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Objective: To assess the screening characteristics of World Health Organization (WHO) body mass index action points for cardiometabolic syndrome (CMS) in Native Hawaiians and people of Asian ancestry (ie, Filipino and Japanese).Design and Setting: Cross-sectional data were collected from 1,452 residents of a rural community of Hawai'i between 1997 and 2000, of which 1,198 were analyzed in this study. Ethnic ancestry was determined by self-report.Main Outcome Measures: Metabolic status was assessed using National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATPIII) criteria. Screening characteristics of WHO criteria for overweight and obesity were compared to WHO public health action points or to WHO West Pacific Regional Office (WPRO) cut-points.Results: Among Asian-ancestry participants, WHO public health action points improved both sensitivity and specificity for detecting CMS. However, similar improvements were not observed for WPRO criteria for Native Hawaiians. Moreover, predictive values were high regardless of which criteria were utilized due to high CMS prevalence.Conclusions: WHO public health actions points for Asians provide a significant improvement in sensitivity in detection of CMS. However, predictive value, which varies greatly with disease prevalence, should be considered when deciding which criteria to apply. [ABSTRACT FROM AUTHOR]

To express object transfer, Cantonese-speakers use a 'ditransitive' ([V-R-T] or [V-T-R] where V=Verb, T=Theme, R=Recipient), or a more complex prepositional/serial-verb (P/SV) construction. Clausal elements in Cantonese datives can be optional (resulting in 'full' versus 'non-full' forms) or appear in variant orders (full non-canonical and full canonical). We report on usage of dative constructions with the word bei2 'to give' in 86 parents and 53 three-year-old children during conversations. The parents used more P/SV than ditransitive bei2-datives, and vice versa for the children. Both groups showed a similar usage pattern of optional elements and variant structures in their ditransitive and P/SV bei2-datives. The roles of multiple construction types, optional elements and variant structures in children's learning of bei2-dative constructions are described. [ABSTRACT FROM AUTHOR]

Acquired Immunodeficiency Syndrome (AIDS) has become the biggest problem facing the health profession of Thailand today. The Ministry of Public Health reports that there are 400,000 individuals in Thailand already infected with the Human Immunodeficiency Virus (HIV) and is predicting that 4 million will be infected by the year 2000. This explosive epidemic first occurred among intravenous drug abusers (IVDAs) and subsequently spread to other high risk groups, especially prostitutes. The heterosexual population was next affected. The AIDS problem in Thailand was seen close-up by this writer, then a fourth year medical student, studying during an international health elective. At all three hospitals where I worked, I encountered large numbers of AIDS related admissions. Ten percent of medical beds at a Bangkok hospital were occupied by patients with AIDS related problems. In comparison, two hospitals located in the northern province of Chiang Mai had 15-20% and 30-40% of their beds occupied by patients with AIDS complications. Opportunistic infections were the primary reason for admissions. This paper describes the current AIDS epidemic in Thailand and the preventive measures being undertaken to combat it. Strategies to combat AIDS focus on preventive measures. The current program in Thailand emphasizes AIDS education and awareness, the promotion of condom usage, decreasing needle sharing, the screening of donated blood, and the development of the GP160 vaccine. The program, however, has been undermined by the country's well organized sex industry. Without a clear commitment from the Thai government, Thailand faces serious health and economic consequences from this epidemic in the coming decade. [ABSTRACT FROM AUTHOR]

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., (© 2024. The Author(s).)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Yoon, Dean, Jiyarom, Khadka, Deng, Nerurkar, Chow, Shikuma, Devendra, Koh and Park.)

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.

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 m 2 , respectively; p  = 0.071). In univariable analysis, HIV status was marginally associated with decreased eGFR (β 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.

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 CD16 Lo 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., (© 2023. Springer Nature Limited.)

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.

