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.

Background

Persistent inflammation and immune activation has been hypothesized to contribute to increased prevalence of subclinical atherosclerosis and cardiovascular disease (CVD) risk in patients with chronic HIV infection. In this study, we examined the correlation of peripheral monocyte subsets and soluble biomarkers of inflammation to coronary artery calcium (CAC) progression, as measured by cardiac computed tomography scan.

Methods

We conducted a longitudinal analysis utilizing baseline data of 78 participants with HIV infection on stable antiretroviral therapy (ART) in the Hawaii Aging with HIV-Cardiovascular study who had available baseline monocyte subset analysis as well as CAC measurement at baseline and at 2-year follow up. Monocyte phenotypes were assessed from cryopreserved blood by flow cytometry and plasma was assayed for soluble biomarkers using antibody-coated beads in a high sensitivity Milliplex Luminex platform. Change in CAC over 2 years was analyzed as the primary outcome variable.

Results

Of all monocyte subsets and biomarkers tested, higher non-classical monocyte percentage (ρ = 0.259, p = 0.022), interleukin (IL)-6 (ρ = 0.311, p = 0.012), and monocyte chemoattractant protein (MCP)-1 (ρ = 0.524, p = <0.001) were significantly correlated to higher 2-year CAC progression in unadjusted Spearman's correlation. Non-classical monocyte percentage (ρ = 0.247, p = 0.039), and MCP-1 (ρ = 0.487, p = <0.001), remained significantly correlated to 2-year CAC progression, while IL-6 was not (ρ = 0.209, p = 0.120) after adjustment for age, hypertension, diabetes mellitus, total/HDL cholesterol ratio, smoking history, and BMI.

Conclusion

The percentage of non-classical monocytes and plasma MCP-1 levels were independently associated with CAC progression and may be related to the progression of atherosclerosis and increased CVD risk associated with chronic HIV infection on stable ART.

Inflammation associated with low 25-hydroxyvitamin D (25(OH)D) is associated with increased morbidity and mortality among HIV-infected patients with vitamin D deficiency. We investigated the association between 25(OH)D and soluble biomarkers among HIV-infected patients on stable antiretroviral therapy. This is a cross-sectional study. This study focuses on assessment in subjects 40 years or older on stable antiretroviral therapy (ART) for >3 months. Chemiluminescent immunoassay was used to determine plasma 25(OH)D levels. Plasma soluble biomarkers were measured by Luminex technology. Multivariable linear regression analysis was used to assess the associations between log10-25(OH)D and soluble biomarkers.Of 138 patients, median age was 50.5 (45, 57) years and 25(OH)D was 34.0 (25.0, 42.3) ng/mL. The majority were males (88%) and had undetectable HIV RNA (84.8%); 19 (13.8%) had 25(OH)D ≥50 ng/mL. Spline regression analyses suggested a J-shaped relationship between various plasma biomarkers and 25(OH)D. Among subjects with 25(OH)D ≥20 ng/mL, multivariable linear regression showed positive association between 25(OH)D and interleukin (IL)-10 (β = 1.84, P < 0.001), IL-6 (β = 0.72, P = 0.02), MPO (β = 0.47, P = 0.02), serum amyloid A (β = 1.20, P = 0.04), and tumor necrosis factor (TNF)-α (β = 0.51, P = 0.04). High 25(OH)D (≥50 ng/mL) was associated with higher IL-6 (β = 0.30, P = 0.009), IL-8 (β = 0.14, = 0.005), IL-10 (β = 0.43, P = 0.02), and TNF-α (β = 0.20, P = 0.04), independent of age, sex, ethnicity, body mass index, hepatitis C co-infection, current smoking status, CD4%, and HIV RNA.In older HIV-infected patients, high 25(OH)D was associated with higher (not lower) levels of proinflammatory cytokines. Higher-than-optimal 25(OH)D may be associated with immune dysregulation and may pose a potential health risk among HIV-infected patients.

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.

Background

The 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.

Methods

Participants 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.

Results

A total of 188 (102 female) participants were included. The overall fat free mass (FFM) as measured by DXA (54.1 ± 15.2 kg) and 3DO (55.3 ± 15.0 kg) showed a small mean difference of 1.2 ± 3.4 kg (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 ± 3.4 kg (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 (1.1 L), fat mass (0.41 kg), percent fat (0.60%), arm and leg volumes, (0.11 and 0.21 L, respectively), and waist and hip circumferences (all <0.60 cm). No group differences were observed when stratified by body mass index, sex, or race/ethnicity.

Conclusions

The anthropometric and body composition estimates provided by the 3DO scanner are precise and accurate to criterion methods if offsets are considered. This method offers a rapid, broadly available, and automated method of body composition assessment regardless of body size. Further studies are recommended to examine the relationship between measurements obtained by 3DO scans and metabolic health in healthy and clinical populations.

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.

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.

Background

Inflammation may contribute to cardiovascular disease (CVD) among antiretrovirally suppressed HIV-infected individuals. We assessed relationships of monocyte, CD8 T-cell activation and plasma biomarkers to changes in carotid artery intima-media thickness (CIMT).

Methods

Longitudinal study of HIV-infected subjects ≥40 years and on stable antiretroviral therapy (ART) ≥3 months. Peripheral blood mononuclear cells were immunophenotyped by multiparameteric flow cytometry to quantify classical (CD14(++)CD16(-)), intermediate (CD14(++)CD16(+)), non-classical (CD14(low/+)CD16(++)) and transitional (CD14(+)CD16(-)) monocyte subsets and activated (CD38(+)HLA-DR(+)) CD8(+) T-cells at baseline. Plasma biomarkers were assessed by multiplex Luminex assay. High-resolution B-mode ultrasounds of right carotid arteries were obtained. Changes in CIMT over two years at the right common carotid artery (CIMTCCA) and right bifurcation (CIMTBIF) were outcome variables.

Results

We studied 50 subjects: 84% male, median age 49 (Q1, Q3; 46, 56) years, median CD4 count 461 (317, 578) cells/mm(3), and with HIV RNA ≤ 50 copies/mL in 84%. Change in CIMTBIF correlated with log values of baseline absolute count of non-classical monocytes (r = 0.37, p = 0.020), and with MCP-1 (r = 0.42, p = 0.0024) and TNF-α (r = 0.30, p = 0.036) levels. In multivariable linear regression, only non-classical monocytes and MCP-1 predicted the change in CIMTBIF, independent of Framingham Risk Score and baseline CIMTBIF. No correlation was noted between CD8 T-cell activation and CIMTBIF change. Monocyte subsets, CD8 T-cell activation, and biomarker concentrations were not correlated with changes in CIMTCCA.

Conclusions

Our findings highlight the role of non-classical monocytes and MCP-1 in the progression of CIMTBIF in HIV-infected individuals on stable ART independent of traditional cardio-metabolic risk factors.

Abstract: 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.

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.