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The impact of HIV antiretroviral therapy (ART) on immune dysregulation associated with hepatitis C virus (HCV)/HIV coinfection is incompletely understood. We serially assessed monocyte activation (neopterin, sCD14, and sCD163) and T cell activation (HLA-DR, CD38) and immune exhaustion [program cell death protein 1 (PD1), TIGIT] in HIV/HCV-coinfected individuals who participated in a randomized trial performed in Vietnam designed to assess the hepatotoxicity of raltegravir (RAL)- versus efavirenz (EFV)-based therapy when used as first-time ART in combination with tenofovir disoproxil fumarate and emtricitabine. Baseline pre-ART values were compared with those from ART-naive HIV-monoinfected and HIV-seronegative individuals. Before ART, HIV/HCV-coinfected individuals had higher levels of neopterin, sCD14, and sCD163, and increased frequencies of CD38(+)HLA-DR(+), PD1(+), and TIGIT(+) CD4 and CD8 T cells compared with ART-naive HIV-monoinfected or HIV-seronegative individuals (all p

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.

BackgroundMonocytes 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.MethodsA 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, ResultsPlasma 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-1β, MIP-1α, Eotaxin, and IFNγ.ConclusionThis study present evidence that COVID convalescents exhibit monocyte alteration beyond the acute COVID-19 infection period even in convalescents with no residual symptoms. These data provide further rational for determining the role of monocyte subsets in PPASC pathogenesis.

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.

OBJECTIVES There is limited evidence for the use of salt tablets in the treatment of hyponatremia. This retrospective study evaluated the effectiveness of salt tablet administration in euvolemic hyponatremia. METHODS This was a single-center, retrospective cohort study. Information on patients' demographics, clinical characteristics, and laboratory data were collected for retrospective review. Treatment for hyponatremia, including the amount of salt tablets, fluid restriction, and diuretics was collected. We compared hyponatremic patients with those who received salt tablets versus those who did not receive salt tablets. The primary outcome of interest was the change in serum sodium at 48 hours between the two groups. RESULTS A total of 1258 medical records were initially screened with inclusion and exclusion criteria. After screening, there were 83 patients included in the study. Forty-two patients received salt tablets and 41 patients were in the group that did not receive salt tablets. Patients treated with salt tablets were older, more often female, and had lower body weight and lower initial serum sodium. The change in serum sodium after 48 hours was higher in the salt tablet group (5.2 mEq/L) than the non-salt tablet group (3.1 mEq/L; P < 0.001). This difference in serum sodium between the two groups remained statistically significant when adjusted for age, sex, weight, and initial serum sodium. CONCLUSIONS The use of salt tablets in the treatment of euvolemic hyponatremia is associated with a small but significant improvement in serum sodium compared with patients who did not receive such therapy, even after adjusting for age, sex, weight, and initial serum sodium. This study supports the effectiveness of salt tablets in the treatment of euvolemic hyponatremia in medical patients.

Background: Brain atrophy and cognitive deficits persist among individuals with suppressed HIV disease. The impact of cannabis use is unknown. Methods: HIV+ and HIV- participants underwent cross-sectional magnetic resonance imaging and neuropsychological testing. Lifetime frequency, duration (years), and recency of cannabis use were self-reported. Relationships of cannabis use to resting-state functional connectivity (RSFC) and to 9 regional brain volumes were assessed with corrections for multiple comparisons. Peripheral blood cytokines and monocyte subsets were measured in the HIV+ group and examined in relation to cannabis exposure. Results: We evaluated 52 HIV+ [50.8 ± 7.1 years old; 100% on antiretroviral therapy ≥ 3 months; 83% with plasma viral load 10 times/lifetime was linked to more somatic symptoms, better executive function, and lower CD14+CD16++ monocyte count. Conclusion: HIV+ individuals demonstrated opposing associations with cannabis. Recent use may weaken RSFC and prolonged consumption may exacerbate atrophy of the accumbens and other brain regions. More frequent or recent cannabis use may reduce the inflammation and CD14+CD16++ monocytes that facilitate HIV neuroinvasion. HIV-specific cannabis studies are necessary.

