Metabolic and inflammatory perturbation of diabetes associated gut dysbiosis in people living with and without HIV infection.

BACKGROUND: Gut dysbiosis has been linked with both HIV infection and diabetes, but its interplay with metabolic and inflammatory responses in diabetes, particularly in the context of HIV infection, remains unclear. METHODS: We first conducted a cross-sectional association analysis to characterize the gut microbial, circulating metabolite, and immune/inflammatory protein features associated with diabetes in up to 493 women (~ 146 with prevalent diabetes with 69.9% HIV +) of the Women's Interagency HIV Study. Prospective analyses were then conducted to determine associations of identified metabolites with incident diabetes over 12 years of follow-up in 694 participants (391 women from WIHS and 303 men from the Multicenter AIDS Cohort Study; 166 incident cases were recorded) with and without HIV infection. Mediation analyses were conducted to explore whether gut bacteria-diabetes associations are explained by altered metabolites and proteins. RESULTS: Seven gut bacterial genera were identified to be associated with diabetes (FDR-q < 0.1), with positive associations for Shigella, Escherichia, Megasphaera, and Lactobacillus, and inverse associations for Adlercreutzia, Ruminococcus, and Intestinibacter. Importantly, the associations of most species, especially Adlercreutzia and Ruminococcus, were largely independent of antidiabetic medications use. Meanwhile, 18 proteins and 76 metabolites, including 3 microbially derived metabolites (trimethylamine N-oxide, phenylacetylglutamine (PAGln), imidazolepropionic acid (IMP)), 50 lipids (e.g., diradylglycerols (DGs) and triradylglycerols (TGs)) and 23 non-lipid metabolites, were associated with diabetes (FDR-q < 0.1), with the majority showing positive associations and more than half of them (59/76) associated with incident diabetes. In mediation analyses, several proteins, especially interleukin-18 receptor 1 and osteoprotegerin, IMP and PAGln partially mediate the observed bacterial genera-diabetes associations, particularly for those of Adlercreutzia and Escherichia. Many diabetes-associated metabolites and proteins were altered in HIV, but no effect modification on their associations with diabetes was observed by HIV. CONCLUSION: Among individuals with and without HIV, multiple gut bacterial genera, blood metabolites, and proinflammatory proteins were associated with diabetes. The observed mediated effects by metabolites and proteins in genera-diabetes associations highlighted the potential involvement of inflammatory and metabolic perturbations in the link between gut dysbiosis and diabetes in the context of HIV infection.

Immunoglobulin G N-glycan markers of accelerated biological aging during chronic HIV infection.

People living with HIV (PLWH) experience increased vulnerability to premature aging and inflammation-associated comorbidities, even when HIV replication is suppressed by antiretroviral therapy (ART). However, the factors associated with this vulnerability remain uncertain. In the general population, alterations in the N-glycans on IgGs trigger inflammation and precede the onset of aging-associated diseases. Here, we investigate the IgG N-glycans in cross-sectional and longitudinal samples from 1214 women and men, living with and without HIV. PLWH exhibit an accelerated accumulation of pro-aging-associated glycan alterations and heightened expression of senescence-associated glycan-degrading enzymes compared to controls. These alterations correlate with elevated markers of inflammation and the severity of comorbidities, potentially preceding the development of such comorbidities. Mechanistically, HIV-specific antibodies glycoengineered with these alterations exhibit a reduced ability to elicit anti-HIV Fc-mediated immune activities. These findings hold potential for the development of biomarkers and tools to identify and prevent premature aging and comorbidities in PLWH.

Distinct intestinal microbial signatures linked to accelerated systemic and intestinal biological aging.

