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Effective antiretroviral therapy (ART) dramatically reduces AIDS-related complications, yet the life expectancy of long-term ART-treated HIV-infected patients remains shortened compared to that of uninfected controls, due to increased risk of non-AIDS related morbidities. Many propose that these complications result from translocated microbial products from the gut that stimulate systemic inflammation--a consequence of increased intestinal paracellular permeability that persists in this population. Concurrent intestinal immunodeficiency and structural barrier deterioration are postulated to drive microbial translocation, and direct evidence of intestinal epithelial breakdown has been reported in untreated pathogenic SIV infection of rhesus macaques. To assess and characterize the extent of epithelial cell damage in virally-suppressed HIV-infected patients, we analyzed intestinal biopsy tissues for changes in the epithelium at the cellular and molecular level. The intestinal epithelium in the HIV gut is grossly intact, exhibiting no decreases in the relative abundance and packing of intestinal epithelial cells. We found no evidence for structural and subcellular localization changes in intestinal epithelial tight junctions (TJ), but observed significant decreases in the colonic, but not terminal ileal, transcript levels of TJ components in the HIV+ cohort. This result is confirmed by a reduction in TJ proteins in the descending colon of HIV+ patients. In the HIV+ cohort, colonic TJ transcript levels progressively decreased along the proximal-to-distal axis. In contrast, expression levels of the same TJ transcripts stayed unchanged, or progressively increased, from the proximal-to-distal gut in the healthy controls. Non-TJ intestinal epithelial cell-specific mRNAs reveal differing patterns of HIV-associated transcriptional alteration, arguing for an overall change in intestinal epithelial transcriptional regulation in the HIV colon. These findings suggest that persistent intestinal epithelial dysregulation involving a reduction in TJ expression is a mechanism driving increases in colonic permeability and microbial translocation in the ART-treated HIV-infected patient, and a possible immunopathogenic factor for non-AIDS related complications.

INTRODUCTION While there may be microbial contributions to Alzheimer's disease (AD), findings have been inconclusive. We recently reported an AD‐associated CD83(+) microglia subtype associated with increased immunoglobulin G4 (IgG4) in the transverse colon (TC). METHODS We used immunohistochemistry (IHC), IgG4 repertoire profiling, and brain organoid experiments to explore this association. RESULTS CD83(+) microglia in the superior frontal gyrus (SFG) are associated with elevated IgG4 and human cytomegalovirus (HCMV) in the TC, anti‐HCMV IgG4 in cerebrospinal fluid, and both HCMV and IgG4 in the SFG and vagal nerve. This association was replicated in an independent AD cohort. HCMV‐infected cerebral organoids showed accelerated AD pathophysiological features (Aβ42 and pTau‐212) and neuronal death. DISCUSSION Findings indicate complex, cross‐tissue interactions between HCMV and the adaptive immune response associated with CD83(+) microglia in persons with AD. This may indicate an opportunity for antiviral therapy in persons with AD and biomarker evidence of HCMV, IgG4, or CD83(+) microglia. Highlights Cross‐tissue interaction between HCMV and the adaptive immune response in a subset of persons with AD. Presence of CD83(+) microglial associated with IgG4 and HCMV in the gut. CD83(+) microglia are also associated presence of HCMV and IgG4 in the cortex and vagal nerve. Replication of key association in an independent cohort of AD subjects. HCMV infection of cerebral organoids accelerates the production of AD neuropathological features.