Lipoatrophy, or fat wasting, remains a syndrome plaguing HIV(+) patients receiving antiretroviral (ARV) therapy. Both HIV infection per se and certain ARV are associated with lowered adipose tissue mitochondrial deoxyribonucleic acid (mtDNA) and mitochondrial ribonucleic acid (mtRNA) levels, but effects on adenosine triphosphate (ATP) production are unclear. We hypothesized that such alterations would accompany lowering of ATP levels in fat of HIV(+) patients and would be worse in those displaying lipoatrophy. Gluteal-fold, subcutaneous adipose tissue was obtained from HIV seronegative control patients, from HIV(+) ARV-naive patients, and those on ARV with or without lipoatrophy. Cellular ATP was measured in isolated adipocytes and preadipocyte fraction cells by bioluminescence. mtDNA copies/cell and oxidative phosphorylation (OXPHOS) mtRNA transcripts were evaluated by quantitative polymerase chain reactions. ATP levels were consistently higher in preadipocyte fraction cells than adipocytes, but values strongly correlated with each other (r = 0.66, p

BackgroundThe accurate assessment of total body and regional body circumferences, volumes, and compositions are critical to monitor physical activity and dietary interventions, as well as accurate disease classifications including obesity, metabolic syndrome, sarcopenia, and lymphedema. We assessed body composition and anthropometry estimates provided by a commercial 3-dimensional optical (3DO) imaging system compared to criterion measures.MethodsParticipants of the Shape Up! Adults study were recruited for similar sized stratifications by sex, age (18-40, 40-60, >60 years), BMI (under, normal, overweight, obese), and across five ethnicities (non-Hispanic [NH] Black, NH White, Hispanic, Asian, Native Hawaiian/Pacific Islander). All participants received manual anthropometry assessments, duplicate whole-body 3DO (Styku S100), and dual-energy X-ray absorptiometry (DXA) scans. 3DO estimates provided by the manufacturer for anthropometry and body composition were compared to the criterion measures using concordance correlation coefficient (CCC) and Bland-Altman analysis. Test-retest precision was assessed by root mean square error (RMSE) and coefficient of variation.ResultsA total of 188 (102 female) participants were included. The overall fat free mass (FFM) as measured by DXA (54.1±15.2kg) and 3DO (55.3±15.0kg) showed a small mean difference of 1.2±3.4kg (95% limits of agreement-7.0 to+5.6) and the CCC was 0.97 (95% CI: 0.96-0.98). The CCC for FM was 0.95 (95% CI: 0.94-0.97) and the mean difference of 1.3±3.4kg (95% CI:-5.5 to+8.1) reflected the difference in FFM measures. 3DO anthropometry and body composition measurements showed high test-retest precision for whole body volume (1.1L), fat mass (0.41kg), percent fat (0.60%), arm and leg volumes, (0.11 and 0.21L, respectively), and waist and hip circumferences (all

Despite long term antiretroviral therapy (ART), insulin resistance (IR) is common among people living with HIV/AIDS (PLWHA) exposing this population to a greater risk of cardiometabolic complications when compared to their uninfected counterparts. We previously identified an expansion in monocyte subpopulations in blood that were linked to the degree of IR in persons with HIV on stable ART. In this study, we directly assessed monocyte inflammatory functional properties from PLWHA on ART (n = 33) and HIV-uninfected controls (n = 14) of similar age, gender, and cardiovascular disease risk and determined the relationship with IR (homeostatic model assessment-insulin resistance (HOMA-IR)), calculated from fasting blood glucose and insulin measurements. Peripheral blood mononuclear cells were stimulated with oxidized low-density lipoproteins (oxLDL) and polyfunctional monocyte cytokine responses (IL-1&beta, IL-6, IL-8, or TNF-&alpha, ) were determined by flow cytometry. Higher monocyte IL-1&beta, and IL-8 responses to oxLDL were associated with higher IR in PLWHA but not in the control group. We observed that higher basal monocyte cytokine responses were associated with both duration since HIV diagnosis and ART initiation. In the management of IR in chronic HIV, strategies lowering monocyte IL-1&beta, and IL-8 responses should be considered in addition to ART in order to limit adverse cardio-metabolic outcomes.

Maximum carotid plaque thickness (MCPT) measures the largest plaque thickness in the carotid artery and reflects atherosclerosis plaque burden. MCPT may be a better predictor of cardiovascular disease than carotid artery intima-media thickness (cIMT) because it identifies potential unstable arterial atherosclerosis plaques. We assessed the relationships of monocyte and T cell populations and plasma soluble mediators with MCPT measures. We performed a cross-sectional and small follow-up analysis in people living with HIV (PLWH) aged >40 years on stable antiretroviral therapy (ART) >6 months. MCPT was acquired by high-resolution B-mode ultrasound. Existing monocyte subsets and T cell activation frequencies were determined by flow cytometry and plasma mediators of inflammation and apolipoproteins were measured by Luminex assay. One hundred twenty-five ART-treated PLWH, 88% male, 55% Caucasian, with a median age of 51 years, median CD4 count of 477 cells/μL (Q1: 325, Q3: 612), 84% undetectable plasma HIV RNA (