BACKGROUND: People living with HIV (PLWH), even when viral replication is controlled through antiretroviral therapy (ART), experience persistent inflammation. This inflammation is partly attributed to intestinal microbial dysbiosis and translocation, which may lead to non-AIDS-related aging-associated comorbidities. The extent to which living with HIV - influenced by the infection itself, ART usage, sexual orientation, or other associated factors - affects the biological age of the intestines is unclear. Furthermore, the role of microbial dysbiosis and translocation in the biological aging of PLWH remains to be elucidated. To investigate these uncertainties, we used a systems biology approach, analyzing colon and ileal biopsies, blood samples, and stool specimens from PLWH on ART and people living without HIV (PLWoH) as controls. RESULTS: PLWH exhibit accelerated biological aging in the colon, ileum, and blood, as measured by various epigenetic aging clocks, compared to PLWoH. Investigating the relationship between microbial translocation and biological aging, PLWH had decreased levels of tight junction proteins in the intestines, along with increased microbial translocation. This intestinal permeability correlated with faster biological aging and increased inflammation. When investigating the relationship between microbial dysbiosis and biological aging, the intestines of PLWH had higher abundance of specific pro-inflammatory bacteria, such as Catenibacterium and Prevotella. These bacteria correlated with accelerated biological aging. Conversely, the intestines of PLWH had lower abundance of bacteria known for producing the anti-inflammatory short-chain fatty acids, such as Subdoligranulum and Erysipelotrichaceae, and these bacteria were associated with slower biological aging. Correlation networks revealed significant links between specific microbial genera in the colon and ileum (but not in feces), increased aging, a rise in pro-inflammatory microbe-related metabolites (e.g., those in the tryptophan metabolism pathway), and a decrease in anti-inflammatory metabolites like hippuric acid. CONCLUSIONS: We identified specific microbial compositions and microbiota-related metabolic pathways that are intertwined with intestinal and systemic biological aging. This microbial signature of biological aging is likely reflecting various factors including the HIV infection itself, ART usage, sexual orientation, and other aspects associated with living with HIV. A deeper understanding of the mechanisms underlying these connections could offer potential strategies to mitigate accelerated aging and its associated health complications. Video Abstract.

Predictors of HIV rebound differ by timing of antiretroviral therapy initiation.

BACKGROUNDIdentifying factors that predict the timing of HIV rebound after treatment interruption will be crucial for designing and evaluating interventions for HIV remission.METHODSWe performed a broad evaluation of viral and immune factors that predict viral rebound (AIDS Clinical Trials Group A5345). Participants initiated antiretroviral therapy (ART) during chronic (N = 33) or early (N = 12) HIV infection with ≥ 2 years of suppressive ART and restarted ART if they had 2 viral loads ≥ 1,000 copies/mL after treatment interruption.RESULTSCompared with chronic-treated participants, early-treated individuals had smaller and fewer transcriptionally active HIV reservoirs. A higher percentage of HIV Gag-specific CD8+ T cell cytotoxic response was associated with lower intact proviral DNA. Predictors of HIV rebound timing differed between early- versus chronic-treated participants, as the strongest reservoir predictor of time to HIV rebound was level of residual viremia in early-treated participants and intact DNA level in chronic-treated individuals. We also identified distinct sets of pre-treatment interruption viral, immune, and inflammatory markers that differentiated participants who had rapid versus slow rebound.CONCLUSIONThe results provide an in-depth overview of the complex interplay of viral, immunologic, and inflammatory predictors of viral rebound and demonstrate that the timing of ART initiation modifies the features of rapid and slow viral rebound.TRIAL REGISTRATIONClinicalTrials.gov NCT03001128FUNDINGNIH National Institute of Allergy and Infectious Diseases, Merck.

COVID-19 waves in an urban setting 2020-2022: an electronic medical record analysis.

