Dynamics of peripheral T cell exhaustion and monocyte subpopulations in neurocognitive impairment and brain atrophy in chronic HIV infection.

BACKGROUND: HIV-associated neurocognitive disorders (HAND) is hypothesized to be a result of myeloid cell-induced neuro-inflammation in the central nervous system that may be initiated in the periphery, but the contribution of peripheral T cells in HAND pathogenesis remains poorly understood. METHODS: We assessed markers of T cell activation (HLA-DR + CD38+), immunosenescence (CD57 + CD28-), and immune-exhaustion (TIM-3, PD-1 and TIGIT) as well as monocyte subsets (classical, intermediate, and non-classical) by flow cytometry in peripheral blood derived from individuals with HIV on long-term stable anti-retroviral therapy (ART). Additionally, normalized neuropsychological (NP) composite test z-scores were obtained and regional brain volumes were assessed by magnetic resonance imaging (MRI). Relationships between proportions of immune phenotypes (of T-cells and monocytes), NP z-scores, and brain volumes were analyzed using Pearson correlations and multiple linear regression models. RESULTS: Of N = 51 participants, 84.3% were male, 86.3% had undetectable HIV RNA < 50 copies/ml, median age was 52 [47, 57] years and median CD4 T cell count was 479 [376, 717] cells/uL. Higher CD4 T cells expressing PD-1 + and/or TIM-3 + were associated with lower executive function and working memory and higher CD8 T cells expressing PD-1+ and/or TIM-3+ were associated with reduced brain volumes in multiple regions (putamen, nucleus accumbens, cerebellar cortex, and subcortical gray matter). Furthermore, higher single or dual frequencies of PD-1 + and TIM-3 + expressing CD4 and CD8 T-cells correlated with higher CD16 + monocyte numbers. CONCLUSIONS: This study reinforces evidence that T cells, particularly those with immune exhaustion phenotypes, are associated with neurocognitive impairment and brain atrophy in people living with HIV on ART. Relationships revealed between T-cell immune exhaustion and inflammatory in CD16+ monocytes uncover interrelated cellular processes likely involved in the immunopathogenesis of HAND.

Serum amyloid P (SAP) is associated with impaired brachial artery flow-mediated dilation in chronically HIV-1 infected adults on stable antiretroviral therapy.

OBJECTIVE: This study aimed to evaluate the relationship between inflammatory biomarkers and endothelial dysfunction (ED), as measured by brachial artery flow-mediated dilation (FMD). METHODS: We conducted a cross-sectional analysis utilizing baseline data of 135 participants with HIV infection on stable antiretroviral therapy (ART) in the Hawaii Aging with HIV-Cardiovascular (HAHC-CVD) study who had available baseline inflammatory biomarkers and brachial artery FMD measurements. RESULTS: We observed significant associations between brachial artery FMD and baseline brachial artery diameter, age, male gender, traditional cardiovascular disease (CVD) risk factors such as BMI, waist to hip ratio, hypertension, systolic blood pressure (BP), diastolic BP, and LDL cholesterol, and 10-year coronary heart disease (CHD) risk estimated by Framingham risk score (FRS). Of all biomarkers tested, higher level of C-reactive protein (CRP) (beta = - 0.695, P = 0.030) and serum amyloid P (SAP) (beta = - 1.318, P = 0.021) were significantly associated with lower brachial artery FMD in univariable regression analysis. After adjusting for baseline brachial artery diameter, age, and selected traditional CVD risk factors in multivariable model, SAP remained significantly associated with brachial artery FMD (beta = - 1.094, P = 0.030), while CRP was not (beta = - 0.391, P = 0.181). DISCUSSION: Serum amyloid P was independently associated with impaired brachial artery FMD and may potentially relate to ED and increased CVD risk in HIV-infected patients on stable ART.

Treatment intensification with maraviroc (CCR5 antagonist) leads to declines in CD16-expressing monocytes in cART-suppressed chronic HIV-infected subjects and is associated with improvements in neurocognitive test performance: implications for HIV-associated neurocognitive disease (HAND).

