with combination antiretroviral therapy and is possibly linked to microbial translocation. We used a rapidly progressing SIV/pigtailed macaque model of HIV to examine enteropathy and microbial translocation. Histologic evidence of intestinal disease was observed in only half of infected macaques during late-stage infection (LSI). Combination antiretroviral therapy initiated during acute infection prevented intestinal disease. In the ileum and colon, enteropathy was associated with increased caspase-3 staining, decreased CD3+ T cells, and increased SIV-infected cells. CD3+ T cells were preserved in LSI animals without intestinal disease, and levels of CD3 staining in all LSI animals strongly correlated with the number of infected cells in the intestine and plasma viral load. Unexpectedly, there was little evidence of microbial translocation as measured by soluble CD14, soluble CD163, lipopolysaccharide binding protein, and microbial 16s ribosomal DNA. Loss of epithelial integrity indicated by loss of the tight junction protein claudin-3 was not observed during acute infection despite significantly fewer T cells. Claudin-3 was reduced in LSI animals with severe intestinal disease but did not correlate with increased microbial translocation. LSI animals that did not develop intestinal disease had increased T-cell intracytoplasmic antigen 1-positive cytotoxic T lymphocytes, suggesting a robust adaptive cytotoxic T-lymphocyte response may, in part, confer resilience to SIV-induced intestinal damage.

HIV enteropathy: HAART reduces HIV-induced stem cell hyperproliferation and crypt hypertrophy to normal in jejunal mucosa.

OBJECTIVE: To analyse the structural and kinetic response of small intestinal crypt epithelial cells including stem cells to highly active antiretroviral therapy (HAART). DESIGN: Crypt size and proliferative activity of transit and stem cells in jejunal mucosa were quantified using morphometric techniques. METHODS: Crypt length was measured by counting the number of enterocytes along one side of a number of crypts in each biopsy specimen and the mean crypt length was calculated. Proliferating crypt cells were identified with MIB-1 monoclonal antibody, and the percentage of crypt cells in proliferation was calculated at each cell position along the length of the crypt (proliferation index). Data were obtained from 9 HIV-positive test patients co-infected with microsporidia, 34 HIV-positive patients receiving HAART and 13 control cases. RESULTS: Crypt length was significantly greater in test patients than in controls, but crypt length in patients receiving HAART was normal. The proliferation index was greater in test subjects than in controls in stem and transit cell compartments, and was decreased in patients treated with HAART only in the stem cell region of the crypt. CONCLUSIONS: Villous atrophy in HIV enteropathy is attributed to crypt hypertrophy and encroachment of crypt cells onto villi. HAART restores normal crypt structure by inhibition of HIV-driven stem cell hyperproliferation at the crypt bases.

HIV infection and the gastrointestinal immune system.

There has recently been a resurgence of interest in the gastrointestinal pathology observed in patients infected with HIV. The gastrointestinal tract is a major site of HIV replication, which results in massive depletion of lamina propria CD4 T cells during acute infection. Highly active antiretroviral therapy leads to incomplete suppression of viral replication and substantially delayed and only partial restoration of gastrointestinal CD4 T cells. The gastrointestinal pathology associated with HIV infection comprises significant enteropathy with increased levels of inflammation and decreased levels of mucosal repair and regeneration. Assessment of gut mucosal immune system has provided novel directions for therapeutic interventions that modify the consequences of acute HIV infection.

HIV enteropathy: crypt stem and transit cell hyperproliferation induces villous atrophy in HIV/Microsporidia-infected jejunal mucosa.

