Brahmchetna Bedi

Integrase strand-transfer inhibitors (INSTIs) are associated with weight gain in people with HIV (PWH), particularly in women with HIV (WWH), but underlying mechanisms remain unclear. We used longitudinal untargeted metabolomics to identify metabolic signatures of INSTI-related weight gain in WWH. We analyzed serum from 192 participants in the Women's Interagency HIV Study: 38 virologically suppressed WWH who initiated INSTIs (INSTI group), 88 virologically suppressed WWH who remained on their original antiretroviral therapy (non-INSTI group), and 66 women without HIV (WWoH). Samples were collected at baseline (6-12 months before INSTI initiation), 1-6 months post-initiation, and 1-2 years post-initiation, with matched visits for controls. High-resolution metabolomics was performed by liquid chromatography-mass spectrometry. Within each group, linear mixed-effects models adjusted for baseline age and BMI compared longitudinal metabolite changes between weight gainers and maintainers, and significant features were analyzed by Mummichog v2.0 pathway enrichment. Mean age was 45.7 ± 8.9 years and mean BMI 32.4 ± 8.3 kg/m2, with no differences across groups; within each group, gainers and maintainers were demographically comparable (p > 0.05). In the INSTI group, metabolites differentiating gainers from maintainers were enriched in 16 pathways across timepoints, predominantly lipid-related (56%), including the polyunsaturated fatty acid (PUFA) pathways linoleic acid and arachidonic acid metabolism. In the non-INSTI and WWoH groups, differentiating metabolites spanned a broader range of pathways, including amino acid metabolism. Weight gain among INSTI-treated WWH is characterized by a distinct, lipid- and PUFA-dominated metabolic profile, providing mechanistic insight that may inform therapeutic strategies.

Background: Fractures are common in people with HIV (PWH). Interleukin 4 (IL-4), an antiosteoclastogenic product of CD4 Th2 T cells, becomes depleted in PWH; however, its role in skeletal deterioration in PWH is unknown. We therefore examined associations between IL-4 and bone mineral density (BMD), bone resorption and formation markers (β-C-terminal telopeptide of type I collagen and osteocalcin), and the osteoclastogenic regulators receptor activator of NF-κB ligand (RANKL) and osteoprotegerin in PWH who were antiretroviral therapy (ART) naive and people without HIV (PWoH). Methods: Commercial enzyme-linked immunosorbent assays were used to measure factors in a cohort of 37 ART-naive PWH and 28 PWoH and in an independent cohort of 29 ART-experienced PWH. BMD was quantified by bone densitometry, and IL-4 associations were analyzed by sex and HIV status via Spearman correlation and multivariable linear regression. Results: IL-4 was significantly lower in ART-naive PWH as compared with PWoH and higher in ART-experienced PWH vs ART-naive PWH. With ART-naive PWH and PWoH combined, IL-4 correlated inversely with β-C-terminal telopeptide of type I collagen, RANKL, and RANKL/osteoprotegerin ratio in males and females, individually and when aggregated, but not in ART-naive PWH or PWoH individually. In PWoH and ART-naive PWH combined, IL-4 was significantly associated with higher lumbar spine Z score and most femoral BMD T and Z scores in males but not females. Conclusions: IL-4 levels are reduced in treatment-naive PWH and higher in ART-experienced PWH. IL-4 positively correlates with BMD in men but not women, suggesting that IL-4 protects the male skeleton and that IL-4 decline may contribute to bone loss in men with HIV.

Cystic fibrosis (CF) is a progressive multiorgan autosomal recessive disease with devastating impact on the lungs caused by derangements of the CF transmembrane conductance regulator (CFTR) gene. Morbidity and mortality are caused by the triad of impaired mucociliary clearance, microbial infections and chronic inflammation. Pseudomonas aeruginosa is the main respiratory pathogen in individuals with CF infecting most patients in later stages. Despite its recognized clinical impact, molecular mechanisms that underlie P. aeruginosa pathogenesis and the host response to P. aeruginosa infection remain incompletely understood. The nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR) γ (PPARγ), has shown to be reduced in CF airways. In the present study, we sought to investigate the upstream mechanisms repressing PPARγ expression and its impact on airway epithelial host defense. Endoplasmic reticulum-stress (ER-stress) triggered unfolded protein response (UPR) activated by misfolded CFTR and P. aeruginosa infection contributed to attenuated expression of PPARγ. Specifically, the protein kinase RNA (PKR)-like ER kinase (PERK) signaling pathway led to the enhanced expression of the CCAAT-enhancer-binding-protein homologous protein (CHOP). CHOP induction led to the repression of PPARγ expression. Mechanistically, we showed that CHOP induction mediated PPARγ attenuation, impacted the innate immune function of normal and ∆F508 primary airway epithelial cells by reducing expression of antimicrobial peptide (AMP) and paraoxanse-2 (PON-2), as well as enhancing IL-8 expression. Furthermore, mitochondrial reactive oxygen species production (mt-ROS) and ER-stress positive feedforward loop also dysregulated mitochondrial bioenergetics. Additionally, our findings implicate that PPARγ agonist pioglitazone (PIO) has beneficial effect on the host at the multicellular level ranging from host defense to mitochondrial re-energization.

Objective: Excessive alcohol misusers are 2–4 times more likely to develop respiratory infections and acute respiratory distress syndrome as compared to non‐alcoholics. Alcohol misuse enhances oxidative stress in the lung, leading to impaired lung immunity. The molecular mechanisms by which this lung immune dysfunction occurs remain poorly defined. Inflammasome activation occurs in alcoholic steatohepatitis and functions in oxidative stress and host defense. Autophagy is critical for the engulfment and degradation of intracellular pathogens and regulates inflammasome activation. Thus, we hypothesized that autophagy prevents oxidative stress and inflammasome activation in the lung induced by alcohol. Methods: Lungs were collected from littermate Atg5 ^F/F control or LysM‐Cre‐Atg5 ^F/F mice with a macrophage‐specific knockout of the autophagy gene Atg5 that were fed either a control or ethanol‐containing (5% vol/vol) Lieber‐DeCarli diet for 5 weeks. Markers of oxidative stress and inflammation were measured in the lungs from these mice. mRNA levels of NADPH oxidase 4 (Nox4) and transforming growth factor beta (TGFβ) were assessed by qRT‐PCR. Protein expression of NLRP3, caspase‐1 and ASC were measured by western blotting and interleukin (IL)‐1β was quantitated by ELISA. Results: In vivo studies demonstrated that alcohol: 1) increased the mRNA levels of Nox4 and TGFβ; 2) increased components of the inflammasome complex, namely NLRP3, ASC and caspase‐1; and 3) elevated IL‐1β expression, indicative of inflammasome activation. Knockdown of Atg5 enhanced inflammasome activation and exacerbated the oxidative stress and inflammatory effects of alcohol. Conclusions: Macrophage autophagy likely plays a critical role in regulating lung oxidative stress and inflammasome activation during chronic alcohol ingestion. Inactivation of the autophagic pathway exacerbates the deleterious effects of alcohol. Therapeutic targeting of autophagy or inflammasome activation pathways could mitigate alcohol's detrimental effects on the lung and improve lung host immune defense. Support or Funding Information Research Funding Source : Department of Veterans Affairs 2I01BX001786 (RTS), and National Institute of Alcohol Abuse and Alcoholism 4R00AA021803 (SMY) and 5R01AA022601 (MJC). This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .