Project description:Genome-wide DNA methylation profiling of blood samples from people living with HIV HIV-1 infection impacts biological ageing, and epigenetic clocks highlight epigenetic age acceleration in people with HIV. Despite evidence indicating sex differences in clinical, immunological, and virological measures, females have been underrepresented in most HIV epigenetic studies. Hence, we generated a more representative epigenetic dataset to examine sex differences in epigenetic ageing and relationships to clinical phenotypes.
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.
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).
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.
Project description:Understanding the evolution of broadly neutralizing antibody (bNAb) activity in people living with HIV is crucial for vaccine design and immunization strategies. It has been proposed that antibody cross-reactive activity is associated with lower CD4+ T cell counts during people living with HIV, but the underlying mechanisms remain unclear. To further explore the correlation between antibody reactivity and CD4+ T cell counts, we recruited people living with HIV with varying CD4+ T cell counts: (i) CD4+ T cell <= 50 cells/mL, (ii) 50 cells/mL < CD4+ T cell <= 200 cells/mL, (iii) 200 cells/mL < CD4+ T cell <= 500 cells/mL, (iv) 500 cells/mL < CD4+ T cell. We constructed four SOSIPs.664 trimers and evaluated the antigen-specific antibodies in serum. Immune repertoire sequencing was used to characterize the BCR repertoire of these individuals. The evaluation of antigen-specific antibodies with different SOSIP.664 trimers showed enhanced reactivity in individuals with low CD4+ T cell counts compared to those with high/normal CD4+ T cell counts. Analysis of antibody gene repertoires through BCR high throughput sequencing revealed an increased proportion of IgG with heavy chain complementarity-determining region 3 (CDRH3) loops exceeding 20 amino acids in individuals with CD4+ T cell counts below 50 cells/mL. Notably, the IGHV1-46 and IGHV4-34 germlines, which result in most polyreactive B cells, were preferentially used in individuals with low CD4+ T cell counts. These results suggest that limited engagement of CD4+ T cells could facilitate the survival of aberrant B cell repertoire with long CDRH3 regions.
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.
Project description:Background: Although acquired immunodeficiency syndrome-related mortality has decreased since the introduction of antiretroviral therapy, the incidence of lung cancer in patients living with HIV (PLWH) remains high. Understanding the effects of tobacco smoke on airway gene expression in PLWH may provide insight into the elevated lung cancer risk associated with HIV. Methods: Airway epithelial brushings were collected from 12 PLWH who smoke and 19 PLWH who have never smoked and profiled using RNA-seq. Linear models were used to identify genes differentially expressed between people who smoke and have never smoked and between people who previously smoked and have never smoked. Gene set enrichment analysis was used to validate smoking-related gene signatures across datasets. Data was integrated with gene expression data from a cohort of patients without HIV to identify genes differentially modulated by both smoking and HIV status. Results: We found that previous smoking-related gene signatures are similarly associated with smoking in PLWH, including the persistent differential expression of a subset of "irreversibly altered" genes in people who previously smoked compared to people who have never smoked. We also identified and validated two gene signatures specifically modulated in people who smoke without HIV. Conclusions: Many of the effects of smoking on bronchial gene expression are shared between PLWH and non-HIV individuals. Of the subset of genes that differ between PLWH and non-HIV individuals, it appears that the effect of smoking on gene expression is more attenuated in PLWH. This includes genes related to oxidative stress and epithelial integrity, and suggests potential mechanisms that may contribute to smoking-related outcomes that are more prevalent in PLWH, such as lung cancer.
Project description:Neutrophil function declines with age, but little is known about the changes in neutrophil metabolism that take place in robust older people and older people with frailty. We used <sup>1</sup>H-NMR spectroscopy to investigate the metabolomic and lipidomic profiles of blood neutrophils from healthy younger (HY, n = 21, mean age 22Y) and robust older (RO, n = 24, mean age 66Y) people and older people with frailty (FR, n = 31, mean age 84Y), to identify metabolites and metabolic pathways altered with ageing with and without frailty. We also compared FR metabolites to rheumatoid arthritis (RA, n = 16, mean age 55Y) neutrophils to identify inflammation markers in FR neutrophils. Seventeen polar metabolites were significantly different between the participant groups (ANOVA adj. P < 0.05). NADP was uniquely elevated in FR compared with RO, HY and RA neutrophils, and lysine and choline were lower in FR vs. RO. Seven metabolites were significantly different between RO and HY neutrophils, and only two metabolites were different between FR and RA neutrophils, identifying underlying similarities between FR and RA that may be driven by inflammation. Four lipid peaks were significantly different between FR and HY neutrophils. These were attributed to total cholesterol and omega 6 fatty acids. This is the first study of polar and lipid metabolism in neutrophils from people with frailty, providing evidence that metabolic signalling pathways involved in neutrophil activation, oxidative stress and lipid metabolism are altered during healthy ageing and ageing with frailty, and we identify NADP as a unique biomarker of altered neutrophil function in people with frailty.