Background: Global and national surveillance efforts have tracked COVID-19 incidence and clinical outcomes, but few studies have compared comorbid conditions and clinical outcomes across each wave of the pandemic. We analyzed data from the COVID-19 registry of a large urban healthcare system to determine the associations between presenting comorbidities and clinical outcomes during the pandemic. Methods: We analyzed registry data for all inpatients and outpatients with COVID-19 from March 2020 through September 2022 (N = 44,499). Clinical outcomes were death, hospitalization, and intensive care unit (ICU) admission. Demographic and clinical outcomes data were analyzed overall and for each wave. Unadjusted and multivariable logistic regressions were performed to explore the associations between age, sex, race, ethnicity, comorbidities, and mortality. Results: Waves 2 and 3 (Alpha and Delta variants) were associated with greater hospitalizations, ICU admissions, and mortality than other variants. Chronic pulmonary disease was the most common comorbid condition across all age groups and waves. Mortality rates were higher in older patients but decreased across all age groups in later waves. In every wave, mortality was associated with renal disease, congestive heart failure, cerebrovascular disease, diabetes, and chronic pulmonary disease. Multivariable analysis found that liver disease and renal disease were significantly associated with mortality, hospitalization, and ICU admission, and diabetes was significantly associated with hospitalization and ICU admission. Conclusion: The COVID-19 registry is a valuable resource to identify risk factors for clinical outcomes. Our findings may inform risk stratification and care planning for patients with COVID-19 based on age and comorbid conditions.

Alterations in Th17 Cells and Non-Classical Monocytes as a Signature of Subclinical Coronary Artery Atherosclerosis during ART-Treated HIV-1 Infection.

Cardiovascular disease (CVD) remains an important comorbidity in people living with HIV-1 (PLWH) receiving antiretroviral therapy (ART). Our previous studies performed in 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 the 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 monocytes, 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.

Associations between host microbiome and inflammation suggest role for host microbiome in driving COVID-19 disease severity.

Systemic inflammation and innate immune activation are associated with COVID-19 disease severity. Knowledge gaps remain in the relationships between microbiome, inflammation and COVID-19 disease severity. To better characterise these associations, we performed 16SrDNA analysis of stool samples in COVID-19 subjects to explore diversity and taxanomic composition. We correlated these to host inflammatory profiles, derived from soluble plasma biomarkers measured by bead-based fluorescence and electrochemiluminescence immunoassays. Associations of microbial diversity and inflammatory biomarkers on maximal COVID-19 severity (mild, moderate v severe/critical) was explored using logistic regression and weighted gene correlation network analysis (WGCNA). Of 79 subjects, 58% were male and 88% were Caucasian with 36% experiencing mild disease, 22% moderate disease and 40% critical/severe COVID-19. Hierarchical clustering and principal component analysis (PCo) revealed distinct inflammatory clusters that were found to correlate with 4 modules of microbiome profiles. Modules 3 and 4 were associated with both older age and severe/critical disease outcomes. These modules were enriched in pathogenic and inflammatory bacteria that mapped to a pro-inflammatory biomarker cluster. In contrast, module 1 exhibited enrichment of anti-inflammatory bacteria, was associated with younger age and mild/moderate disease outcomes and mapped to a less-inflamed biomarker cluster. This study provides further insights into links between host microbiome, inflammatory responses to SARS-CoV-2 infection and clinical COVID-19 disease severity, suggesting a role for the microbiome in shaping distinct host inflammatory responses to infection.

Tryptophan metabolism, gut microbiota, and carotid artery plaque in women with and without HIV infection.