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., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Helen Chu reported consulting for Merck, GSK, Pfizer, Ellume, Janssen, Vindico CME, and the Bill and Melinda Gates Foundation, and receiving research support from Gates Ventures, Ellume, and Sanofi Pasteur. She also serves as a co-investigator on studies funded by Pfizer, Novavax, and GSK. Maged Costantine reported receiving grant support for work not related to RECOVER work/publications from Baxter International and Siemens Healthcare and personal consulting fees not related to this paper from Progenity, Quidel Ortho, and Siemens Healthcare. Kristine Erlandson reported research funding from Gilead Sciences and consulting payments from Gilead Sciences, Merck, and ViiV Pharmaceuticals, all paid to the University of Colorado. Emily Gallagher reported consulting for Novartis, Flare Therapeutics and Seagen. Edward Gardner reported research support (clinical trials) from Gilead Sciences, ViiV Healthcare, and Cepheid. Jason Goldman reported research support from Gilead, Eli Lilly and Regeneron; grants from Gilead, Merck (BARDA); personal fees for consulting from Gilead, Eli Lilly; and non-financial support from Adaptive Biotechnologies and Labcorp/Monogram Biosciences outside the submitted work. Timothy Heinrich reported grant support from Merck Inc. and consulting fees from Roche. Rachel Hess reported serving as Data Safety Monitoring Board member for Astellas Pharmaceuticals unrelated to the current work. Leora Horwitz reported being a member of the National Academy of Medicine Committee on the Long-Term Health Effects Stemming from COVID-19 and Implications for the Social Security Administration. Priscilla Hsue reported receiving honoraria from Gilead and Merck unrelated to study topic, receiving study drug from Regeneron unrelated to study topic, and receiving a research grant from Novartis. Judith James reported OMRF has licensed her IP to Progentec Biosciences, has received grant support from Progentec Biosciences, and serves on Advisory Committees to Glaxo Smith Klein, Merck and Novartis. Arthur Kim reports providing educational materials to Clinical Care Options and UpToDate and serving on a Data Safety Monitoring board for Kintor Pharmaceuticals, Ltd. Bruce Levy reported serving as a consultant for AstraZeneca, Entrinsic Biosciences, Gossamer Bio and Nocion Therapeutics and receiving research support from Amgen, Genentech, GlaxoSmithKline, Pieris Pharmaceuticals, SRA and Sanofi unrelated to the current work. Vincent Marconi reported receiving grants from NIH during the conduct of the study and grants from NIH, Veteran Affairs, and Centers for Disease Control and Prevention; grants, personal fees, nonfinancial support, and other from Lilly and Gilead; grants and personal fees from ViiV; and nonfinancial support from Bayer outside the submitted work. Grace McComsey reported serving as consultant for Merck, Gilead, ViiV, Janssen and have received research support from Pfizer, Vanda, Genentech, Roche, Redhill and Cognivue. Torri Metz reported being a site PI and a participant in the medical advisory board for the planning of a Pfizer clinical trial of SARS-CoV-2 vaccination in pregnancy. She also reported being a site PI for a Pfizer study evaluating the pharmacokinetics of Paxlovid in pregnant people with COVID-19. Janet Mullington reported support for investigator-initiated research by "Open Medicine Foundation and the Patient-Led Research Collaborative" Princess Ogbogu reported research support from Astrazeneca, GSK, Blueprint medical; advisory board for Astrazeneca, GSK, Sanofi, Kalvista; and consulting for Astrazeneca, GSK Sairam Parthasarathy reported research funding to Institution from Sergey Brin foundation of COVID and Long-COVID research. Michael Peluso reported consulting fees from Gilead Sciences and AstraZeneca, and service on data safety monitoring board for American Gene Technologies. Sean Quigley reported service on speaker Board for Servier, Alnylam, Agios; service on advisory board for Recordati, Alexion. Franz Rischard reported research support from NIH/NHLBI, United Therapeutics, Acceleron/Merck, Janssen, Insmed, Aerovate, and Bayer; and consulting/advisory compensation from Acceleron and Bayer. Nadine Rouphael reported being a consultant for ICON and EMMES as a safety consultant for clinical trials; service on the advisory boards for Moderna; funds to institution from Sanofi, Lilly, Merck, Quidel and Pfizer. PJ Utz reported stock ownership of Gilead and PI of biomarker studies for Pfizer STOP-PASC paxlovid trial Juan Wisnivesky received receiving consulting honorarium from Sanofi, Banook, Prospero, PPD and Atea and research grants from Sanofi, Regeneron, Axella, and Arnold Consultants., (Copyright: © 2023 Horwitz et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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-1β, 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Park, Dean, Jiyarom, Gangcuangco, Shah, Awamura, Ching, Nerurkar, Chow, Igno, Shikuma and Devendra.)

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.

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.

