Autophagy-enhancing ATG16L1 polymorphism is associated with improved clinical outcome and T-cell immunity in chronic HIV-1 infection.

Chronic HIV-1 infection is characterized by T-cell dysregulation that is partly restored by antiretroviral therapy. Autophagy is a critical regulator of T-cell function. Here, we demonstrate a protective role for autophagy in HIV-1 disease pathogenesis. Targeted analysis of genetic variation in core autophagy gene ATG16L1 reveals the previously unidentified rs6861 polymorphism, which correlates functionally with enhanced autophagy and clinically with improved survival of untreated HIV-1-infected individuals. T-cells carrying ATG16L1 rs6861(TT) genotype display improved antiviral immunity, evidenced by increased proliferation, revamped immune responsiveness, and suppressed exhaustion/immunosenescence features. In-depth flow-cytometric and transcriptional profiling reveal T-helper-cell-signatures unique to rs6861(TT) individuals with enriched regulation of pro-inflammatory networks and skewing towards immunoregulatory phenotype. Therapeutic enhancement of autophagy recapitulates the rs6861(TT)-associated T-cell traits in non-carriers. These data underscore the in vivo relevance of autophagy for longer-lasting T-cell-mediated HIV-1 control, with implications towards development of host-directed antivirals targeting autophagy to restore immune function in chronic HIV-1 infection.

CD10 and Das1: a biomarker study using immunohistochemistry to subtype gastric intestinal metaplasia.

BACKGROUND: Intestinal metaplasia (IM) is considered a key pivot point in the Correa model of gastric cancer (GC). It is histologically subtyped into the complete and incomplete subtypes, the latter being associated with a greater risk of progression. However, the clinical utility of IM subtyping remains unclear, partially due to the absence of reliable defining biomarkers. METHODS: Based on gene expression data and existing literature, we selected CD10 and Das1 as candidate biomarkers to distinguish complete and incomplete IM glands in tissues from patients without GC (IM-GC) and patients with GC (IM + GC). Immunohistochemical staining of individually subtyped IM glands was scored after blinding by two researchers using tissue belonging to both IM-GC and IM + GC patients. Whole tissue Das1 staining was further assessed using digital image quantification (cellSens Dimension, Olympus). RESULTS: Across both cohorts CD10 stained the IM brush border and was shown to have a high sensitivity (87.5% and 94.9% in IM-GC and IM + GC patients respectively) and specificity (100.0% and 96.7% respectively) with an overall AUROC of 0.944 for complete IM glands. By contrast Das1 stained mainly goblet cells and the apical membrane of epithelial cells, mostly of incomplete IM glands with a low sensitivity (28.6% and 29.3% in IM-GC and IM + GC patients respectively) but high specificity (98.3% and 85.1% respectively) and an overall AUROC of 0.603 for incomplete IM glands. A combined logistic regression model showed a significant increase in AUROC for detecting complete IM glands (0.955 vs 0.970). Whole tissue digital quantification of Das1 staining showed a significant association with incomplete IM compared to complete IM, both in IM-GC and in IM + GC patients (p = 0.016 and p = 0.009 respectively, Mann-Whitney test and unpaired t test used). Additionally, complete IM in IM + GC patients exhibited significantly more Das1 staining than in IM-GC patients (p = 0.019, Mann-Whitney test). CONCLUSIONS: These findings suggest that CD10 is an outstanding biomarker for complete IM and Das1 may be useful as a secondary biomarker for IM glands at greater risk of progression irrespective of IM subtype. Overall, the clinical use of these biomarkers could lead to improved patient stratification and targeted surveillance.

Premalignant lesions and gastric cancer: Current understanding.

Over the last two decades there has been a broad paradigm shift in our understanding of gastric cancer (GC) and its premalignant states from gross histological models to increasingly precise molecular descriptions. In this review we reflect upon the historic approaches to describing premalignant lesions and GC, highlight the current molecular landscape and how this could inform future risk assessment prevention strategies.

The role of the microenvironment in human immunodeficiency virus-associated classical Hodgkin lymphoma.

AIMS: To characterize the microenvironment of classical Hodgkin lymphoma (cHL) in people living with human immunodeficiency virus (PLWH). The objective was to identify and then quantify the immune cells present in the microenvironment. METHODS AND RESULTS: Ten samples of cHL from PLWH were compared with 10 samples of cHL from the general population using tissue microarray technology and immunohistochemistry. Sections were immunostained with antibodies for CD30, CD3, CD4, CD8, CD20, CD68R, CD56, CD57, CD123, FoxP3 and granzyme B. A statistically significant reduction of CD4(+) T cells, CD56(+) cells, CD57(+) cells, CD123(+) cells and B cells and an increase in numbers in FoxP3(+) CD8(+) cells was observed in cHL diagnosed in PLWH. No significant differences were seen in the number of CD8(+) T cells, CD4(+) FoxP3(+) T cells and macrophages. CONCLUSION: There are considerable differences in the microenvironment of cHL occurring with and without HIV.