OBJECTIVE: The perturbation of tryptophan (TRP) metabolism has been linked with HIV infection and cardiovascular disease (CVD), but the interrelationship among TRP metabolites, gut microbiota, and atherosclerosis remain unclear in the context of HIV infection. METHODS: We included 361 women (241 HIV+, 120 HIV-) with carotid artery plaque assessments from the Women's Interagency HIV Study, measured 10 plasma TRP metabolites and profiled fecal gut microbiome. TRP metabolite-related gut bacteria were selected through the Analysis of Compositions of Microbiomes with Bias Correction method. Associations of TRP metabolites and related microbial features with plaque were examined using multivariable logistic regression. RESULTS: Although plasma kynurenic acid (KYNA) [odds ratio (OR) = 1.93, 95% confidence interval (CI): 1.12-3.32 per one SD increase; P  = 0.02) and KYNA/TRP [OR = 1.83 (95% CI 1.08-3.09), P  = 0.02] were positively associated with plaque, indole-3-propionate (IPA) [OR = 0.62 (95% CI 0.40-0.98), P  = 0.03] and IPA/KYNA [OR = 0.51 (95% CI 0.33-0.80), P  < 0.01] were inversely associated with plaque. Five gut bacterial genera and many affiliated species were positively associated with IPA (FDR-q < 0.25), including Roseburia spp ., Eubacterium spp., Lachnospira spp., and Coprobacter spp.; but no bacterial genera were found to be associated with KYNA. Furthermore, an IPA-associated-bacteria score was inversely associated with plaque [OR = 0.47 (95% CI 0.28-0.79), P  < 0.01]. But no significant effect modification by HIV serostatus was observed in these associations. CONCLUSION: In a cohort of women living with and without HIV infection, plasma IPA levels and related gut bacteria were inversely associated with carotid artery plaque, suggesting a potential beneficial role of IPA and its gut bacterial producers in atherosclerosis and CVD.

Evaluating the Sick Quitting Hypothesis for Frailty Status and Reducing Alcohol Use Among People With HIV in a Longitudinal Clinical Cohort Study.

ABSTRACT: "Sick quitting," a phenomenon describing reductions in alcohol consumption following poor health, may explain observations that alcohol appears protective for frailty risk. We examined associations between frailty and reductions in drinking frequency among people with HIV (PWH). At six Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) sites between January 2012 and August 2021, we assessed whether frailty, measured through validated modified frailty phenotype, precedes reductions in drinking frequency. We associated time-updated frailty with quitting and reducing frequency of any drinking and heavy episodic drinking (HED), adjusted for demographic and clinical characteristics in Cox models. Among 5,654 PWH reporting drinking, 60% reported >monthly drinking and 18% reported ≥monthly HED. Over an average of 5.4 years, frail PWH had greater probabilities of quitting (HR: 1.56, 95% confidence interval [95% CI] [1.13-2.15]) and reducing (HR: 1.35, 95% CI [1.13-1.62]) drinking frequency, as well as reducing HED frequency (HR: 1.58, 95% CI [1.20-2.09]) versus robust PWH. Sick quitting likely confounds the association between alcohol use and frailty risk, requiring investigation for control.

The immunogenicity of an HIV-1 gag conserved element DNA vaccine in people with HIV and receiving antiretroviral therapy.

OBJECTIVE: The primary objective of the study was to assess the immunogenicity of an HIV-1 Gag conserved element DNA vaccine (p24CE DNA) in people with HIV (PWH) receiving suppressive antiretroviral therapy (ART). DESIGN: AIDS Clinical Trials Group A5369 was a phase I/IIa, randomized, double-blind, placebo-controlled study of PWH receiving ART with plasma HIV-1 RNA less than 50 copies/ml, current CD4+ T-cell counts greater than 500 cells/µl, and nadir CD4+ T-cell counts greater than 350 cells/µl. METHODS: The study enrolled 45 participants randomized 2 : 1 : 1 to receive p24CE DNA vaccine at weeks 0 and 4, followed by p24CE DNA admixed with full-length p55Gag DNA vaccine at weeks 12 and 24 (arm A); full-length p55Gag DNA vaccine at weeks 0, 4, 12, and 24 (arm B); or placebo at weeks 0, 4, 12, and 24 (arm c). The active and placebo vaccines were administered by intramuscular electroporation. RESULTS: There was a modest, but significantly greater increase in the number of conserved elements recognized by CD4+ and/or CD8+ T cells in arm A compared with arm C (P = 0.014). The percentage of participants with an increased number of conserved elements recognized by T cells was also highest in arm A (8/18, 44.4%) vs. arm C (0/10, 0.0%) (P = 0.025). There were no significant differences between treatment groups in the change in magnitude of responses to total conserved elements. CONCLUSION: A DNA-delivered HIV-1 Gag conserved element vaccine boosted by a combination of this vaccine with a full-length p55Gag DNA vaccine induced a new conserved element-directed cellular immune response in approximately half the treated PWH on ART.