Background: Low-density granulocytes (LDGs) are a distinct subset of neutrophils whose increased abundance is associated with the severity of COVID-19. However, the long-term effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on LDG levels and phenotypic alteration remain unexplored., Methods: Using participants naïve to SARS-CoV-2 (NP), infected with SARS-CoV-2 with no residual symptoms (NRS), and infected with SARS-CoV-2 with chronic pulmonary symptoms (PPASC), we compared LDG levels and their phenotype by measuring the expression of markers for activation, maturation, and neutrophil extracellular trap (NET) formation using flow cytometry., Results: The number of LDGs was elevated in PPASC compared to NP. Individuals infected with SARS-CoV-2 (NRS and PPASC) demonstrated increased CD10 + and CD16 hi subset counts of LDGs compared to NP group. Further characterization of LDGs demonstrated that LDGs from COVID-19 convalescents (PPASC and NRS) displayed increased markers of NET forming ability and aggregation with platelets compared to LDGs from NP, but no differences were observed between PPASC and NRS., Conclusions: Our data from a small cohort study demonstrates that mature neutrophils with a heightened activation phenotype remain in circulation long after initial SARS-CoV-2 infection. Persistent elevation of markers for neutrophil activation and NET formation on LDGs, as well as an enhanced proclivity for platelet-neutrophil aggregation (PNA) formation in COVID-19 convalescent individuals may be associated with PPASC prognosis and development., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Dean, Devendra, Jiyarom, Subia, Tallquist, Nerurkar, Chang, Chow, Shikuma and Park.)

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., (Copyright © 2022 The Authors.)

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., (© 2022 The Obesity Society.)

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., Competing Interests: Conflict of Interest All authors report no conflict of interest., (Published by Elsevier Ltd.)

Emtricitabine/tenofovir disoproxil fumarate [FTC-TDF] is a daily oral medication taken by HIV-negative individuals for pre-exposure prophylaxis (PrEP) to prevent human immunodeficiency virus (HIV) infection. A higher incidence of sexually transmitted infections (STIs) among PrEP users has been reported compared to STI incidence before PrEP use. Asymptomatic incident STI rates were investigated among 78 patients presenting for PrEP in Honolulu, Hawai'i, from April 2018 to May 2019. Testing for oropharyngeal gonorrhea, urethral gonorrhea and chlamydia, rectal gonorrhea and chlamydia, and syphilis was performed. Incident STI percentages were calculated at each follow-up visit. Ninety-seven percent of patients were men who have sex with men (MSM). Forty-seven percent of patients had follow-up data 6 months after initiation and 28% after 1 year. Thirty-two percent of patients self-reported an STI before initiating PrEP. More than half reported anonymous partners. There were 35 positive STI tests during the study period, and 25% of patients had one or more positive tests during this time. At initiation, 17% of patients were found to have an STI, followed by 16% at 3 months, 14% at 6 months, 8% at 9 months, and 5% at 12 months. At all visits, chlamydia was the most common STI detected; at 6 months, 18% of all rectal tests were positive for chlamydia. There were inconsistent condom use and high STI rates from screening during PrEP initiation and follow-up, offering an opportunity to identify asymptomatic STIs in this population. This study is the first report in Hawai'i of STI rates among PrEP users., (©Copyright 2021 by University Health Partners of Hawai‘i (UHP Hawai‘i).)

Background: Long-term neurocognitive outcomes following first-line suppressive anti-retroviral therapy (ART) remain uncertain for individuals with HIV and hepatitis C (HCV) co-infection. The study examined neurocognitive performance before and after 72 weeks of ART using repeated multivariate analyses and latent trajectory models. Methods: One hundred and sixty adults with chronic, untreated HIV infection ( n = 80 with HCV co-infection and n = 80 HIV mono-infected) and 80 demographically similar healthy controls were recruited from the Hospital for Tropical Diseases in Ho Chi Minh City and the surrounding community, respectively. Neurocognitive measures (adapted for use in Vietnam) and liver enzyme tests were compared across groups at baseline. Repeated multivariate and group-based trajectory analyses (GBTA) examined neurocognitive subgroup profiles of the co-infected individuals after 72 weeks of de novo efavirenz- ( n = 41) or raltegravir-based ( n = 39) ART. Results: Baseline analyses revealed worse motor function in HIV-HCV co-infected individuals compared to both comparison groups. Longitudinal analyses revealed improved neurocognitive performance by week 48 for most participants regardless of treatment arm. GBTA identified a subgroup (35% of HIV-HCV sample) with persistent motor impairment despite otherwise successful ART. Higher HIV viral load and lower CD4 + T cell count at baseline predicted persistent motor dysfunction. Liver indices and ART regimen did not predict neurocognitive outcomes in HIV-HCV co-infected individuals. Conclusions: Most HIV-HCV co-infected individuals achieve normative neurocognitive performance after 48 weeks of de novo suppressive ART. However, individuals with more severe HIV disease prior to ART exhibited motor impairment at baseline and 72 weeks after otherwise successful treatment. Interventions aimed at improving motor symptoms at the time of HIV treatment onset may improve long-term clinical outcomes in HIV-HCV co-infected adults., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Paul, Shikuma, Chau, Ndhlovu, Thanh, Belden, Chow, Chew, Premeaux, Ly, McBride, Bolzenius and Le.)

