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Dysfunctional effector memory CD8 T cells in the bronchoalveolar compartment of people living with HIV

ABSTRACT: Mechanisms by which HIV causes susceptibility to respiratory pathogens remain incompletely understood. We obtained whole blood and bronchoalveolar lavage (BAL) from people with latent TB infection in the presence or absence of ARV-naïve HIV co-infection. Transcriptomic and flow cytometric analyses demonstrated HIV-associated cell proliferation and type I interferon activity in blood and effector memory CD8 T-cells in BAL. Both compartments displayed reduced induction of CD8 T cell-related IL-17A in people with HIV, associated with elevated T cell regulatory molecule expression. We propose dysfunctional CD8 T cell responses in uncontrolled HIV contribute to susceptibility to secondary bacterial infections, including tuberculosis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE230738 | GEO | 2024/12/31

REPOSITORIES: GEO

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Dysfunctional effector memory CD8 T cells in the bronchoalveolar compartment of people living with HIV

Project description:Mechanisms by which HIV causes susceptibility to respiratory pathogens remain incompletely understood. We obtained whole blood and bronchoalveolar lavage (BAL) from people with latent TB infection in the presence or absence of ARV-naïve HIV co-infection. Transcriptomic and flow cytometric analyses demonstrated HIV-associated cell proliferation and type I interferon activity in blood and effector memory CD8 T-cells in BAL. Both compartments displayed reduced induction of CD8 T cell-related IL-17A in people with HIV, associated with elevated T cell regulatory molecule expression. We propose dysfunctional CD8 T cell responses in uncontrolled HIV contribute to susceptibility to secondary bacterial infections, including tuberculosis.

2024-12-20 | GSE231628 | GEO

DNA methylation demonstrates bronchoalveolar cell senescence in people living with HIV: An observational cohort study

Project description:Background: Age-related comorbidities remain a burden in People living with HIV (PLWH). DNA methylation may be a link between HIV, aging, and the increased risk of lung comorbidities. Here, we investigate whether bronchoalveolar lavage (BAL) cells of PLWH demonstrate epigenome wide disruptions and advanced epigenetic aging. Methods: BAL cell DNA methylation profiles from 25 PLWH and 16 uninfected controls were tested for differential methylation of transposable elements Alu and LINE-1, a marker of aging. We used a weighted gene correlation network analysis to identify co-methylation networks associated with HIV and age. We tested the effect of HIV on DNA methylation using a robust linear model. An enrichment analysis was conducted to identify differentially methylated pathways (false discovery rate <0.10). Results: The BAL cells of PLWH were marked by global hypomethylation in both Alu and LINE-1 elements. Six co-methylated CpG networks were identified that were significantly associated with age; of these, the red module was significantly differentially methylated in PLWH and enriched pathways associated with HIV, Ras signaling, T cell receptors, and bacterial invasion of epithelial cells. We identified 6,428 differentially methylated sites associated with HIV. Conclusions: We have shown here for the first time that alterations in the DNA methylation of BAL cells (mainly macrophages) in the lung HIV show in a pattern of advanced aging. In conjunction with our findings in blood cells and airway cells, this study strongly support that HIV may contribute to increase the risk of lung comorbidities through the epigenetic regulation of aging.

2024-07-03 | GSE262656 | GEO

Myeloid Dendritic Cells from People Living with HIV have Altered Gene Expression Not Restored by Anti-Retroviral Therapy

Project description:Myeloid dendritic cells (mDC) were isolated from antiretroviral therapy (ARV)-treated and untreated people living with HIV (PLWH), and from HIV uninfected Individuals. The results indicate that mDC are altered in genes expression from PLWH. Some RNA transcriptional changes are not completely restored by ARV. This provides more data on myeloid cells, an understudied cell type, and alterations in PLWH.