Objectives The aim of this study was to examine the relationship between gut microbial communities in HIV-infected individuals on suppressive antiretroviral therapy (cART), and the peripheral HIV-Gag-specific CD8 T-cell responses before and after ex-vivo immune checkpoint blockade (ICB). Design Thirty-four HIV-seropositive, 10 HIV-seronegative and 12 HIV-seropositive receiving faecal microbiota transplant (FMT) participants were included. Gut microbial communities, peripheral and gut associated negative checkpoint receptors (NCRs) and peripheral effector functions were assessed. Methods Bacterial 16s rRNA sequencing for gut microbiome study and flow-based assays for peripheral and gut NCR and their cognate ligand expression, including peripheral HIV-Gag-specific CD8 T-cell responses before and after ex-vivo anti-PD-L1 and anti-TIGIT ICB were performed. Results Fusobacteria abundance was significantly higher in HIV-infected donors compared to uninfected controls. In HIV-infected participants receiving Fusobacteria-free FMT, Fusobacteria persisted up to 24 weeks in stool post FMT. PD-1 TIGIT and their ligands were expanded in mucosal vs. peripheral T cells and dendritic cells, respectively. PD-L1 and TIGIT blockade significantly increased the magnitude of peripheral anti-HIV-Gag-specific CD8 T-cell responses. Higher gut Fusobacteria abundance was associated with lower magnitude of peripheral IFN-γ+ HIV-Gag-specific CD8 T-cell responses following ICB. Conclusion The gut colonization of Fusobacteria in HIV infection is persistent and may influence anti-HIV T-cell immunity to PD-1 or TIGIT blockade. Strategies modulating Fusobacteria colonization may elicit a favourable mucosal immune landscape to enhance the efficacy of ICB for HIV cure.

Increased negative immune checkpoint receptors (NCR) on T cells are linked to T cell exhaustion, dysfunctional effector responses, and HIV viral persistence. Metformin, an oral hypoglycemic agent used for diabetes, may have previously unrecognized beneficial immunologic effects. Using cryopreserved blood from a 24-week pilot study involving 12 virally suppressed HIV-infected individuals randomized 1:1 to metformin versus observation (OBS), we assessed change in the frequencies of T cell activation (CD38(+)HLA-DR(+)) and NCR [programmed cell death protein 1 (PD1), T cell immunoreceptor with Ig and ITIM domains (TIGIT), and T cell mucin-domain containing-3 (TIM3)]. No differences in 24-week change were seen between arms in CD4 or CD8 T cells, in the CD4/CD8 ratio, or in activated (CD38(+)HLA-DR(+)) CD4 or CD8 T cells. However, metformin over 24 weeks led to decreases compared with OBS in single PD1(+) (percent decrease: −9.6% vs. 7.5%, p = .015), in dual PD1(+)TIGIT(+) (−15.0% vs. 10.4%, p = .002), and in triple PD1(+)TIGIT(+)TIM3(+) (−24.0% vs. 8.1%, p = .041) CD4 T cells. Metformin led to no changes in CD8 T cell NCR frequencies. Metformin decreases the frequency of PD1(+), PD1(+)TIGIT(+), and PD1(+)TIGIT(+)TIM3(+) expressing CD4 T cells. This may have relevance to HIV cure strategies and to efforts to mitigate the risk of chronic complications of HIV.

Background: Chronic HIV is associated with increased inflammation and tissue fibrosis despite suppressive antiretroviral therapy (ART). Monocytes and macrophages have been implicated in the pathoge...

Incidences of cardiovascular diseases (CVD) are high among virologically suppressed HIV-infected individuals. Monocyte activation and trafficking are key mechanisms in the evolution of CVD. We studied the ability of cenicriviroc (CVC), a dual C-C chemokine receptor type 2 (CCR2) and CCR5 antagonist, to influence the migration of monocytes from HIV-infected individuals on antiretroviral therapy (ART). Monocytes were derived from 23 ART-suppressed HIV-infected and 16 HIV-uninfected donors. In a trans-endothelial migration model, monocytes, and human aortic endothelial cells (HAoECs) were exposed to cenicriviroc and migrated monocytes, quantified. Expression of CCR2 and CCR5 on monocytes and adhesion molecules (E-selectin, ICAM-1, VCAM-1, PECAM-1, and CD99) on HAoECs were measured. The single antagonists, BMS-22 (CCR2), and maraviroc (CCR5), served as controls. When both HAoECs and monocytes together were exposed to the antagonists, cenicriviroc led to a greater decrease in monocyte migration compared to BMS-22 or vehicle in both HIV-infected and HIV-uninfected groups (P < 0.05), with maraviroc having no inhibitory effect. Cenicriviroc treatment of HAoECs alone decreased monocyte migration in the HIV-infected group when compared to vehicle (P < 0.01). Inhibition of migration was not evident when monocytes alone were exposed to cenicriviroc, BMS-22 or maraviroc. Incubation of HAoECs with cenicriviroc decreased E-selectin expression (P = 0.045) but had limited effects on the other adhesion molecules. Cenicriviroc inhibits monocyte trans-endothelial migration more effectively than single chemokine receptor blockade, which may be mediated via disruption of monocyte-endothelial tethering through reduced E-selectin expression. Cenicriviroc should be considered as a therapeutic intervention to reduce detrimental monocyte trafficking. Cenicriviroc, a dual CCR2 and CCR5 antagonist, inhibits monocyte trafficking in an in vitro trans-endothelial migration assay more effectively than a single chemokine receptor blockade.