Targeting inhibitory immune checkpoint receptor pathways has shown remarkable success in improving anticancer T cell responses for the elimination of tumors. Such immunotherapeutic strategies are being pursued for HIV remission. Metformin has shown favorable clinical outcomes in enhancing the efficacy of programmed cell death-1 (PD-1) blockade and restoring antitumor T cell immunity. Furthermore, monocytes are known to be a strong predictor of progression-free survival in response to anti-PD-1 immunotherapy. In a single-arm clinical trial, we evaluated the immunological effects over an 8-week course of metformin therapy in seven euglycemic, virally suppressed HIV-infected participants on combination antiretroviral therapy (cART). We assessed changes in peripheral HIV-Gag-specific T cell responses to immune checkpoint blockade (ICB) with anti-PD-L1 and anti-T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) monoclonal antibodies (mAbs) and changes in CD8 T cell and monocyte subsets using flow cytometry. Study participants were all male, 71% (5/7) Caucasian, with a median age of 61 years, CD4 count of 739 cells/μL, and plasma HIV RNA of <50 copies/mL on stable cART for >1 year. Ex vivo polyfunctional HIV-Gag-specific CD8 T cell responses to anti-PD-L1 mAb significantly improved ( p  < .05) over the 8-week course of metformin therapy. Moreover, frequencies of both intermediate (CD14 + CD16 + ; r  = 0.89, p  = .01) and nonclassical (CD14 low CD16 + ; r  = 0.92, p  = .01) monocytes at entry were predictive of the magnitude of the anti-HIV CD8 T cell responses to PD-L1 blockade. Collectively, these findings highlight that 8-week course of metformin increases the polyfunctionality of CD8 T cells and that baseline monocyte subset frequencies may be a potential determinant of PD-L1 blockade efficacy. These data provide valuable information for HIV remission trials that utilize ICB strategies to enhance anti-HIV CD8 T cell immunity.

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 (<50 copies/mL). Twenty-five PLWH had detectable carotid plaque. MCPT correlated with monocyte chemoattractant protein-1 (MCP-1; r  = 0.487, p  = .016), tumor necrosis factor-α (TNF-α; r  = 0.474 p  = .019), soluble vascular cell adhesion molecule-1 (sVCAM-1; r  = 0.472, p  = .020), apolipoprotein B6 (ApoB6; r  = -0.473, p  = .019), and interleukin-6 (IL-6; r  = 0.455, p  = .025). In a multivariable regression model, MCP-1, TNF-α, and sVCAM-1 remained significant after adjustment for age. Carotid plaque burden was associated with increased inflammatory, monocyte, and endothelial measures, including MCP-1, TNF-α, and sVCAM-1 levels. Further investigation on the evolution or severity of plaque burden in this population is warranted.

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-1β, IL-6, IL-8, or TNF-α) were determined by flow cytometry. Higher monocyte IL-1β 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-1β and IL-8 responses should be considered in addition to ART in order to limit adverse cardio-metabolic outcomes.

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 < 50 copies/mL] and 55 HIV- [54.0 ± 7.5 years old] individuals. Among HIV+ participants, recent cannabis use (within 12 months) was associated with diminished RSFC, including of occipital cortex, controlling for age. Duration of use correlated negatively with volumes of all regions (most strikingly the nucleus accumbens) independently of recent use and intracranial volume. Recent use was associated with larger caudate and white matter volumes and lower soluble vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1 concentrations. Duration of use correlated positively with psychomotor speed. Use > 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., Competing Interests: Conflicts of Interest The authors declare no conflicts of interest regarding the publication of this paper.