OBJECTIVES: The study aim was to analyse the kinetics of stem and transit cells in the crypts of jejunal mucosa infected with HIV and Microsporidia. DESIGN: The size of villi, depth of crypts and proliferative activity of transit and stem cells in jejunal mucosa were measured using morphometric techniques. METHODS: The surface area/volume ratio (S/V) of jejunal biopsies was estimated under light microscopy using a Weibel graticule. Crypt length was measured by counting enterocytes along the crypt side from the base to the villus junction, and the mean crypt length was calculated. The S/V and crypt lengths of the jejunal mucosa of 21 HIV and Microsporidia-infected test cases were compared with 14 control cases. The labelling index in relation to the crypt cell position of 10 of the test cases was analysed compared with 13 control cases. RESULTS: Differences were found in the S/V and crypt length, and there was a negative correlation between S/V and crypt length in test and control cases combined. Cell labelling indices fell into low and high proliferation groups. There were significant differences in labelling indices between low proliferation test cases and controls, between high proliferation test cases and controls, and between high and low proliferation test cases. CONCLUSION: Villous atrophy induced by HIV and Microsporidia is attributed to crypt cell hyperplasia and the encroachment of crypt cells onto villi. These infections induce crypt hypertrophy by stimulating cell mitosis predominantly in transit cells but also in stem cells. Increased stem cell proliferation occurs only in high proliferation cases.

The virotoxin model of HIV-1 enteropathy: involvement of GPR15/Bob and galactosylceramide in the cytopathic effects induced by HIV-1 gp120 in the HT-29-D4 intestinal cell line.

BACKGROUND: Malabsorption and diarrhea are common, serious problems in AIDS patients, and are in part due to the incompletely understood entity HIV enteropathy. Our prior in vitro work has shown that increased transepithelial permeability and glucose malabsorption, similar to HIV enteropathy, are caused by HIV surface protein gp120, although the mechanism remains unclear. RESULTS: We studied the effects of HIV surface protein gp120 on the differentiated intestinal cell line HT-29-D4, specifically the effects on microtubules, transepithelial resistance, and sodium glucose cotransport. gp120 induced extensive microtubule depolymerization, an 80% decrease in transepithelial resistance, and a 70% decrease in sodium-dependent glucose transport, changes closely paralleling those of HIV enteropathy. The effects on transepithelial resistance were used to study potential inhibitors. Neutralizing antibodies to GPR15/Bob but not to CXCR4 (the coreceptor allowing infection with these HIV strains) inhibited these effects. Antibodies to galactosylceramide (GalCer) and a synthetic analog of GalCer also inhibited the gp120-induced changes, suggesting the involvement of GalCer-enriched lipid rafts in gp120 binding to intestinal epithelial cells. CONCLUSION: We conclude that direct HIV infection and gp120-induced cytopathic effects are distinct phenomena. While in vivo confirmation is needed to prove this, gp120 could be a virotoxin significantly contributing to HIV enteropathy.

Gastrointestinal mucosal biopsy in HIV disease and AIDS.

The role of the gastroenterologist as consultant for patients with HIV infection is reviewed, with a particular focus on when endoscopy with biopsy may be helpful in the diagnostic evaluation. Suggestions on where to biopsy, how to collect samples, and what pathologies might be anticipated are included. In the clinical setting of new antiviral therapies, there has been a dramatic change in the etiologic factors for common presentations such as diarrhea. A review of suspect infections and malignancies is included.

A prospective study of endoscopy in HIV-associated diarrhea.

OBJECTIVE: Diarrhea commonly occurs in persons with human immunodeficiency virus (HIV) infection. The optimal use of endoscopic procedures remains poorly studied for patients with HIV-related diarrhea. The purpose of this study is to compare the diagnostic yield of a complete endoscopic work-up including an esophagogastroduodenoscopy and colonoscopy to a more limited approach of biopsies obtainable by flexible sigmoidoscopy. METHODS: A prospective study of 79 patients with HIV-related diarrhea. Upper endoscopy and colonoscopy were performed with tissue biopsies labelled according to location within the colon or small intestine. RESULTS: A new infection was diagnosed in 22 of 79 patients (28%). Biopsy of the left colon yielded an enteric pathogen in 17 of 22 patients (sensitivity: 77%) and in 15 of 15 patients with cytomegalovirus colitis (sensitivity: 100%). Combined left and right colonic biopsies had a sensitivity of 82%. Combined colonic and terminal ileum biopsies missed no pathogens. Duodenal biopsies yielded no additional pathogens beyond those identified by colonoscopy and terminal ileal biopsy. Patients with a new pathogen diagnosed had significantly lower CD4 lymphocyte counts as compared to patients without a new pathogen (p = 0.001). CONCLUSIONS: For patients with CD4 counts < 100/mm3 and unexplained AIDS-related diarrhea, flexible sigmoidoscopy with biopsy is a sufficiently thorough endoscopic evaluation.