OBJECTIVE: The antiretroviral drug efavirenz (EFV) has been linked to disordered sleep and cognitive abnormalities. We examined sleep and cognitive function and subsequent changes following switch to an alternative integrase inhibitor-based regimen. METHODS: Thirty-two HIV-infected individuals on EFV, emtricitabine, and tenofovir (EFV/FTC/TDF) without traditional risk factors for obstructive sleep apnea (OSA) were randomized 2:1 to switch to elvitegravir/cobicistat/emtricitabine/tenofovir (EVG/COBI/FTC/TDF) or to continue EFV/FTC/TDF therapy for 12 weeks. Overnight polysomnography and standardized sleep and neuropsychological assessments were performed at baseline and at 12 weeks. RESULTS: No significant differences in change over 12 weeks were noted between the two arms in any sleep or neuropsychological test parameter. At entry, however, the rate of sleep disordered breathing (SDB) was substantially higher in study subjects compared to published age-matched norms and resulted in a high assessed OSA rate of 59.4%. Respiratory Disturbance Index (RDI), a measure of SDB, correlated with age- and education-adjusted global neuropsychological z-score (NPZ) (r=-0.35, p=0.05). Sleep Maintenance Efficiency, Wake after Sleep Onset, REM Sleep and RDI correlated with domain-specific NPZ for learning and memory (all p-values ≤ 0.05). CONCLUSION: Among HIV-infected individuals on EFV-based therapy and without traditional risk factors for OSA, sleep and neuropsychological abnormalities do not readily reverse after discontinuation of EFV. High baseline rates of SDB and abnormalities in sleep architecture exist in this population correlating with neuropsychological impairment. The role of HIV immuno-virologic or lifestyle factors as contributing etiologies should be explored. OSA may be an under-recognized etiology for cognitive dysfunction during chronic HIV.

Nontuberculous mycobacteria (NTM) respiratory infections represent a growing public health problem in many countries. However, there are limited published epidemiologic studies for the Western Pacific region. We reviewed respiratory specimens submitted to Diagnostic Laboratory Services in Hawaii, USA, for culture of Mycobacterium tuberculosis during August 2007-December 2011 to determine the NTM isolation rate. We observed a statistically significant increase in the rate of specimens with NTM isolated in respiratory culture (adjusted rate ratio per year 1.65, 95% CI 1.54-1.77; p

Objective Prolongation of the QT interval, i.e., measure of the time between the start of the Q wave and the end of the T wave, is a precursor to fatal cardiac arrhythmias commonly observed in individuals infected with the Human Immunodeficiency Virus (HIV), and is related to dysregulation of the autonomic nervous system. We investigated the relationship between QT interval length and resting state functional connectivity (rsFC) of the ventromedial prefrontal cortex (VMPFC), a core region of the brain that is involved with cardio-autonomic regulation. Method Eighteen HIV+ men on antiretroviral therapy and with no history of heart disease were compared with 26 HIV-negative control subjects who had similar demographic and cardio-metabolic characteristics. A seed-based rsFC analysis of the right and left VMPFC was performed at the individual subject level, and 2nd-level analyses were conducted to identify the following: group differences in connectivity, brain regions correlating with corrected (QTc) interval length before and after controlling for those group differences, and regions where seed-based rsFC correlates with CD4 count and QTc interval within HIV+ individuals. Results HIV-negative adults showed greater rsFC between the VMPFC seed regions and several default mode network structures. Across groups greater rsFC with the left anterior insula was associated with shorter QTc intervals, whereas right posterior insula connectivity with the VMPFC correlated with greater QTc intervals. HIV patients with lower CD4 counts and higher QTc intervals showed greater rsFC between the right VMPFC and the right posterior insula and dorsal cingulate gyrus. Conclusions This study demonstrates that QTc interval lengths are associated with distinct patterns of VMPFC rsFC with posterior and anterior insula. In HIV patients, longer QTc interval and lower CD4 count corresponded to weaker VMPFC connectivity with the dorsal striatrum. Significance A forebrain control mechanism may be implicated in the suppression of cardiovagal influence that confers risk for ventricular arrhythmias and sudden cardiac death in HIV+ individuals.