HIV-associated neurocognitive disorders (HAND) continues to be prevalent (30-50%) despite plasma HIV-RNA suppression with combination antiretroviral therapy (cART). There is no proven therapy for individuals on suppressive cART with HAND. We have shown that the degree of HIV reservoir burden (HIV DNA) in monocytes appear to be linked to cognitive outcomes. HIV infection of monocytes may therefore be critical in the pathogenesis of HAND. A single arm, open-labeled trial was conducted to examine the effect of maraviroc (MVC) intensification on monocyte inflammation and neuropsychological (NP) performance in 15 HIV subjects on stable 6-month cART with undetectable plasma HIV RNA (<48 copies/ml) and detectable monocyte HIV DNA (>10 copies/10(6) cells). MVC was added to their existing cART regimen for 24 weeks. Post-intensification change in monocytes was assessed using multiparametric flow cytometry, monocyte HIV DNA content by PCR, soluble CD163 (sCD163) by an ELISA, and NP performance over 24 weeks. In 12 evaluable subjects, MVC intensification resulted in a decreased proportion of circulating intermediate (median; 3.06% (1.93, 6.45) to 1.05% (0.77, 2.26)) and nonclassical (5.2% (3.8, 7.9) to 3.2% (1.8, 4.8)) CD16-expressing monocytes, a reduction in monocyte HIV DNA content to zero log10 copies/10(6) cells and in levels of sCD163 of 43% by 24 weeks. This was associated with significant improvement in NP performance among six subjects who entered the study with evidence of mild to moderate cognitive impairment. The results of this study suggest that antiretroviral therapy with potency against monocytes may have efficacy against HAND.

Feasibility and potential role of ferumoxytol-enhanced neuroimaging in HIV-associated neurocognitive disorder.

We assessed ferumoxytol-enhanced brain MRI to identify monocyte/macrophage accumulation in HIV-associated neurocognitive disorder (HAND). Four HIV-infected subjects with undetectable HIV RNA levels on antiretroviral therapy, HIV DNA level in CD14+ cells ≥10 copies/10(6) cells, and cognitive impairment underwent ferumoxytol-enhanced brain MRI. On post-ferumoxytol susceptibility-weighted images, all HIV-infected subjects demonstrated a diffuse "tram track" appearance in the perivascular regions of cortical and deep white matter vessels suggesting ferumoxytol uptake in monocytes/macrophages. This finding was not present in an HIV-seronegative control. While ferumoxytol may have potential as an imaging biomarker for monocyte/macrophage accumulation in patients with HAND, future study is needed.

Health Disparities Investigator Development through a Team-Science Pilot Projects Program.

Profound health disparities are widespread among Native Hawaiians, other Pacific Islanders, and Filipinos in Hawai'i. Efforts to reduce and eliminate health disparities are limited by a shortage of investigators trained in addressing the genetic, socio economic, and environmental factors that contribute to disparities. In this conference proceedings report from the 2022 RCMI Consortium National Conference, we describe our mentoring program, with an emphasis on community-engaged research. Elements include our encouragement of a team-science, customized Pilot Projects Program (PPP), a Mentoring Bootcamp, and a mentoring support network. During 2017-2022, we received 102 PPP preproposals. Of these, 45 (48%) were invited to submit full proposals, and 22 (19%) were awarded (8 basic biomedical, 7 clinical, 7 behavioral). Eighty-three percent of awards were made to early-career faculty (31% ethnic minority, 72% women). These 22 awards generated 77 related publications; 84 new grants were submitted, of which 31 were awarded with a resultant return on investment of 5.9. From 5 to 11 investigators were supported by PPP awards each year. A robust usage of core services was observed. Our descriptive report (as part of a scientific conference session on RCMI specialized centers) focuses on a mentoring vehicle and shows how it can support early-stage investigators in pursuing careers in health disparities research.

Plasma galectin-3 is associated with decreased glomerular filtration rate in chronic HIV.