Impact of vaccination and variants of concern on long COVID clinical phenotypes.

BACKGROUND: Defining patterns of symptoms in long COVID is necessary to advance therapies for this heterogeneous condition. Here we aimed to describe clusters of symptoms in individuals with long COVID and explore the impact of the emergence of variants of concern (VOCs) and vaccination on these clusters. METHODS: In a prospective, multi centre cohort study, individuals with symptoms persisting > 4 weeks from acute COVID-19 were divided into two groups based on timing of acute infection; pre-Alpha VOC, denoted wild type (WT) group and post-Alpha VOC (incorporating alpha and delta dominant periods) denoted VOC group. We used multiple correspondence analysis (MCA) and hierarchical clustering in the WT and VOC groups to identify symptom clusters. We then used logistic regression to explore factors associated with individual symptoms. RESULTS: A total of 417 individuals were included in the analysis, 268 in WT and 149 in VOC groups respectively. In both groups MCA identified three similar clusters; a musculoskeletal (MSK) cluster characterised by joint pain and myalgia, a cardiorespiratory cluster and a less symptomatic cluster. Differences in characteristic symptoms were only seen in the cardiorespiratory cluster where a decrease in the frequency of palpitations (10% vs 34% p = 0.008) and an increase in cough (63% vs 17% p < 0.001) in the VOC compared to WT groups was observed. Analysis of the frequency of individual symptoms showed significantly lower frequency of both chest pain (25% vs 39% p = 0.004) and palpitations (12% vs 32% p < 0.001) in the VOC group compared to the WT group. In adjusted analysis being in the VOC group was significantly associated with a lower odds of both chest pain and palpitations, but vaccination was not associated with these symptoms. CONCLUSION: This study suggests changes in long COVID phenotype in individuals infected later in the pandemic, with less palpitations and chest pain reported. Adjusted analyses suggest that these effects are mediated through introduction of variants rather than an effect from vaccination.

Distinct Intestinal Microbial Signatures Linked to Accelerated Biological Aging in People with HIV.

Background: People with HIV (PWH), even with controlled viral replication through antiretroviral therapy (ART), experience persistent inflammation. This is partly due to intestinal microbial dysbiosis and translocation. Such ongoing inflammation may lead to the development of non-AIDS-related aging-associated comorbidities. However, there remains uncertainty regarding whether HIV affects the biological age of the intestines and whether microbial dysbiosis and translocation influence the biological aging process in PWH on ART. To fill this knowledge gap, we utilized a systems biology approach, analyzing colon and ileal biopsies, blood samples, and stool specimens from PWH on ART and their matched HIV-negative counterparts. Results: Despite having similar chronological ages, PWH on ART exhibit accelerated biological aging in the colon, ileum, and blood, as measured by various epigenetic aging clocks, compared to HIV-negative controls. Investigating the relationship between microbial translocation and biological aging, PWH on ART had decreased levels of tight junction proteins in the colon and ileum, along with increased microbial translocation. This increased intestinal permeability correlated with faster intestinal and systemic biological aging, as well as increased systemic inflammation. When investigating the relationship between microbial dysbiosis and biological aging, the intestines of PWH on ART had higher abundance of specific pro-inflammatory bacterial genera, such as Catenibacterium and Prevotella. These bacteria significantly correlated with accelerated local and systemic biological aging. Conversely, the intestines of PWH on ART had lower abundance of bacterial genera known for producing short-chain fatty acids and exhibiting anti-inflammatory properties, such as Subdoligranulum and Erysipelotrichaceae, and these bacteria taxa were associated with slower biological aging. Correlation networks revealed significant links between specific microbial genera in the colon and ileum (but not in feces), increased aging, a rise in pro-inflammatory microbial-related metabolites (e.g., those in the tryptophan metabolism pathway), and a decrease in anti-inflammatory metabolites like hippuric acid and oleic acid. Conclusions: We identified a specific microbial composition and microbiome-related metabolic pathways that are intertwined with both intestinal and systemic biological aging in PWH on ART. A deeper understanding of the mechanisms underlying these connections could potentially offer strategies to counteract premature aging and its associated health complications in PWH.