2020-01-10 | GSE139559 | GEO

Contrasting inflammatory signatures in peripheral blood and bronchoalveolar cells reveal compartment-specific effects of HIV infection

Project description:The mechanisms by which HIV increases susceptibility to tuberculosis and other respiratory infections are incompletely understood. We used transcriptomics of paired whole bronchoalveolar lavage (BAL) fluid and peripheral blood mononuclear cells to compare the effect of HIV at the lung mucosal surface and in the peripheral blood. The large majority of HIV-induced differentially expressed genes (DEGs) were specific to either the peripheral or lung mucosa compartments (1,307/1,404, 93%). Type I interferon signaling was the dominant signature of DEGs in HIV-positive blood with a less dominant and qualitatively distinct type I interferon gene set expression pattern in HIV-positive BAL. DEGs in the HIV-positive BAL were significantly enriched for infiltration with cytotoxic CD8+ T cells. Higher expression of representative transcripts and proteins in BAL CD8+ T cells during HIV infection, including IFNG (IFN-), GZMB (Granzyme B) and PDCD1 (PD-1), was confirmed by cell-subset specific transcriptional analysis and flow cytometry. Thus, we report that a whole transcriptomic approach revealed qualitatively distinct effects of HIV in blood and bronchoalveolar compartments. Further work exploring the impact of distinct type I interferon programs and CD8+ T cells infiltration of the lung mucosa during HIV infection may provide novel insights into HIV-induced susceptibility to respiratory pathogens.

2020-05-26 | GSE139327 | GEO

Dysfunctional effector memory CD8 T cells in the bronchoalveolar compartment of people living with HIV

Project description:Dysfunctional effector memory CD8 T cells in the bronchoalveolar compartment of people living with HIV

| PRJNA967034 | ENA

Dysfunctional effector memory CD8 T cells in the bronchoalveolar compartment of people living with HIV

Project description:Dysfunctional effector memory CD8 T cells in the bronchoalveolar compartment of people living with HIV

| PRJNA962490 | ENA

Gene expresison of effector and exhausted CD8+ T cells from viremic people living with HIV

Project description:The differential expression of metabolic genes between effector and exhausted CD8+ Tcells has been characterized in the people living with HIV (PLWH) using 768 genes from the NanoString Human Metabolic Pathways Panel.

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Project description:In this study we performed data-independet mass-spectrometry analysis of blood plasma collected from a cohort consisting of people living with HIV-1, people living with HIV-2, and HIV seronegative individuals. The data was used to infer signs of damage to a wide array of tissues and cell types.

2024-02-16 | PXD045155 | Pride

Blood RNA sequencing in HIV-negative healthy volunteers and people living with HIV on effective, long-term anti-retroviral therapy

Project description:Immune activation in people living with HIV on anti-retroviral therapy is associated with increased risk of morbidity and mortality, but the underlying mechanisms are poorly understood. To identify whether perturbation of immunological pathways persist at systems level, we compared genome-wide whole blood transcriptomes from 26 people living with HIV on long-term anti-retroviral therapy with 12 HIV-negative healthy controls. All participants were Caucasian male adults recruited from London, UK. People living with HIV were on anti-retroviral therapy for a median of 8.5 years (interquartile range 3-16 years). They had undetectable plasma HIV viral load (<40 copies/ml) and median circulating CD4 counts of 703 cells/µl (interquartile range 491-841 cells/µl).

2021-02-26 | E-MTAB-8891 | biostudies-arrayexpress

Aminobisphosphonates reactivate the latent reservoir in people living with HIV-1

Project description:Antiretroviral therapy (ART) is not curative due to the existence of cellular reservoirs of latent HIV-1 that persist during therapy 1. Current research efforts to cure HIV-1 infection include “shock and kill” strategies to disrupt latency using small molecules or latency-reversing agents (LRAs) to induce expression of HIV-1 enabling cytotoxic immune cells to eliminate infected cells 2. However, the modest success of current LRAs urges the field to identify novel drugs with increased clinical efficacy 3,4. Aminobisphosphonates that include pamidronate, zoledronate, or alendronate, are the first-line treatment of bone-related diseases including osteoporosis and bone malignancies 5. Here, we show the use of aminobisphosphonates as a novel class of LRA: we found in ex vivo assays using primary cells from ART-suppressed people living with HIV-1 that aminobisphosphonates induce HIV-1 from latency to levels that are comparable to the T cell activator phytohemagglutinin. RNA sequencing and mechanistic data suggested that reactivation may occur through activation of the activator protein 1 signaling pathway. Stored samples from a prior clinical trial aimed at analyzing the effect of alendronate on bone mineral density, provided further of alendronate-mediated latency reversal and activation of immune effector cells.Decay of the reservoir measured by IPDA was however not detected. Our results demonstrate the novel use of aminobisphosphonates to reverse HIV-1 latency while inducing immune effector functions. This preliminary evidence merits further investigation in a controlled clinical setting possibly in combination with therapeutic vaccination.

2023-09-13 | GSE224546 | GEO

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