BACKGROUND: People living with HIV (PLWH) have higher rates of chronic kidney disease (CKD) compared with HIV-uninfected individuals. The pathogenesis of CKD in HIV remains poorly understood but is likely from a combination of various factors, such as traditional comorbidities, prolonged antiretroviral therapy, immune dysregulation, and direct HIV effect on the kidneys. We evaluated plasma galectin-3 (Gal-3), a circulating marker of fibrosis, and its association with renal function. METHODS: Estimated glomerular filtration rate (eGFR) was assessed by CKD-EPI. Plasma galectin-3 was obtained from banked specimens by ELISA. Factors associated with eGFR were analyzed using step-wise multiple linear regression. RESULTS: A total of 45 PLWH and 58 HIV-uninfected participants were included with similar demographic parameters. Among PLWH, majority had undetectable plasma HIV RNA (82.2%). Gal-3 was significantly higher in PLWH than in HIV-uninfected participants (6.4 [IQR 4.0, 8.5] ng/mL and 4.5 [IQR 2.3, 6.5] ng/mL, respectively; p = 0.020) while a trend towards lower eGFR was found in PLWH compared to the HIV-uninfected cohort (86.8 [IQR 71.3, 91.8] and 89.0 [IQR 78.6, 97.4] mL/min/1.73 m2, respectively; p = 0.071). In univariable analysis, HIV status was marginally associated with decreased eGFR (ß coefficient= -0.035, p = 0.051). In the final multivariable regression model adjusted for traditional risk factors of CKD, Gal-3 independently predicted a decrease in eGFR (unstandardized B= -0.008, p < 0.001) while HIV status did not demonstrate any significant association. CONCLUSION: Gal-3 was higher in PLWH compared with HIV-uninfected participants. In multivariable adjusted analyses, Gal-3, but not HIV status, was associated with decreased eGFR. The role of Gal-3 as a biomarker of kidney function needs to be further elucidated.

Platelet and HIV Interactions and Their Contribution to Non-AIDS Comorbidities.

Platelets are anucleate cytoplasmic cell fragments that circulate in the blood, where they are involved in regulating hemostasis. Beyond their normal physiologic role, platelets have emerged as versatile effectors of immune response. During an infection, cell surface receptors enable platelets to recognize viruses, resulting in their activation. Activated platelets release biologically active molecules that further trigger host immune responses to protect the body against infection. Their impact on the immune response is also associated with the recruitment of circulating leukocytes to the site of infection. They can also aggregate with leukocytes, including lymphocytes, monocytes, and neutrophils, to immobilize pathogens and prevent viral dissemination. Despite their host protective role, platelets have also been shown to be associated with various pathophysiological processes. In this review, we will summarize platelet and HIV interactions during infection. We will also highlight and discuss platelet and platelet-derived mediators, how they interact with immune cells, and the multifaceted responsibilities of platelets in HIV infection. Furthermore, we will give an overview of non-AIDS comorbidities linked to platelet dysfunction and the impact of antiretroviral therapy on platelet function.

Low-density granulocytes display immature cells with enhanced NET formation in people living with HIV.

While the protective role of neutrophil extracellular traps (NETs) in limiting human immunodeficiency virus (HIV) spread to susceptible cells has been documented, there is comparatively little insight into whether NET formation is harmful in people living with HIV (PLWH). To gain insight into neutrophil dysregulation and the pathological role of NETs in HIV, we examined expressions of NET-associated markers [cell-free DNA (cfDNA) and citrullinated histone H3 (CitH3)] in the plasmas from a cohort of the Hawaii Aging with HIV-cardiovascular and HIV-seronegative (HIV-) individuals. In a subset of participants, circulating low-density granulocyte (LDG) levels and their maturation and activation status were analyzed via flow cytometry. We demonstrated higher plasma levels of CitH3 in PLWH compared to HIV- individuals. LDGs from PLWH had heightened CD66b, but reduced CD16 expression. The percentages and counts of CD10+ LDGs were significantly decreased in PLWH. In addition, the CD16Lo LDG subsets were enriched in PLWH, compared to HIV- group, indicating that immature LDGs are increased in PLWH. Moreover, LDGs from PLWH exhibited significantly higher NET forming capacity. In summary, our study presents evidence that LDGs from PLWH on ART display an immature and altered phenotype with increased NET formation. Among PLWH, plasma NET levels as well as LDG parameters correlated with blood markers for inflammation and coagulation, suggesting that neutrophil activation and NETs may exert proinflammatory and coagulation effects. Our data provide insights into the pathologic role of LDGs at least in part mediated through NET formation in PLWH.