HIV enteropathy: comparative morphometry of the jejunal mucosa of HIV infected patients resident in the United Kingdom and Uganda.

AIMS: To compare jejunal mucosal morphometry in HIV infected patients resident in London and Uganda. PATIENTS: Twenty HIV positive patients from London and 16 from Uganda were studied, and compared with HIV negative control subjects from both sites. METHODS: Stools and biopsy specimens were examined for enteropathogens. Surface area to volume (S:V) ratio was estimated morphometrically, mean crypt length of jejunal biopsy specimens was measured, and HIV infected cells detected immunohistochemically were quantified. RESULTS: Enteric pathogens were detected in none of the London patients, and in three Ugandan patients. S:V ratio was lower, and mean crypt length higher, in the specimens of London patients than in normal subjects, but there was no difference in S:V ratio or mean crypt length between Ugandan patients and controls. A negative correlation was present between S:V ratio and mean crypt length in all biopsy specimens analysed. HIV infected cells were detected only in lamina propria. CONCLUSION: Infection of cells in the lamina propria of the jejunum with HIV stimulates crypt cell proliferation, and a fall in villous surface area. The mucosal response to HIV is masked by other pathogens in the African environment.

Comparison of duodenal with jejunal biopsy and aspirate in chronic human immunodeficiency virus-related diarrhea.

OBJECTIVES: In human immunodeficiency virus (HIV)-infected patients with chronic unexplained diarrhea, upper endoscopy with small bowel biopsy and aspirate is often performed to identify treatable pathogens. The purpose of this study was to compare the diagnostic yield of duodenal with jejunal biopsy and aspirate. METHODS: All HIV-infected patients with chronic unexplained diarrhea who were evaluated by upper endoscopy at Bellevue Hospital Center between January 1992 and January 1997 were identified. Data were collected by reviewing patient charts, endoscopy reports, and pathology records. RESULTS: During the 5-yr study period, 442 patients underwent upper endoscopy with sampling of the duodenum (N=173) or jejunum (N=269). A pathogen was identified in 123 patients (27.8%). Microsporidia was the most common organism detected (12.2%). The diagnostic yield of jejunal biopsy and aspirate was significantly higher than that obtained from the duodenum (32.3% vs 20.8%, p=0.009). Small bowel aspirates detected a pathogen in only 1.8% of patients evaluated, and there was no difference in the yield of duodenal and jejunal aspirates (1.3% vs 2.1%, p=0.7). Patients with a CD4 count of < 100 cells/mm3 were significantly more likely to have a pathogen identified than those with higher CD4 counts (38.8% vs 7.1%,p < 0.0001). CONCLUSIONS: Upper endoscopy with small bowel biopsy and aspirate identifies a pathogen in 27.8% of individuals with HIV-related chronic unexplained diarrhea. In this patient population, jejunal biopsies acquired by enteroscopy are superior to those obtained from the duodenum. Small bowel aspirates are of little value in the workup of chronic HIV-related diarrhea.

[Intestinal diseases in HIV infection]. / Darmerkrankungen bei HIV-Infektion.