Plasminogen activator inhibitor type 1 (PAI-1), a key negative regulator of fibrinolysis, has been investigated to be one of the potential mechanisms of the development of impaired insulin sensitivity, insulin resistance, and diabetes mellitus. Because chronically stable HIV-infected individuals frequently develop abnormal glucose metabolism, including insulin resistance and diabetes mellitus, we postulated that PAI-1 could be one of the multifactorial pathogenic roles in the development of impaired insulin sensitivity and insulin resistance among chronic HIV-infected individuals. From our longitudinal cohort study, we selectively recruited chronically stable HIV-infected individuals without diagnosis of diabetes mellitus at baseline (N = 62) to analyze the correlation of baseline inflammatory cytokines, including PAI-1 and whole-body insulin sensitivity, with 2-year follow-up, as measured by Matsuda Index. We found a negative correlation between baseline PAI-1 and Matsuda Index (r = −0.435, p = .001) and a negative correlation between baseline PAI-1 and Matsuda Index at 2 years (r = −0.377, p = .005). In a linear regression model that included age, total body fat mass percentage, serum amyloid A, and family history of diabetes mellitus, PAI-1 still remained significantly associated with Matsuda Index at 2-year follow-up (β = −.397, p = .002). Our longitudinal study suggests that PAI-1 is an independent predictor of impaired insulin sensitivity among chronic HIV-infected individuals.

Objective This study aimed to explore the accuracy and precision of three-dimensional optical (3DO) whole-body scanning for automated anthropometry and estimating total and regional body composition. Methods Healthy children and adolescents (n = 181, ages 5-17 years) were recruited for the Shape Up! Kids study. Each participant underwent whole-body dual-energy x-ray absorptiometry and 3DO scans; multisite conventional tape measurements served as the anthropometric criterion measure. 3DO body shape was described using automated body circumference, length, and volume measures. 3DO estimates were compared with criterion measures using simple linear regression by the stepwise selection method. Results Of the 181 participants, 112 were used for the training set, 49 were used for the test set, and 20 were excluded for technical reasons. 3DO body composition estimates were strongly associated with dual-energy x-ray absorptiometry measures for percent body fat, fat mass, and fat-free mass (R2 : 0.83, 0.96, and 0.98, respectively). 3DO provided reliable measurements of fat mass (coefficient of variation, 3.30; root mean square error [RMSE], 0.53), fat-free mass (coefficient of variation, 1.34; RMSE, 0.53 kg), and percent body fat (RMSE = 1.2%). Conclusions 3DO surface scanning provides accurate and precise anthropometric and body composition estimates in children and adolescents with high precision. 3DO is a safe, accessible, and practical method for evaluating body shape and composition in research and clinical settings.

Aims: Cardiovascular disease (CVD) remains the leading cause of death worldwide despite improvements in the treatment of atherosclerosis, an inflammatory disease and major underlying cause of CVD. Monocytes, an innate immune cell type, are linked to CVD progression; however, given their heterogeneity, the association between distinct monocyte subsets and increased risk of CVD remains unclear. This study investigated the association between peripheral monocyte subpopulation numbers and carotid intima-media thickness (cIMT), a sensitive measure of CVD risk, in a cohort of adults recruited from the general population. Methods: We used clinical data and peripheral blood mononuclear cell (PBMC) specimens from 67 individuals. cIMT was measured by high-resolution, B-mode, ultrasound images of the right carotid artery. PBMCs were stained with conjugated monoclonal antibodies to define monocyte subpopulations based on CD14 and CD16 co-expressions into classical (CD14++CD16−), intermediate/inflammatory (CD14++CD16+), and non-classical/patrolling (CD14low/+CD16++) monocytes. Results: We found a higher intermediate monocyte count was significantly correlated with increased right common carotid artery (RCCA) and right carotid bifurcation (RBIF) intima-media thickness (IMT) (p = 0.004 and 0.006, respectively), even after adjusting for CVD-associated clinical data (p = 0.006 and 0.004, respectively). Conclusion: Our study demonstrated a strong correlation between inflammatory monocyte counts and cIMT. These results suggest that, in the general population, there is a relationship between intermediate monocyte expansion and elevated predictors for CVD risk, and intermediate monocytes may be involved in the development of atherosclerosis and metabolic diseases. Strategies targeting inflammatory monocytes may be needed to slow CVD progression.