Corrigendum: Phenotypic alteration of low-density granulocytes in people with pulmonary post-acute sequelae of SARS-CoV-2 infection.

[This corrects the article DOI: 10.3389/fimmu.2022.1076724.].

Elevated circulating monocytes and monocyte activation in COVID-19 convalescent individuals.

Background: Monocytes and macrophages play a pivotal role in inflammation during acute SARS-CoV-2 infection. However, their contribution to the development of post-acute sequelae of SARS-CoV-2 infection (PASC) are not fully elucidated. Methods: A cross-sectional study was conducted comparing plasma cytokine and monocyte levels among three groups: participants with pulmonary PASC (PPASC) with a reduced predicted diffusing capacity for carbon monoxide [DLCOc, <80%; (PG)]; fully recovered from SARS-CoV-2 with no residual symptoms (recovered group, RG); and negative for SARS-CoV-2 (negative group, NG). The expressions of cytokines were measured in plasma of study cohort by Luminex assay. The percentages and numbers of monocyte subsets (classical, intermediate, and non-classical monocytes) and monocyte activation (defined by CD169 expression) were analyzed using flow cytometry analysis of peripheral blood mononuclear cells. Results: Plasma IL-1Ra levels were elevated but FGF levels were reduced in PG compared to NG. Circulating monocytes and three subsets were significantly higher in PG and RG compared to NG. PG and RG exhibited higher levels of CD169+ monocyte counts and higher CD169 expression was detected in intermediate and non-classical monocytes from RG and PG than that found in NG. Further correlation analysis with CD169+ monocyte subsets revealed that CD169+ intermediate monocytes negatively correlated with DLCOc%, and CD169+ non-classical monocytes positively correlated with IL-1α, IL-1ß, MIP-1α, Eotaxin, and IFN-γ. Conclusion: This study present evidence that COVID convalescents exhibit monocyte alteration beyond the acute COVID-19 infection period even in convalescents with no residual symptoms. Further, the results suggest that monocyte alteration and increased activated monocyte subsets may impact pulmonary function in COVID-19 convalescents. This observation will aid in understanding the immunopathologic feature of pulmonary PASC development, resolution, and subsequent therapeutic interventions.

Increased transmigration of intermediate monocytes associated with atherosclerotic burden in people with HIV on antiretroviral therapy.

This study evaluated the association between the transmigration of monocyte subpopulations that contributes to atherosclerosis development, along with surrogate biomarkers of inflammation and atherosclerosis, through carotid intima-media thickness (cIMT) measurements of 72 people with HIV (PWH) on suppressive antiretroviral therapy (ART). We found that the transmigration of intermediate monocytes was positively correlated with D-dimer and cIMT, suggesting that intermediate monocytes may have a greater propensity to promote cardiovascular disease (CVD) in PWH on ART.

Single-cell RNA sequencing reveals characteristics of myeloid cells in pulmonary post-acute sequelae of SARS-CoV-2.

