Biology subjects

Landay, A. L.

Publications and source records attributed to Landay, A. L..

5 recordsLinked to original sources

bioRxiv2026

Senescence-associated loss of intestinal α1,2-fucose disrupts a modifiable host-microbiome homeostasis axis in people with HIV

BackgroundPeople with HIV (PWH), despite effective antiretroviral therapy (ART), experience disrupted intestinal homeostasis characterized by microbial dysbiosis and impaired intestinal barrier integrity, which contribute to chronic inflammation and aging-associated comorbidities. However, tractable mechanisms contributing to this dysfunction remain poorly defined. ObjectiveTo determine whether acquired loss of intestinal 1,2-fucose, a host-derived intrinsic prebiotic glycan that supports colonization by short-chain fatty acid (SCFA)-producing bacteria essential for intestinal barrier integrity, contributes to microbiome disruption, impaired epithelial resilience, inflammation, and biological aging in PWH. DesignIleal and colonic biopsies, isolated crypts, stool, and blood from PWH on ART and controls underwent multi-omic analyses. Findings were mechanistically interrogated using stool anaerobic fermentation assays and 3D intestinal organoid models of stress-mediated epithelial disruption. ResultsIn intestinal tissues, PWH exhibited reduced 1,2-fucosylation and increased senescence-associated expression of the fucose-degrading enzyme -L-fucosidase. Lower 1,2-fucose tracked with depletion of SCFA-producing bacteria, increased inflammation, and premature biological aging. In anaerobic fermentations, stool from PWH produced fewer SCFAs than controls, whereas supplementation with the human-milk-oligosaccharide-derived 1,2-fucose donor 2'-fucosyllactose restored SCFA production and improved intestinal organoid resilience to stress-mediated disruption. ConclusionThese findings identify acquired loss of intestinal 1,2-fucose as a modifiable host-microbiome mechanism linking epithelial senescence, microbial metabolic dysfunction, impaired barrier resilience, inflammation, and biological aging in treated HIV infection. SUMMARY BOXO_ST_ABSWhat is already known on this topicC_ST_ABSPeople with HIV on suppressive antiretroviral therapy frequently have persistent intestinal barrier dysfunction, microbial dysbiosis, chronic inflammation, and accelerated biological aging, but the host mechanisms that maintain this disrupted mucosal state remain incompletely defined. What this study addsThis study identifies acquired loss of intestinal 1,2-fucosylation as a feature of treated HIV infection and links this defect to a host fucosidase-high, senescence-enriched mucosal niche, depletion of SCFA-producing bacteria, impaired tight junction-associated barrier signatures, inflammation, and biological aging phenotypes. How this study might affect research, practice or policyThese findings support intestinal glycan ecology as a modifiable host-microbiome axis and provide a rationale for testing 1,2-fucose-replenishing strategies, such as 2'-fucosyllactose, to restore microbial metabolic output and improve epithelial resilience in people with HIV.

microbiology↗

bioRxiv2023

A Blood Immunological Signature of Subclinical Coronary Artery Atherosclerosis in People Living with HIV-1 Receiving Antiretroviral Therapy

Cardiovascular disease (CVD) remains an important co-morbidity in people living with HIV-1 (PLWH) receiving antiretroviral therapy (ART). Our previous studies performed on the Canadian HIV/Aging Cohort Study (CHACS) (>40 years-old; Framingham Risk Score (FRS) >5%), revealed a 2-3-fold increase in non-calcified coronary artery atherosclerosis (CAA) plaque burden, measured by Computed tomography angiography scan (CTAScan) as total (TPV) and low attenuated plaque volume (LAPV) in ART-treated PLWH (HIV+) versus uninfected controls (HIV-). In an effort to identify novel correlates of subclinical CAA, markers of intestinal damage (sCD14, LBP, FABP2); cell trafficking/inflammation (CCL20, CX3CL1, MIF, CCL25); subsets of Th17-polarized and regulatory (Tregs) CD4+ T-cells, classical/intermediate/non-classical monocytes, and myeloid/plasmacytoid dendritic cells, were studied in relationship with HIV and TPV/LAPV status. The TPV detection/values coincided with higher plasma sCD14, FABP2, CCL20, MIF, CX3CL1 and triglyceride levels, lower Th17/Treg ratios, and classical monocyte expansion. Among HIV+, TPV+ versus TPV- exhibited lower Th17 frequencies, reduced Th17/Treg ratios, higher frequencies of non-classical CCR9lowHLADRhigh monocyte, and increased plasma fibrinogen levels. Finally, Th17/Treg ratios and non-classical CCR9lowHLADRhigh monocyte frequencies remained associated with TPV/LAPV after adjusting for FRS and HIV/ART duration in a logistic regression model. These findings point to Th17 paucity and non-classical monocyte abundance as novel immunological correlates of subclinical CAA that may fuel the CVD risk in ART-treated PLWH.