Distinct receptor binding domain IgG thresholds predict protective host immunity across SARS-CoV-2 variants and time.

SARS-CoV-2 neutralising antibodies provide protection against COVID-19. Evidence from early vaccine trials suggested binding antibody thresholds could serve as surrogate markers of neutralising capacity, but whether these thresholds predict sufficient neutralising capacity against variants of concern (VOCs), and whether this is impacted by vaccine or infection history remains unclear. Here we analyse individuals recovered from, vaccinated or with hybrid immunity against SARS-CoV-2. An NT50 ≥ 100 IU confers protection in vaccine trials, however, as VOC induce a reduction in NT50, we use NT50 ≥ 1000 IU as a cut off for WT NT50 that would retain neutralisation against VOC. In unvaccinated convalescent participants, a receptor binding domain (RBD) IgG of 456 BAU/mL predicts an NT50 against WT of 1000 IU with an accuracy of 80% (95%CI 73-86%). This threshold maintains accuracy in determining loss of protective immunity against VOC in two vaccinated cohorts. It predicts an NT50 < 100 IU against Beta with an accuracy of 80% (95%CI 67-89%) in 2 vaccine dose recipients. In booster vaccine recipients with a history of COVID-19 (hybrid immunity), accuracy is 87% (95%CI 77-94%) in determining an NT50 of <100 IU against BA.5. This analysis provides a discrete threshold that could be used in future clinical studies.

Serotonin reduction in post-acute sequelae of viral infection.

Post-acute sequelae of COVID-19 (PASC, "Long COVID") pose a significant global health challenge. The pathophysiology is unknown, and no effective treatments have been found to date. Several hypotheses have been formulated to explain the etiology of PASC, including viral persistence, chronic inflammation, hypercoagulability, and autonomic dysfunction. Here, we propose a mechanism that links all four hypotheses in a single pathway and provides actionable insights for therapeutic interventions. We find that PASC are associated with serotonin reduction. Viral infection and type I interferon-driven inflammation reduce serotonin through three mechanisms: diminished intestinal absorption of the serotonin precursor tryptophan; platelet hyperactivation and thrombocytopenia, which impacts serotonin storage; and enhanced MAO-mediated serotonin turnover. Peripheral serotonin reduction, in turn, impedes the activity of the vagus nerve and thereby impairs hippocampal responses and memory. These findings provide a possible explanation for neurocognitive symptoms associated with viral persistence in Long COVID, which may extend to other post-viral syndromes.

Can statin preventative treatment inform geroscience-guided therapeutics?

Potential senotherapeutic effect of statins may lead to prevention and reduction of frailty.

Plasma Glycomic Markers of Accelerated Biological Aging During Chronic HIV Infection.

People with HIV (PWH) experience an increased vulnerability to premature aging and inflammation-associated comorbidities, even when HIV replication is suppressed by antiretroviral therapy (ART). However, the factors that contribute to or are associated with this vulnerability remain uncertain. In the general population, alterations in the glycomes of circulating IgGs trigger inflammation and precede the onset of aging-associated diseases. Here, we investigate the IgG glycomes of cross-sectional and longitudinal samples from 1,216 women and men, both living with virally suppressed HIV and those without HIV. Our glycan-based machine learning models indicate that living with chronic HIV significantly accelerates the accumulation of pro-aging-associated glycomic alterations. Consistently, PWH exhibit heightened expression of senescence-associated glycan-degrading enzymes compared to their controls. These glycomic alterations correlate with elevated markers of inflammatory aging and the severity of comorbidities, potentially preceding the development of such comorbidities. Mechanistically, HIV-specific antibodies glycoengineered with these alterations exhibit reduced anti-HIV IgG-mediated innate immune functions. These findings hold significant potential for the development of glycomic-based biomarkers and tools to identify and prevent premature aging and comorbidities in people living with chronic viral infections.