The gastrointestinal tract is very frequently affected by the manifestations of the acquired immunodeficiency syndrome (AIDS). A variety of opportunistic viral, fungal, bacterial, protozoal and helmintic infections and different unusual malignancies such as Kaposi's sarcoma, non-Hodgkin's lymphoma and papilloma-virus associated anal cancer are responsible for much of the morbidity and mortality in AIDS. Because specific therapy is not always available, in particular diagnosis of potentially infections should be attempted.

Gastrointestinal pathology in HIV-infected patients.

Specific pathologic processes, particularly oral, esophageal, and intestinal infections, are common in the alimentary tract of AIDS patients. Many of these diseases are adequately assessed only by biopsy with histologic examination. Most are rare or unreported in immunocompetent hosts and are easily missed by those not familiar with them. This article describes the gross or endoscopic and histologic appearances and the diagnostic criteria for enteric pathologic processes seen in HIV-infected individuals.

Morphological injury of the intestinal mucosa and infection in patients with AIDS. The role of combined tissue and stool examination.

AIMS: To define the relationship between morphological injury of the intestinal mucosa and infections in AIDS patients. METHODS: Forty-nine AIDS patients were examined by upper gastrointestinal (GI) endoscopy and 8 of them also by lower GI endoscopy. Biopsy specimens, taken from the lower duodenum, esophagus and rectum, were studied by light (L.M.) and transmission electron microscopy (T.E.M.). Stool examination for microorganisms was routinely performed in all patients. RESULTS: Microorganisms were detected in 37 of the 49 patients (75.5%) by combined tissue and stool examination. The histological study revealed villous atrophy, inter- and intra-enterocyte oedema and epithelial degenerative changes in most of the patients whether or not they had detectable microorganisms. CONCLUSIONS: Combined methods (endoscopy, L.M. and T.E.M., studies of tissue samples, microbiological study of stool samples) may be used to improve the documentation of infections and morphological injury of the intestinal mucosa in AIDS patients.

Diagnosis and management of AIDS-related diarrhea.

The spectrum of illness associated with the acquired immunodeficiency syndrome (AIDS) has been increasing since the initial description in 1981. While virtually all organ systems may be affected, the gastrointestinal tract appears to be a major target. Diarrhea is the most common symptom, affecting up to half of all AIDS patients during the course of their disease. Although diarrhea occurs frequently, its optimal management remains controversial. An extensive evaluation including stool studies and endoscopic biopsies of both the colon and small intestine has been widely recommended to identify all potential pathogenic organisms. An alternative approach is a more limited evaluation consisting of stool and blood cultures followed by symptomatic treatment with antidiarrheal agents if no specific organisms are identified. The clinical presentation of the most common opportunistic pathogens are reviewed, including several recently discovered organisms. Recommendations for treatment are followed by a brief discussion of management strategies used to care for patients with AIDS-related diarrhea.

Uncertain clinical significance of duodenal mucosal abnormalities in HIV-infected individuals. Results of a case-control study.

Previous research has described abnormalities of duodenal mucosal morphology in human immunodeficiency virus (HIV)-infected individuals. We wanted to determine the frequency of disturbed villus architecture and investigate its relationship to HIV-related chronic diarrhea. We conducted a case-control study of 120 HIV-infected men, 63 with and 57 without chronic diarrhea. Stools were cultured for bacteria and examined for ova and parasites; esophagogastroduodenoscopy and flexible sigmoidoscopy with mucosal biopsies were performed. Biopsy tissue was examined using light and electron microscopy to detect enteric pathogens and to evaluate mucosal morphology. The mean CD4+ cell count was 143/min3, and enteric pathogens were detected in 56 of 120 men (47%). In approximately half the study sample (57%), duodenal villus architecture was normal; complete villus flattening was not observed. We detected no association between chronic diarrhea and altered villus architecture. Although further study is needed to clarify the pathogenesis of altered duodenal mucosal morphology, our results suggest that the clinical significance of the abnormalities may be small.