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.

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 (CD14 low/＋ 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: Cellular 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., Methods: PLWH ≥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., Results: PLWH had a median age of 51 years. Majority were male (88.6%), Caucasian (57.7%), and with undetectable plasma HIV RNA <50 copies/mL (84.6%). Median CI level was lower in PLWH compared with the HIV-seronegative group (65.5 vs 155.0 optical density/μg protein x 103, p <0.0001). There was no significant difference in median CIV levels. Lower OXPHOS levels correlated with lower CD4% and CD4/CD8 ratio. On multivariable linear regression adjusted for age, current use of zidovudine/didanosine, and HIV RNA (detectable versus undetectable), lower OXPHOS levels were significantly associated with higher MPO, SAA, SAP, and sVCAM, and higher frequencies of intermediate (CD14++CD16+) monocytes and TIGIT+TIM3+ CD4 T-cell (p<0.01)., Conclusion: CI 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., Competing Interests: The authors have declared that no competing interests exist.

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  < .001). ATP levels in adipocytes were higher in both ARV-naive and nonlipoatrophic HIV + patients compared to seronegative controls, but significantly lower in adipocytes and preadipocytes of lipoatrophic versus other HIV + patients. Fat mtDNA copies/cell and OXPHOS mtRNA transcripts were lower in lipoatrophic patient samples compared to HIV seronegative. The ratio of specific OXPHOS transcripts to each other was significantly higher in nonlipoatrophic patients versus all groups, and this ratio correlated significantly with ATP levels in adipocytes. Thus, HIV infection is associated with an increase in adipose tissue ATP stores. Decreases in adipose mtDNA and OXPHOS mtRNA are found in those with HIV on ARV; however, ATP level is effected only in patients displaying lipoatrophy.

Cognitive dysfunction persists in 30-50% of chronically HIV-infected individuals despite combination antiretroviral therapy (ART). Although monocytes are implicated in poor cognitive performance, distinct biological mechanisms associated with cognitive dysfunction in HIV infection are unclear. We previously showed that a regulatory region of the interferon regulatory factor-8 ( IRF8 ) gene is hyper-methylated in HIV-infected individuals with cognitive impairment compared to those with normal cognition. Here, we investigated IRF-8 protein expression and assessed relationships with multiple parameters associated with brain health. Intracellular IRF-8 expression was measured in cryopreserved peripheral blood mononuclear cells from chronically HIV-infected individuals on ART using flow cytometry. Neuropsychological performance was assessed by generating domain-specific standardized (NPZ) scores, with a global score defined by aggregating individual domain scores. Regional brain volumes were obtained by magnetic resonance imaging and soluble inflammatory factors were assessed by immunosorbent assays. Non-parametric analyses were conducted and statistical significance was defined as p < 0.05. Twenty aviremic (HIV RNA<50 copies/ml) participants, 84% male, median age 51 [interquartile range (IQR) 46, 55], median CD4 count 548 [439, 700] were evaluated. IRF-8 expression was highest in plasmacytoid dendritic cells (pDCs). Assessing cognitive function, lower IRF-8 density in classical monocytes significantly correlated with worse NPZ&#95;learning memory (LM; rho = 0.556) and NPZ&#95;working memory (WM; rho = 0.612) scores, in intermediate monocytes with worse NPZ&#95;LM (rho = 0.532) scores, and in non-classical monocytes, lower IRF-8 correlated with worse global NPZ (rho = 0.646), NPZ&#95;LM (rho = 0.536), NPZ&#95;WM (rho = 0.647), and NPZ&#95;executive function (rho = 0.605) scores. In myeloid DCs (mDCs) lower IRF-8 correlated with worse NPZ&#95;WM (rho = 0.48) scores and in pDCs with worse NPZ&#95;WM (rho = 0.561) scores. Declines in IRF-8 in classical monocytes significantly correlated with smaller hippocampal volume (rho = 0.573) and in intermediate and non-classical monocytes with smaller cerebral white matter volume (rho = 0.509 and rho = 0.473, respectively). IRF-8 density in DCs did not significantly correlate with brain volumes. Among biomarkers tested, higher soluble ICAM-1 levels significantly correlated with higher IRF-8 in all monocyte and DC subsets. These data may implicate IRF-8 as a novel transcription factor in the neuropathophysiology of brain abnormalities in treated HIV and serve as a potential therapeutic target to decrease the burden of cognitive dysfunction in this population., (Copyright © 2019 D'Antoni, Kallianpur, Premeaux, Corley, Fujita, Laws, Ogata-Arakaki, Chow, Khadka, Shikuma and Ndhlovu.)