immunology↗

bioRxiv2021

COVID-19 Severity Is Associated with Differential Antibody Fc-mediated Innate Immune Functions

Beyond neutralization, antibodies elicit several innate immune functions including complement deposition (ADCD), phagocytosis (ADCP), and cytotoxicity (ADCC). These functions can be both beneficial (by clearing pathogens) and/or detrimental (by inducing inflammation). We tested the possibility that qualitative differences in SARS-CoV-2 specific antibody-mediated innate immune functions contribute to Coronavirus disease 2019 (COVID-19) severity. We found that antibodies from hospitalized COVID-19 patients elicited higher ADCD but lower ADCP compared to antibodies from non-hospitalized COVID-19 patients. Consistently, higher ADCD was associated with higher systemic inflammation during COVID-19. Our study points to qualitative, differential features of anti-SARS-CoV-2 antibodies as potential contributors to COVID-19 severity.

microbiology↗

bioRxiv2020

Phospholipid Metabolism Is Associated with HIV Rebound Upon Treatment Interruption

Lipids are biologically active molecules involved in a variety of cellular processes and immunological functions, including inflammation. It was recently shown that phospholipids and their derivatives, lysophospholipids, can reactivate latent (dormant) tumor cells, causing cancer recurrence. However, the potential link between lipids and HIV latency, persistence, and viral rebound after cessation of antiretroviral therapy (ART) has never been investigated. We explored the links between plasma lipids and the burden of HIV during ART. We profiled the circulating lipidome from the plasma of 24 chronically HIV-infected individuals on suppressive ART who subsequently underwent an analytic treatment interruption (ATI) without concurrent immunotherapies. The pre-ATI viral burden was estimated as time-to-viral-rebound and viral load setpoints post-ATI. We found that higher pre-ATI levels of lysophospholipids, including the pro-inflammatory lysophosphatidylcholine, were associated with faster time-to-viral-rebound and higher viral setpoints upon ART cessation. Furthermore, higher pre-ATI levels of the pro-inflammatory byproduct of intestinal lysophosphatidylcholine metabolism, trimethylamine-N-oxide (TMAO), were also linked to faster viral rebound post-ART. Finally, pre-ATI levels of several phosphatidylcholine species (lysophosphatidylcholine precursors) correlated strongly with higher pre-ATI levels of HIV DNA in peripheral CD4+ T cells. Our proof-of-concept data point to phospholipids and lysophospholipids as plausible pro-inflammatory contributors to HIV persistence and rapid post-ART HIV rebound. The potential interplay between phospholipid metabolism and both the establishment and maintenance of HIV latent reservoirs during- and post-ART warrants further investigation. IMPORTANCEThe likelihood of HIV rebound after stopping antiretroviral therapy (ART) is a function of the interplay between the size of HIV reservoirs that persist despite ART and the host immunological and inflammatory factors that modulate these reservoirs. There is a need to comprehensively understand these host factors to develop a strategy to cure HIV infection and prevent viral rebound post-ART. Lipids are important biologically active molecules that are known to mediate several cellular functions, including reactivating latent tumor cells; however, their role in HIV latency, persistence, and post-ART rebound has never been investigated. We observed significant links between higher levels of the pro-inflammatory lysophosphatidylcholine and its intestinal metabolic byproduct, trimethylamine-N-oxide, and both faster time-to-viral rebound and higher viral load setpoint post ART. These data highlight the need for further studies to understand the potential contribution of phosphatidylcholine and lysophosphatidylcholine metabolism in shaping host immunological and inflammatory milieu during- and post-ART.

microbiology↗

bioRxiv2020

Combined protein and transcript single cell RNA sequencing reveals cardiovascular disease and HIV signatures

Cryopreserved peripheral blood mononuclear cells (PBMCs) are frequently collected and provide disease- and treatment-relevant data in clinical studies. Here, we developed combined protein (40 antibodies) and transcript single cell (sc)RNA sequencing in PBMCs. Among 31 participants in the WIHS Study, we sequenced 41,611 cells. Using Boolean gating followed by Seurat UMAPs and Louvain clustering, we identified 58 subsets among CD4 T, CD8 T, B, NK cells and monocytes. This resolution was superior to flow cytometry, mass cytometry or scRNA-sequencing without antibodies. Since the transcriptome was not needed for cell identification, combined protein and transcript scRNA-Seq allowed for the assessment of disease-related changes in transcriptomes and cell type proportion. As a proof-of-concept, we showed such differences between healthy and matched individuals living with HIV with and without cardiovascular disease. In conclusion, combined protein and transcript scRNA sequencing is a suitable and powerful method for clinical investigations using PBMCs.

immunology↗