HIV enteropathy (HIVE) and Slim disease (SD): historical and current perspectives.

INTRODUCTION: Chronic diarrhoea and severe wasting associated with HIV infection were first described in East African patients as SD in 1985. The main histological features are flattening of the villi (villous atrophy) and crypt hyperplasia (elongated crypts), i.e. HIVE. Selective loss of mucosal CD4+Th17+ lymphocytes is the immunological hallmark of HIVE.

AIMS AND METHODS: Recent studies have highlighted the role of intestinal-resident intra-epithelial gamma delta (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. The aims of the review are to explore (i) the historical background of HIVE and SD; (ii) the relationship between gut mucosal CD4+ Th17+ and IRIE T lymphocytes in pathogenesis of HIVE; (iii) the role of cytokines in regulation of intestinal epithelial proliferation; (iv) the role of antiretroviral therapy in HIVE.

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 (IFN-gamma, TNF-alpha, IL-17) and chemokines e.g. keratinocyte growth factor, KGF post exposure to HIV-infected cells. KGF 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.