Vedolizumab and ART in recent HIV-1 infection unveil the role of α4ß7 in reservoir size.

BACKGROUNDWe evaluated the safety and viral rebound, after analytical treatment interruption (ATI), of vedolizumab and ART in recent HIV-1 infection. We used this model to analyze the effect of α4ß7 on the HIV-1 reservoir size.METHODSParticipants started ART with monthly vedolizumab infusions, and ATI was performed at week 24. Biopsies were obtained from ileum and cecum at baseline and week 24. Vedolizumab levels, HIV-1 reservoir, flow cytometry, and cell-sorting and antibody competition experiments were assayed.RESULTSVedolizumab was safe and well tolerated. No participant achieved undetectable viremia off ART 24 weeks after ATI. Only a modest effect on the time to achieve more than 1,000 HIV-1 RNA copies/mL and the proportion of participants off ART was observed, being higher in the vedolizumab group compared with historical controls. Just before ATI, α4ß7 expression was associated with HIV-1 DNA and RNA in peripheral blood and with PD1 and TIGIT levels. Importantly, a complete blocking of α4ß7 was observed on peripheral CD4+ T cells but not in gut (ileum and cecum), where α4ß7 blockade and vedolizumab levels were inversely associated with HIV-1 DNA.CONCLUSIONOur findings support α4ß7 as an important determinant in HIV-1 reservoir size, suggesting the complete α4ß7 blockade in tissue as a promising tool for HIV-cure combination strategies.TRIAL REGISTRATIONClinicalTrials.gov NCT03577782.FUNDINGThis work was supported by the Instituto de Salud Carlos III (Fondo Europeo de Desarrollo Regional, "a way to make Europe," research contracts FI17/00186 and FI19/00083 and research projects PI18/01532, PI19/01127, PI22/01796), Conserjería de Economía, Conocimiento, Empresas y Universidad, Junta de Andalucía (research projects P20/00906), the Red Temática de Investigación Cooperativa en SIDA (RD16/0025/0020), and the Spanish National Research Council.

Caecum OX40+CD4 T-cell subset associates with mucosal damage and key markers of disease in treated HIV-infection.

BACKGROUND: Blood OX40-expressing CD4 T-cells from antiretroviral (ART)-treated people living with HIV (PWH) were found to be enriched for clonally-expanded HIV sequences, hence contributing to the HIV reservoir. OX40-OX40L is also a checkpoint regulator of inflammation in multiple diseases. We explored gut mucosal OX40+CD4+ T-cells and their potential significance in HIV disease. METHODS: Biopsies of caecum and terminal-ileum of ART-treated PWH (n = 32) were obtained and mucosal damage and HIV reservoir were assessed. Mucosal OX40+ and Ki67+ CD4 T-cell subsets, as well as several tissue T-cell subsets modulating mucosal integrity and homeostasis (Th17, Th22, Treg, Tc17, Tc22, IL17+TCRγδ, IL22+TCRγδ) were quantified. Inflammatory-related markers, T-cell activation and thymic output were also determined in blood samples. Correlations were explored using Spearman rank test and corrected for multiple comparisons by Benjamini-Hochberg. RESULTS: Compared to healthy controls, a high frequency of mucosal, mainly caecum, CD4 T-cells were OX40+ in PWH. Such frequency strongly correlated with nadir CD4 (r = -0.836; p < 0.0001), CD4/CD8 ratio (r = -0.630; p = 0.002), caecum mucosal damage (r = 0.606; p = 0.008), caecum Th22 (r = -0.635; p = 0.002), caecum Th17 (r = 0.474; p = 0.03) and thymic output (r = -0.686; p < 0.001). It also correlated with Neutrophil-to-Lymphocyte Ratio and blood CD4 T-cell activation and tended to with mucosal HIV reservoir. CONCLUSION: High frequencies of caecum OX40+CD4 T-cells are found in people with HIV (PWH) and successful viral control. Interestingly, this cellular subset reflects key markers of disease and peripheral T-cell activation, as well as HIV-driven mucosal damage. OX40+CD4 T-cells deserve further investigation since they could expand because of T-cell homeostatic proliferation and relate to the Th22/Th17 gut mucosal ratio.

Gastroduodenal involvement in patients with familial adenomatous polyposis. Prospective study of the nature and evolution of polyps: evaluation of the treatment and surveillance methods applied.

OBJECTIVES: Analysis of the incidence rate and the evolution of duodenal and stomach polyps in our familial adenomatous polyposis (FAP) patients, the suitability of the surveillance method and the cancer-preventing treatment applied and the analysis of the complications arising from each procedure employed. MATERIALS AND METHODS: Twenty-nine patients diagnosed with FAP underwent study and endoscopic surveillance of the upper digestive tract. Front-view and side-view endoscopies were used. Papillary biopsies were performed even when the papilla were macroscopically normal. The Spigelman classification was used to determine the seriousness of the condition and to establish the surveillance and treatment intervals. RESULTS: Duodenal and/or papillary polyps were presented by 79.3% of the patients. Endoscopic polypectomy was performed in 13 patients with duodenal polyps. Endoscopic polypectomies for the papilla were performed in all patients. One patient required a cephalic duodenopancreatectomy and another endoscopic ampullectomy. The condition did not become cancerous in any of the patients who underwent surveillance. We report two complications arising from treatment: one postpolypectomy haemorrhage and one stenosis of the biliary-enteric anastomosis after cephalic duodenopancreatectomy. CONCLUSION: Our study shows a high incidence rate of duodenal polyps in FAP patients. A minute examination of the duodenum and papilla is necessary, using side-view endoscopes and duodenal papilla biopsies even when papilla appears to be normal. None of the patients having completed the surveillance and the prescribed treatment developed cancer and all have a low Spigelman score. This method, therefore, seems to be adequate for the treatment and surveillance of duodenal polyps.