Background Three-dimensional optical (3DO) body scanning has been proposed for automatic anthropometry. However, conventional measurements fail to capture detailed body shape. More sophisticated shape features could better indicate health status. Objectives The objectives were to predict DXA total and regional body composition, serum lipid and diabetes markers, and functional strength from 3DO body scans using statistical shape modeling. Methods Healthy adults underwent whole-body 3DO and DXA scans, blood tests, and strength assessments in the Shape Up! Adults cross-sectional observational study. Principal component analysis was performed on registered 3DO scans. Stepwise linear regressions were performed to estimate body composition, serum biomarkers, and strength using 3DO principal components (PCs). 3DO model accuracy was compared with simple anthropometric models and precision was compared with DXA. Results This analysis included 407 subjects. Eleven PCs for each sex captured 95% of body shape variance. 3DO body composition accuracy to DXA was: fat mass R2 = 0.88 male, 0.93 female; visceral fat mass R2 = 0.67 male, 0.75 female. 3DO body fat test-retest precision was: root mean squared error = 0.81 kg male, 0.66 kg female. 3DO visceral fat was as precise (%CV = 7.4 for males, 6.8 for females) as DXA (%CV = 6.8 for males, 7.4 for females). Multiple 3DO PCs were significantly correlated with serum HDL cholesterol, triglycerides, glucose, insulin, and HOMA-IR, independent of simple anthropometrics. 3DO PCs improved prediction of isometric knee strength (combined model R2 = 0.67 male, 0.59 female; anthropometrics-only model R2 = 0.34 male, 0.24 female). Conclusions 3DO body shape PCs predict body composition with good accuracy and precision comparable to existing methods. 3DO PCs improve prediction of serum lipid and diabetes markers, and functional strength measurements. The safety and accessibility of 3DO scanning make it appropriate for monitoring individual body composition, and metabolic health and functional strength in epidemiological settings.This trial was registered at clinicaltrials.gov as NCT03637855.

BackgroundCellular immunometabolism among people living with HIV (PLWH) on antiretroviral therapy (ART) remains under investigated. We assessed the relationships between mitochondrial oxidative phosphorylation (OXPHOS) in peripheral blood mononuclear cells (PBMCs) and blood parameters associated with HIV immune dysregulation.MethodsPLWH ≥40 years old and on stable ART ≥3 months were enrolled (N = 149). OXPHOS complex I (CI, NADH dehydrogenase) and complex IV (CIV, cytochrome c oxidase) protein levels in PBMCs were quantified using immunoassays. Monocyte subsets and markers of T-cell activation, senescence, and exhaustion were measured on PBMC by flow cytometry. Plasma inflammatory mediators were quantified using a multiplex assay. HIV-uninfected group (N = 44) of similar age, gender, and ethnicity had available OXPHOS levels.ResultsPLWH had a median age of 51 years. Majority were male (88.6%), Caucasian (57.7%), and with undetectable plasma HIV RNA ConclusionCI PBMC protein levels were decreased in PLWH on ART. Decreased OXPHOS correlated with disease severity and inflammation. Further studies on the relationship between immunometabolism and immune dysregulation in HIV are warranted.

Background:Chronic HIV disease is associated with neurocognitive impairment and age-related conditions such as frailty.Objective:To determine whether regional brain volumetric changes correlate with frailty parameters in older (≥ 40 years) HIV+ patients on stable combination antiretroviral therapy.Method:Thirty-five HIV-infected participants in the Hawaii Aging with HIV Cohort - Cardiovascular Disease study underwent T1-weighted brain magnetic resonance imaging, frailty assessment and neuropsychological testing. Five physical frailty traits were assessed: low physical activity; exhaustion; unintentional weight loss; weak hand grip strength; slow walking speed. Linear regression quantified cross-sectional relationships of 12 brain regions to walking times and hand grip strength.Results:Participants were 50.6 ± 6.8 years old and 77% had undetectable plasma viral load. One subject was frail (possessing ≥ 3 frailty traits); 23% were pre-frail (1–2 frailty traits) and had worse composite learning and memory z-scores than did non-frail individuals (p=0.06). Pre-frail or frail subjects had reduced hand grip strength relative to the non-frail group (p=0.001). Longer walking times (slower gait) related independently to lower volumes of cerebellar white matter (ppp< 0.05, β=0.4). Caudate volume was negatively associated with grip strength (pConclusion:Volumetric changes in cerebellar white matter and subcortical gray matter, brain regions involved in motor control and cognition, may be connected to frailty development in well-controlled HIV. Gait speed is particularly sensitive to white matter alterations and should be investigated as a predictor of frailty and brain atrophy in chronically infected patients.