Background: Although our understanding of the immunopathology and subsequent risk and severity of COVID-19 disease is evolving, a detailed account of immune responses that contribute to the long-term consequences of pulmonary complication in COVID-19 infection remain unclear. Few studies have detailed the immune and cytokine profiles associated with post-acute sequalae of SARS-CoV-2 infection with persistent pulmonary symptoms (PPASC). However, the dysregulation of the immune system that drives pulmonary sequelae in COVID-19 survivors and PASC sufferers remains largely unknown. Results: To characterize the immunological features of pulmonary PASC (PPASC), we performed droplet-based single-cell RNA sequencing to study the transcriptomic profiles of peripheral blood mononuclear cells (PBMCs) from participants naïve to SARS-CoV-2 (Control) and infected with SARS-CoV-2 with chronic pulmonary symptoms (PPASC). We analyzed more than 34,139 PBMCs by integrating our dataset with previously reported control datasets (GSM4509024) cell distribution. In total, 11 distinct cell populations were identified based on the expression of canonical markers. The proportion of myeloid-lineage cells ([MLCs]; CD14 + /CD16 + monocytes and dendritic cells) was increased in PPASC compared to controls. MLCs from PPASC displayed up-regulation of genes associated with pulmonary symptoms/fibrosis, while glycolysis metabolism-related genes were downregulated. Similarly, pathway analysis showed that fibrosis- related ( VEGF , WNT , and SMAD ) and cell death pathways were up-regulated, but immune pathways were down-regulated in PPASC. In PPASC, we observed interactive VEGF ligand- receptor pairs among MLCs, and network modules in CD14 + (cluster 4) and CD16 + (Cluster 5) monocytes displayed a significant enrichment for biological pathways linked to adverse COVID- 19 outcomes, fibrosis, and angiogenesis. Further analysis revealed a distinct metabolic alteration in MLCs with a down-regulation of glycolysis/gluconeogenesis in PPASC compared to SARS- CoV-2 naïve samples. Conclusion: This study offers valuable insights into the immune response and cellular landscape in PPASC. The presence of elevated MLC levels and their corresponding gene signatures associated with fibrosis, immune response suppression, and altered metabolic states suggests their potential role as a driver of PPASC.

Single-cell RNA sequencing reveals characteristics of myeloid cells in post-acute sequelae of SARS-CoV-2 patients with persistent respiratory symptoms.

Background: Although our understanding of the immunopathology and subsequent risk and severity of COVID-19 disease is evolving, a detailed account of immune responses that contribute to the long-term consequences of pulmonary complications in COVID-19 infection remains unclear. Few studies have detailed the immune and cytokine profiles associated with post-acute sequelae of SARS-CoV-2 infection (PASC) with persistent pulmonary symptoms. The dysregulation of the immune system that drives pulmonary sequelae in COVID-19 survivors and PASC sufferers remains largely unknown. Results: To characterize the immunological features of pulmonary PASC (PPASC), we performed droplet-based single-cell RNA sequencing (scRNA-seq) to study the transcriptomic profiles of peripheral blood mononuclear cells (PBMCs) from a participant naïve to SARS-CoV-2 (Control) (n=1) and infected with SARS-CoV-2 with chronic pulmonary symptoms (PPASC) (n=2). After integrating scRNA-seq data with a naïve participant from a published dataset, 11 distinct cell populations were identified based on the expression of canonical markers. The proportion of myeloid-lineage cells ([MLCs]; CD14+/CD16+monocytes, and dendritic cells) was increased in PPASC (n=2) compared to controls (n=2). MLCs from PPASC displayed up-regulation of genes associated with pulmonary symptoms/fibrosis, while glycolysis metabolism-related genes were downregulated. Similarly, pathway analysis showed that fibrosis-related (VEGF, WNT, and SMAD) and cell death pathways were up-regulated, but immune pathways were down-regulated in PPASC. Further comparison of PPASC with scRNA-seq data with Severe COVID-19 (n=4) data demonstrated enrichment of fibrotic transcriptional signatures. In PPASC, we observed interactive VEGF ligand-receptor pairs among MLCs, and network modules in CD14+ (cluster 4) and CD16+ (Cluster 5) monocytes displayed a significant enrichment for biological pathways linked to adverse COVID-19 outcomes, fibrosis, and angiogenesis. Further analysis revealed a distinct metabolic alteration in MLCs with a down-regulation of glycolysis/gluconeogenesis in PPASC compared to SARS-CoV-2 naïve samples. Conclusion: Analysis of a small scRNA-seq dataset demonstrated alterations in the immune response and cellular landscape in PPASC. The presence of elevated MLC levels and their corresponding gene signatures associated with fibrosis, immune response suppression, and altered metabolic states suggests a potential role in PPASC development.

Researching COVID to Enhance Recovery (RECOVER) adult study protocol: Rationale, objectives, and design.