Association of Immune Cell Subsets with Incident Hip Fracture: The Cardiovascular Health Study.

In this study, we aimed to evaluate the association of innate and adaptive immune cell subsets in peripheral blood mononuclear cells (PBMCs) with hip fracture. To conduct this study, we used data from the Cardiovascular Health Study (CHS), a U.S. multicenter observational cohort of community-dwelling men and women aged ≥ 65 years. Twenty-five immune cell phenotypes were measured by flow cytometry from cryopreserved PBMCs of CHS participants collected in 1998-1999. The natural killer (NK), γδ T, T helper 17 (Th17), and differentiated/senescent CD4+CD28- T cell subsets were pre-specified as primary subsets of interest. Hip fracture incidence was assessed prospectively by review of hospitalization records. Multivariable Cox hazard models evaluated associations of immune cell phenotypes with incident hip fracture in sex-stratified and combined analyses. Among 1928 persons, 259 hip fractures occurred over a median 9.7 years of follow-up. In women, NK cells were inversely associated with hip fracture [hazard ratio (HR) 0.77, 95% confidence interval (CI) 0.60-0.99 per one standard deviation higher value] and Th17 cells were positively associated with hip fracture [HR 1.18, 95% CI 1.01-1.39]. In men, γδ T cells were inversely associated with hip fracture [HR 0.60, 95% CI 0.37-0.98]. None of the measured immune cell phenotypes were significantly associated with hip fracture incidence in combined analyses. In this large prospective cohort of older adults, potentially important sex differences in the associations of immune cell phenotypes and hip fracture were identified. However, immune cell phenotypes had no association with hip fracture in analyses combining men and women.

SuPAR mediates viral response proteinuria by rapidly changing podocyte function.

Elevation in soluble urokinase receptor (suPAR) and proteinuria are common signs in patients with moderate to severe coronavirus disease 2019 (COVID-19). Here we characterize a new type of proteinuria originating as part of a viral response. Inoculation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes increased suPAR levels and glomerulopathy in African green monkeys. Using an engineered mouse model with high suPAR expression, inhaled variants of SARS-CoV-2 spike S1 protein elicite proteinuria that could be blocked by either suPAR antibody or SARS-CoV-2 vaccination. In a cohort of 1991 COVID-19 patients, suPAR levels exhibit a stepwise association with proteinuria in non-Omicron, but not in Omicron infections, supporting our findings of biophysical and functional differences between variants of SARS-CoV-2 spike S1 protein and their binding to podocyte integrins. These insights are not limited to SARS-CoV-2 and define viral response proteinuria (VRP) as an innate immune mechanism and co-activation of podocyte integrins.

T cell activation is insufficient to drive SIV disease progression.

Resolution of T cell activation and inflammation is a key determinant of the lack of SIV disease progression in African green monkeys (AGMs). Although frequently considered together, T cell activation occurs in response to viral stimulation of acquired immunity, while inflammation reflects innate immune responses to mucosal injury. We dissociated T cell activation from inflammation through regulatory T cell (Treg) depletion with Ontak (interleukin-2 coupled with diphtheria toxin) during early SIV infection of AGMs. This intervention abolished control of T cell immune activation beyond the transition from acute to chronic infection. Ontak had no effect on gut barrier integrity, microbial translocation, inflammation, and hypercoagulation, despite increasing T cell activation. Ontak administration increased macrophage counts yet decreased their activation. Persistent T cell activation influenced SIV pathogenesis, shifting the ramp-up in viral replication to earlier time points, prolonging the high levels of replication, and delaying CD4+ T cell restoration yet without any clinical or biological sign of disease progression in Treg-depleted AGMs. Thus, by inducing T cell activation without damaging mucosal barrier integrity, we showed that systemic T cell activation per se is not sufficient to drive disease progression, which suggests that control of systemic inflammation (likely through maintenance of gut integrity) is the key determinant of lack of disease progression in natural hosts of SIVs.