Increased risk of atherosclerotic cardiovascular diseases is common in HIV+ adults on stable antiretroviral treatment (ART). A key step in the development of the atherosclerotic plaque is the transmigration of monocytes to the plaque area and their differentiation into macrophages and eventually foam cells. The objective of this study was to determine if the propensity of monocytes to transmigrate as well as their ability to take up and efflux cholesterol is affected by HIV infection. Monocytes (transmigration) and differentiated macrophages (lipid metabolism) from HIV+ ART treated patients were compared against those from matched controls as a single point cross-sectional study. Monocyte transmigration was assessed by transwell assay using MCP1 as a chemoattractant, whereas lipid uptake was measured by flow cytometry analysis of internalized acetylated LDL and cholesterol efflux by tracking tritiated cholesterol excreted from the cell after exposure to HDL. Interestingly, isolation of monocytes via negative selection with magnetic beads revealed that the yield of monocyte was significantly lower from HIV+ patients compared to controls. While no significant differences were found in cholesterol uptake or efflux parameter, the ability of monocyte to transmigrate was slightly increased in HIV patients compared to controls suggesting that the chemotactic function of monocytes may be partly responsible for the differences in the atherosclerosis risk in patients with HIV.

BACKGROUND: Chronic inflammation and immune dysfunction occur in human immunodeficiency virus (HIV)-infection despite stable antiretroviral therapy (ART). Red blood cell distribution width (RDW) has been shown to correlate with markers of inflammation in non-HIV conditions. The study objective was to determine associations between RDW with cellular markers of immune activation and immune dysfunction including soluble inflammatory mediators in ART treated HIV infection. METHODS: We performed a cross-sectional analysis of the Hawaii Aging with HIV-Cardiovascular study. RDW was defined as one standard deviation of RBC size divided by mean corpuscular volume multiplied by 100%. Correlations were analyzed between RDW, soluble inflammatory biomarkers and T cell activation (CD38 + HLA-DR+), senescence (CD28-CD57+), and immune exhaustion (PD-1, TIGIT, TIM-3 expression). RESULTS: Of 158 participants analyzed, median age was 50 years, duration of ART 12.6 years, virally suppressed 84.4%, and CD4 count 503 cells/mm3. Significant positive correlations were identified between RDW and soluble biomarkers including sICAM, IL-8, IL-6, SAA, TNF-α, sE-selection, fibrinogen, D-dimer, CRP, CD4/CD8 ratio, and frequency of multiple CD8 T-cell populations such as CD38 + HLA-DR + T-cells, single TIGIT+, and dual expressing of TIGIT + PD1+, TIGIT + TIM3+, and TIM3 + PD1+ CD8+ T-cell subsets (p < .05). Frequencies of CD38 + HLA-DR + CD8+ T-cells and TIGIT + CD8+ T-cells remained significant adjusting for baseline variables (p < .01). CONCLUSION: Our study revealed correlations between RDW with systemic inflammatory biomarkers and CD8+ T-cell populations related to immune activation and exhaustion in HIV-infected individuals on ART. Further studies are warranted to determine the utility of RDW as a marker of immune dysregulation in HIV.

BACKGROUND: We characterized associations between frailty and incident cardiovascular disease (CVD), diabetes mellitus (DM), bone disease, and mortality within a cohort of aging persons with human immunodeficiency virus (PWH). METHODS: Participants underwent frailty evaluations using the Fried frailty assessment (baseline and annually). Frailty was defined as having ≥3 frailty criteria. Clinical outcomes of mortality, CVD events, DM, and bone disease events were recorded throughout the study period (baseline to most recent study or clinic visit, or date of clinical outcome, whichever came first). Poisson regression models were used to evaluate associations between baseline frailty, change in frailty score over 48 weeks, and each clinical outcome. RESULTS: Among 821 men and 195 women (median age 51 years), 62 (6%) were frail at baseline. Frailty scores increased by ≥1 component among 194 participants (19%) from baseline to 48 weeks. Baseline frailty was associated with an increased risk of incident CVD and DM, with a trend toward a significant association with bone events. Among frailty components, slow gait speed was associated with incident DM and borderline associated with incident CVD. An increase in frailty from baseline to week 48 was associated with mortality but not with the other clinical outcomes. CONCLUSIONS: Baseline frailty was associated with multiple adverse health outcomes (incident CVD, DM, and bone disease), while increase in frailty score was associated with mortality among PWH engaged in care. Incorporation of frailty assessments into the care of PWH may assist in improvement of functional status and risk stratification for age-related chronic diseases.