IMPORTANCE: SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or other health effects after the acute phase of infection; termed post-acute sequelae of SARS-CoV-2 infection (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are ill-defined. The objectives of the Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC in Adults (RECOVER-Adult) are to: (1) characterize PASC prevalence; (2) characterize the symptoms, organ dysfunction, natural history, and distinct phenotypes of PASC; (3) identify demographic, social and clinical risk factors for PASC onset and recovery; and (4) define the biological mechanisms underlying PASC pathogenesis. METHODS: RECOVER-Adult is a combined prospective/retrospective cohort currently planned to enroll 14,880 adults aged ≥18 years. Eligible participants either must meet WHO criteria for suspected, probable, or confirmed infection; or must have evidence of no prior infection. Recruitment occurs at 86 sites in 33 U.S. states, Washington, DC and Puerto Rico, via facility- and community-based outreach. Participants complete quarterly questionnaires about symptoms, social determinants, vaccination status, and interim SARS-CoV-2 infections. In addition, participants contribute biospecimens and undergo physical and laboratory examinations at approximately 0, 90 and 180 days from infection or negative test date, and yearly thereafter. Some participants undergo additional testing based on specific criteria or random sampling. Patient representatives provide input on all study processes. The primary study outcome is onset of PASC, measured by signs and symptoms. A paradigm for identifying PASC cases will be defined and updated using supervised and unsupervised learning approaches with cross-validation. Logistic regression and proportional hazards regression will be conducted to investigate associations between risk factors, onset, and resolution of PASC symptoms. DISCUSSION: RECOVER-Adult is the first national, prospective, longitudinal cohort of PASC among US adults. Results of this study are intended to inform public health, spur clinical trials, and expand treatment options. REGISTRATION: NCT05172024.

Cerebrovascular risk factors and brain microstructural abnormalities on diffusion tensor images in HIV-infected individuals.

HIV-associated neurocognitive disorder remains prevalent in HIV-infected individuals despite effective antiretroviral therapy. As these individuals age, comorbid cerebrovascular disease will likely impact cognitive function. Effective tools to study this impact are needed. This study used diffusion tensor imaging (DTI) to characterize brain microstructural changes in HIV-infected individuals with and without cerebrovascular risk factors. Diffusion-weighted MRIs were obtained in 22 HIV-infected subjects aged 50 years or older (mean age = 58 years, standard deviation = 6 years; 19 males, three females). Tensors were calculated to obtain fractional anisotropy (FA) and mean diffusivity (MD) maps. Statistical comparisons accounting for multiple comparisons were made between groups with and without cerebrovascular risk factors. Abnormal glucose metabolism (i.e., impaired fasting glucose, impaired glucose tolerance, or diabetes mellitus) was associated with significantly higher MD (false discovery rate (FDR) critical p value = 0.008) and lower FA (FDR critical p value = 0.002) in the caudate and lower FA in the hippocampus (FDR critical p value = 0.004). Pearson correlations were performed between DTI measures in the caudate and hippocampus and age- and education-adjusted composite scores of global cognitive function, memory, and psychomotor speed. There were no detectable correlations between the neuroimaging measures and measures of cognition. In summary, we demonstrate that brain microstructural abnormalities are associated with abnormal glucose metabolism in the caudate and hippocampus of HIV-infected individuals. Deep gray matter structures and the hippocampus may be vulnerable in subjects with comorbid abnormal glucose metabolism, but our results should be confirmed in further studies.

Alterations in Renin-Angiotensin System (RAS) Peptide Levels in Patients with HIV.