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 (R 2 : 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., (© 2019 The Obesity Society.)

Background: Chronic HIV is associated with increased inflammation and tissue fibrosis despite suppressive antiretroviral therapy (ART). Monocytes and macrophages have been implicated in the pathogenesis of fibrosis, facilitated by chemokine receptor interactions. Methods: We assessed systemic fibrotic biomarkers (transforming growth factor beta-1 [TGF-β1], thrombospondin-1 [TSP-1], C-terminal pro-peptide of collagen type I [CICP], and IL-11) in banked plasma from a previously published 24-week open-label trial of cenicriviroc (CVC), a dual CCR2/CCR5 antagonist, among persons living with HIV (PLWH) on stable ART with undetectable plasma HIV RNA (<50 copies/mL). Fibrotic markers were assessed by ELISA and Luminex. Untreated HIV-seronegative individuals (n = 6) of similar age and demographics served as a comparator group. Results: Median age of PLWH was 55 years. At baseline, PLWH had higher median TGF-β1 (2.11 vs 1.62 ng/mL, p = 0.01), TSP-1 (236.74 vs 83.29 ng/mL, p < 0.0001), and CICP (200.46 vs 111.28 ng/mL, p = 0.01), but lower IL-11 (36.00 vs 53.74 pg/mL, p = 0.01) compared to HIV-uninfected individuals. Over 24 weeks, median TGF-β1 (-0.74 ng/mL, p = 0.006), TSP-1 (-52.12 ng/mL, p < 0.0001), and CICP (-28.12 ng/mL, p < 0.0001) decreased and IL-11 (28.98 pg/mL, p < 0.0001) increased in PLWH. At week 24, TGF-β1, CICP, and IL-11 were similar between the two groups (p > 0.05), while TSP-1 remained elevated in PLWH (p = 0.009) compared to controls. Conclusions: PLWH had higher levels of the plasma fibrotic markers TGF-β1, TSP-1, and CICP. After 24 weeks of CVC, fibrotic markers generally returned to levels comparable to HIV-uninfected controls. Dual CCR2 and CCR5 blockade may ameliorate the detrimental fibrotic events that persist in treated 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.

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. 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. 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). 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.

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 (VO 2MAX ) 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 VO 2MAX 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.

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., (Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

The β-lactamase inhibitory protein (BLIP) binds and inhibits a wide range of class A β-lactamases including the TEM-1 β-lactamase (K i = 0.5 nM), which is widely present in Gram-negative bacteria, and the KPC-2 β-lactamase (K i = 1.2 nM), which hydrolyzes virtually all clinically useful β-lactam antibiotics. The extent to which the specificity of a protein that binds a broad range of targets can be modified to display narrow specificity was explored in this study by engineering BLIP to bind selectively to KPC-2 β-lactamase. A genetic screen for BLIP function in Escherichia coli was used to narrow the binding specificity of BLIP by identifying amino acid substitutions that retain affinity for KPC-2 while losing affinity for TEM-1 β-lactamase. The combination of single substitutions yielded the K74T:W112D BLIP variant, which was shown by inhibition assays to retain high affinity for KPC-2 with a K i of 0.4 nM, while drastically losing affinity for TEM-1 with a K i > 10 μM. The K74T:W112D mutant therefore binds KPC-2 β-lactamase 3 times more tightly while binding TEM-1 > 20000-fold more weakly than wild-type BLIP. The K74T:W112D BLIP variant also exhibited low affinity (K i > 10 μM) for other class A β-lactamases. The high affinity and narrow specificity of BLIP K74T:W112D for KPC-2 β-lactamase suggest it could be a useful sensor for the presence of this enzyme in multidrug-resistant bacteria. This was demonstrated with an assay employing BLIP K74T:W112D conjugated to a bead to specifically pull-down and detect KPC-2 β-lactamase in lysates from clinical bacterial isolates containing multiple β-lactamases.