In HIV-infected individuals, impaired mitochondrial function may contribute to cardiometabolic disease as well as to fatigue and frailty. Aerobic exercise improves total body energy reserves; however, its impact at the cellular level is unknown. We assessed alterations in cellular bioenergetics in peripheral blood mononuclear cells (PBMC) before and after a 12-week aerobic exercise study in sedentary HIV-infected subjects on stable antiretroviral therapy who successfully completed a 12-week aerobic exercise program. In this prospective study, participants underwent supervised 20–40 min of light aerobic exercise (walking or jogging) performed three times per week for 12 weeks, gradually increasing to maintain an intensity of 50%–80% of heart rate reserve. Maximal aerobic capacity (VO2MAX) was assessed by a graded exercise test on a cycle ergometer before and after completion of the study. PBMC from compliant subjects (attended at least 70% of exercise sessions) were assessed for mitochondrial respiration using the Seahorse XF24 Bio-Analyzer. Seven of 24 enrolled subjects were compliant with the exercise regimen. In these individuals, a significant increase (p = .04) in VO2MAX over 12 weeks was found with a median increase of 14%. During the same interval, a 2.45-fold increase in PBMC mitochondrial respiratory capacity (p = .04), a 5.65-fold increase in spare respiratory capacity (p = .01), and a 3.15-fold (p = .04) increase in nonmitochondrial respiration was observed. Aerobic exercise improves respiration at the cellular level. The diagnostic and prognostic value of such improved cellular respiration in the setting of chronic HIV warrants further investigation.

Albuminuria among HIV-infected individuals has been found to be associated with cardiovascular disease (CVD) and mortality. Inflammation has been associated with albuminuria. The pathophysiology of albuminuria in HIV-infected individuals is poorly understood. We investigated the association of albuminuria with inflammatory biomarkers among HIV-infected individuals on combination antiretroviral therapy (cART). This is a cross-sectional analysis of participants enrolled in the Hawaii Aging with HIV-Cardiovascular Cohort. Plasma inflammatory biomarkers were assessed using the Milliplex Human Cardiovascular disease multiplex assays. A random urine sample was collected for albumin measurement. Albuminuria was defined as urine albumin-to-creatinine ratio of ≥30 mg/g. Framingham risk score was calculated and divided into three classes. Simple and multivariable logistic regression analyses were utilized to assess the correlation between plasma inflammatory biomarkers and albuminuria and were adjusted for Framingham risk category. Among 111 HIV-infected patients [median (IQR) age of 52 (46–57) years, 86% male, median (IQR) CD4 count of 489 (341–638) cells/mm3, 85% with HIV RNA

HIV-associated neurocognitive disorders (HAND) continues to be prevalent (30–50 %) despite plasma HIVRNA suppression with combination antiretroviral therapy (cART). There is no proven therapy for individuals on suppressive cARTwith 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 (10 copies/106 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/106 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.

OBJECTIVE To assess the role of HIV and monocytes/macrophages in adipose tissue dysregulation. METHODS Cross-sectional study in 5 groups: HIV seronegative, HIV+ antiretroviral therapy (ART)-naive, HIV+ nonlipoatrophic on zidovudine- and/or stavudine-containing ART, HIV+ lipoatrophic on similar ART, and HIV+ on abacavir- or tenofovir-containing ART. HIV DNA in circulating monocyte subsets was quantitated by real-time polymerase chain reaction. Biopsied subcutaneous fat was examined for macrophage content by CD68 staining. Isolated adipocytes and macrophages were cultured and the supernatant assayed for secretory products by Luminex multiplex cytokine technology. RESULTS Sixty-nine subjects were enrolled. Lipoatrophic subjects had higher median HIV DNA levels (270.5 copies/10 cells) in circulating peripheral CD14CD16 co-expressing monocyte subsets compared with subjects who were ART-naive (25.0 copies), nonlipoatrophic (15.0 copies), or on abacavir/tenofovir (57.5 copies), P < 0.01. Group differences in adipocytes and adipose macrophage content were marginal. Although adipocyte secretory products were similar, HIV-infected subjects had higher adipose macrophage-derived interleukin (IL)-12p40, IL-6, IL-8, and monocyte inflammatory protein 1 alpha and lower eotaxin and interferon gamma levels than HIV seronegative subjects (P < 0.05). Within HIV-infected subjects, adipose macrophage secretory products were comparable between subjects naive with ART versus those on ART. CONCLUSIONS Circulating HIV-infected and proinflammatory CD14CD16 monocyte subsets contribute to the pathogenesis of HIV-associated lipoatrophy. Among HIV-infected individuals, macrophages, rather than adipocytes, are the primary source of low-grade inflammation in subcutaneous adipose tissue. HIV infection modifies these macrophages to a more proinflammatory phenotype, and these changes are not substantially mitigated by the use of ART.