Abstract
HIV infection in the human gastrointestinal (GI) tract is thought to be central to HIV progression, but knowledge of this interaction is primarily limited to cohorts within Westernized countries. Here, we present a large cohort recruited from high HIV endemic areas in South Africa and found that people living with HIV (PLWH) presented at a younger age for investigation in the GI clinic. We identified severe CD4+ T cell depletion in the GI tract, which was greater in the small intestine than in the large intestine and not correlated with years on antiretroviral treatment (ART) or plasma viremia. HIV-p24 staining showed persistent viral expression, particularly in the colon, despite full suppression of plasma viremia. Quantification of mucosal antiretroviral (ARV) drugs revealed no differences in drug penetration between the duodenum and colon. Plasma markers of gut barrier breakdown and immune activation were elevated irrespective of HIV, but peripheral T cell activation was inversely correlated with loss of gut CD4+ T cells in PLWH alone. T cell activation is a strong predictor of HIV progression and independent of plasma viral load, implying that the irreversible loss of GI CD4+ T cells is a key event in the HIV pathogenesis of PLWH in South Africa, yet the underlying mechanisms remain unknown.
Highlights
HIV-1 associated alterations within the gastrointestinal (GI) tract were first described in 1984 by Kotler and colleagues, who reported histologic abnormalities in the GI mucosa of infected patients (1, 2)
CD4 T-cell frequency in the gut of people living with HIV (PLWH) was inversely correlated with activation of circulating T-cells, a biomarker which correlates strongly with HIV disease progression (55). This was not observed in HIV uninfected indivduals, despite elevated levels of plasma markers of innate immune activation and increased gut barrier permeability, such as soluble CD14 (sCD14) or intestinal fatty acid-binding protein (I-FABP), respectively
We cannot rule out that sustained GI tract damage and microbial translocation may contribute to persistent systemic immune activation. This is the largest study of GI participants recruited within a high HIV prevalence area in Sub-Saharan Africa and unequivocally identifies the lack of immune reconstitution throughout the intestinal mucosa as a persistent problem in PLWH despite long-term antiretroviral treatment (ART). 383 this study was not powered to determine differences in clinical presentation in 384 PLWH, we observed a significant increase in biliary pathologies in this group
Summary
HIV-1 associated alterations within the gastrointestinal (GI) tract were first described in 1984 by Kotler and colleagues, who reported histologic abnormalities in the GI mucosa of infected patients (1, 2). ART initiation during early acute HIV-1 infection reduces immune activation and limits reservoir size, but does not appear to prevent its formation or lead to its eradication after prolonged treatment (26, 28–30) The reasons for these are not clear, but may include sub-optimal ARV drug penetration into the gut mucosa (14, 27, 31, 32). Plasma markers of systemic immune activiation, were elevated in all study participants and did not correlate with GI CD4 T-cell levels, suggesting these biomarkers are not directly linked to HIV pathology per se This cohort represent a large and unique resource to further study intestinal health and HIV reservoir dynamics in PLWH from areas of rural Sub-Saharan Africa, which sits at the center of the global HIV epidemic
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