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., Competing Interests: The authors have no conflicts of interest to disclose.

Protein-protein interactions (PPIs) play a central role in most biological processes, and therefore represent an important class of targets for therapeutic development. However, disrupting PPIs using small-molecule inhibitors (SMIs) is challenging and often deemed as "undruggable." We developed a cell-based functional assay for high-throughput screening to identify SMIs for steroid receptor coactivator-3 (SRC-3 or AIB1), a large and mostly unstructured nuclear protein. Without any SRC-3 structural information, we identified SI-2 as a highly promising SMI for SRC-3. SI-2 meets all of the criteria of Lipinski's rule [Lipinski et al. (2001) Adv Drug Deliv Rev 46(1-3):3-26] for a drug-like molecule and has a half-life of 1 h in a pharmacokinetics study and a reasonable oral availability in mice. As a SRC-3 SMI, SI-2 can selectively reduce the transcriptional activities and the protein concentrations of SRC-3 in cells through direct physical interactions with SRC-3, and selectively induce breast cancer cell death with IC50 values in the low nanomolar range (3-20 nM), but not affect normal cell viability. Furthermore, SI-2 can significantly inhibit primary tumor growth and reduce SRC-3 protein levels in a breast cancer mouse model. In a toxicology study, SI-2 caused minimal acute cardiotoxicity based on a hERG channel blocking assay and an unappreciable chronic toxicity to major organs based on histological analyses. We believe that this work could significantly improve breast cancer treatment through the development of "first-in-class" drugs that target oncogenic coactivators.

Cross-sectional relationships were examined between regional brain volumes and mitochondrial DNA (mtDNA) 8-hydroxy-2-deoxyguanosine (8-oxo-dG) in peripheral blood mononuclear cells (PBMCs) of 47 HIV patients [mean age 51years; 81% with HIV RNA ≤50copies/mL] on combination antiretroviral therapy. The gene-specific DNA damage and repair assay measured mtDNA 8-oxo-dG break frequency. Magnetic resonance imaging was performed at 3T. Higher mtDNA 8-oxo-dG was associated with lateral ventricular enlargement and with decreased volumes of hippocampus, pallidum, and total subcortical gray matter, suggesting the involvement of systemic mitochondrial-specific oxidative stress in chronic HIV-related structural brain changes and cognitive difficulties. Clarification of the mechanism may provide potential therapeutic targets., (Copyright © 2016 Elsevier B.V. and Mitochondria Research Society. All rights reserved.)

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.

Objective: High rates of albuminuria are observed among HIV-infected individuals on stable antiretroviral therapy (ART). Though pro-inflammatory and pro-fibrotic responses are described as components of albuminuria in the general population, it is unclear how these responses are associated to albuminuria in ART-treated chronic HIV. We investigated the relationship of monocyte subsets and urine inflammatory and fibrotic biomarkers to albuminuria in ART-treated HIV-infected participants., Design and Methods: Cross-sectional analyses were performed on Hawaii Aging with HIV-cardiovascular disease study cohort participants who were required at entry to be ≥40 years old and on ART ≥3 months. Monocyte subpopulations were determined in banked peripheral blood mononuclear cells (PBMC) using multi-parametric flow-cytometry. Entry random urine samples were assessed for albumin-to-creatinine ratios (UACR). Urine samples were measured for inflammatory and fibrotic biomarkers using Luminex technology., Results: Among 96 HIV-infected subjects with measured UACR (87% male, 59% Caucasian, and 89% undetectable HIV RNA with median CD4 of 495.5 cells/μL), 18 patients (19%) had albuminuria. Non-classical (CD14low/+CD16++) monocytes were significantly elevated in subjects with albuminuria (p = 0.034) and were correlated to UACR (r = 0.238, p = 0.019). Elevated non-classical monocyte counts were significant predictors of worsening albuminuria, independent of traditional- and ART-associated risk factors (β = 0.539, p = 0.007). Urine TGF-β1 and collagen-IV were significantly higher in albuminuric compared to non-albuminuric participants (TGF-β1; p = 0.039 and collagen-IV; p = 0.042). Urine TGF-β1 was significantly correlated with non-classical monocyte counts (r = 0.464, p = 0.017)., Conclusion: Alterations in monocyte subpopulations and urine pro-fibrotic factors may play a role in kidney dysfunction during chronic HIV infection and warrants further study.