Chronic HIV infection has long been associated with an increased risk for cardiovascular diseases. The metabolites of the renin−angiotensin system (RAS) such as angiotensin II (AngII) play an important role in regulating blood pressure and fluid dynamics. Cross-sectional analysis of HIV-positive individuals (n = 71, age > 40 years, stable ART > 3 months with HIV viral load < 50 copies/mL) were compared to a similar HIV seronegative group (n = 72). High-resolution B-mode ultrasound images of the right carotid bifurcation (RBIF) and right common carotid artery (RCCA) were conducted to measure the extent of carotid atherosclerotic vascular disease. Plasma RAS peptide levels were quantified using a liquid chromatography-mass spectrometry-based metabolomics assay. RAS peptide concentrations were compared between persons with HIV and persons without HIV, correlating their association with clinical and cardiac measures. Median precursor peptides (Ang(1-12) and AngI) were significantly higher in the HIV-positive group compared to the HIV-negative. Analyses of the patient subgroup not on antihypertensive medication revealed circulating levels of AngII to be four-fold higher in the HIV-positive subgroup. AngII and TNF-alpha levels were found to have a positive association with RCCA, and AngI/Ang(1-12) ratio and TNF-alpha levels were found to have a positive association with RBIF. In both predictive models, AngIII had a negative association with either RCCA or RBIF, which may be attributed to its ability to bind onto AT2R and thus oppose pro-inflammatory events. These results reveal systemic alterations in RAS as a result of chronic HIV infection, which may lead to the activation of inflammatory pathways associated with carotid thickening. RAS peptide levels and cytokine markers were associated with RCCA and RBIF measurements.

Characterization of Circulating Fibrocytes in People Living with HIV on Stable Antiretroviral Therapy.

Highly effective combination antiretroviral therapy has reduced HIV infection to a manageable chronic disease, shifting the clinical landscape toward management of noninfectious comorbidities in people living with HIV (PLWH). These comorbidities are diverse, generally associated with accelerated aging, and present within multiple organ systems. Mechanistically, immune dysregulation and chronic inflammation, both of which persist in PLWH with well-controlled virally suppressive HIV infection, are suggested to create and exacerbate noninfectious comorbidity development. Persistent inflammation often leads to fibrosis, which is the common end point pathologic feature associated with most comorbidities. Fibrocytes are bone marrow-derived fibroblast-like cells, which emerged as key effector cells in tissue repair and pathologic fibrotic diseases. Despite their relevance to fibrosis, the circulating fibrocyte concentration in PLWH remains poorly characterized, and an understanding of their functional role in chronic HIV is limited. In this study, utilizing PBMCs from a cross-sectional adult HIV cohort study with matched uninfected controls (HIV-), we aimed to identify and compare circulating fibrocytes in blood. Both the percentage and number of fibrocytes and α-smooth muscle actin+ fibrocytes in circulation did not differ between the HIV+ and HIV- groups. However, circulating fibrocyte levels were significantly associated with increasing age in both the HIV+ and HIV- groups (the percentage and number; r = 0.575, p ≤ 0.0001 and r = 0.558, p ≤ 0.0001, respectively). Our study demonstrates that circulating fibrocyte levels and their fibroblast-like phenotype defined as collagen I and α-smooth muscle actin+ expression are comparable between, and strongly associated with, age irrespective of HIV status.

Three-dimensional optical body shape and features improve prediction of metabolic disease risk in a diverse sample of adults.

OBJECTIVE: This study examined whether body shape and composition obtained by three-dimensional optical (3DO) scanning improved the prediction of metabolic syndrome (MetS) prevalence compared with BMI and demographics. METHODS: A diverse ambulatory adult population underwent whole-body 3DO scanning, blood tests, manual anthropometrics, and blood pressure assessment in the Shape Up! Adults study. MetS prevalence was evaluated based on 2005 National Cholesterol Education Program criteria, and prediction of MetS involved logistic regression to assess (1) BMI, (2) demographics-adjusted BMI, (3) 85 3DO anthropometry and body composition measures, and (4) BMI + 3DO + demographics models. Receiver operating characteristic area under the curve (AUC) values were generated for each predictive model. RESULTS: A total of 501 participants (280 female) were recruited, with 87 meeting the criteria for MetS. Compared with the BMI model (AUC = 0.819), inclusion of age, sex, and race increased the AUC to 0.861, and inclusion of 3DO measures further increased the AUC to 0.917. The overall integrated discrimination improvement between the 3DO + demographics and the BMI model was 0.290 (p < 0.0001) with a net reclassification improvement of 0.214 (p < 0.0001). CONCLUSIONS: Body shape measures from an accessible 3DO scan, adjusted for demographics, predicted MetS better than demographics and/or BMI alone. Risk classification in this population increased by 29% when using 3DO scanning.