Association of T-cell subtypes with macrophage-specific arterial infiltration in PWH.

People with human immunodeficiency virus (HIV, PWH) face an increased risk of cardiovascular disease (CVD) compared to the general population. We previously demonstrated that people with (versus without) HIV have higher macrophage-specific arterial infiltration in relation to systemic monocyte activation. We now show that select T lymphocyte subpopulations (naïve CD4+, effector memory CD4+, and central memory CD8+) are differentially associated with macrophage-specific arterial infiltration among participants with versus without HIV, with evidence of interaction by HIV status. Our results suggest that among PWH, circulating T lymphocytes associate with macrophage-specific arterial infiltration, of relevance to atherogenesis and CVD risk. CLINICAL TRIALS REGISTRATION: NCT02542371.

Efficacy and safety of tesamorelin in people with hiv on integrase inhibitors.

OBJECTIVE: Tesamorelin is the only FDA-approved therapy to treat abdominal fat accumulation in people with HIV (PWH). Phase III clinical trials were conducted prior to the introduction of integrase inhibitors (INSTIs), which are now a mainstay of HIV antiretroviral therapy. DESIGN: We leveraged a randomized double-blind trial of 61 PWH and metabolic dysfunction-associated steatotic liver disease to evaluate the efficacy and safety of tesamorelin 2 mg once daily versus identical placebo among participants on INSTI-based regimens at baseline. METHODS: In the parent clinical trial, visceral fat cross-sectional area, hepatic fat fraction, and trunk-to-appendicular fat ratio were quantified using magnetic resonance imaging, proton magnetic resonance spectroscopy, and dual-energy x-ray absorptiometry, respectively, at baseline and 12 months. Metabolic and safety outcomes were compared between treatment arms. RESULTS: Among 38 participants on INSTI-based regimens at baseline, 15 individuals on tesamorelin and 16 individuals on placebo completed the 12-month study. Tesamorelin led to significant declines in visceral fat (median [interquartile range]: -25 [-93, -2] vs. 14 [3, 41] cm2, P = 0.001), hepatic fat (-4.2% [-12.3%, -2.7%] vs. -0.5% [-3.9%, 2.7%], P = 0.01), and trunk-to-appendicular fat ratio (-0.1 [-0.3, 0.0] vs. 0.0 [-0.1, 0.1], P = 0.03). Tesamorelin was well-tolerated with a similar frequency of adverse events including hyperglycemia between groups. CONCLUSIONS: The current analysis provides the first dedicated data on the efficacy and safety of tesamorelin among PWH on INSTI-based regimens. Despite the association of INSTI use with weight gain and adipose tissue dysfunction, tesamorelin had beneficial effects on body composition with no exacerbation of glycemic control.

In Utero Exposure to Maternal SARS-CoV-2 Infection Is Associated With Higher Left Ventricular Mass in Toddlers.

The intrauterine environment plays a critical role in shaping chronic disease risk over the life course. We prospectively evaluated cardiometabolic outcomes in toddlers born to mothers with versus without prenatal severe acute respiratory syndrome coronavirus 2 infection. Children with in utero severe acute respiratory syndrome coronavirus 2 exposure had higher left ventricular mass in association with altered maternal immunologic indices.

Adiposity, immunity, and inflammation: interrelationships in health and disease: a report from 24th Annual Harvard Nutrition Obesity Symposium, June 2023.

The rapidly evolving field of immunometabolism explores how changes in local immune environments may affect key metabolic and cellular processes, including that of adipose tissue. Importantly, these changes may contribute to low-grade systemic inflammation. In turn, chronic low-grade inflammation affecting adipose tissue may exacerbate the outcome of metabolic diseases. Novel advances in our understanding of immunometabolic processes may critically lead to interventions to reduce disease severity and progression. An important example in this regard relates to obesity, which has a multifaceted effect on immunity, activating the proinflammatory pathways such as the inflammasome and disrupting cellular homeostasis. This multifaceted effect of obesity can be investigated through study of downstream conditions using cellular and systemic investigative techniques. To further explore this field, the National Institutes of Health P30 Nutrition Obesity Research Center at Harvard, in partnership with Harvard Medical School, assembled experts to present at its 24th Annual Symposium entitled "Adiposity, Immunity, and Inflammation: Interrelationships in Health and Disease" on 7 June, 2023. This manuscript seeks to synthesize and present key findings from the symposium, highlighting new research and novel disease-specific advances in the field. Better understanding the interaction between metabolism and immunity offers promising preventative and treatment therapies for obesity-related immunometabolic diseases.

Growth hormone and nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is a prevalent cause of liver disease and metabolic comorbidities. Obesity is strongly associated with NAFLD and is also a state of relative deficiency of growth hormone (GH). Evidence supports a role of reduced GH and insulin-like growth factor-1 (IGF-1) in NAFLD pathogenesis. Physiological actions of GH in the liver include suppression of de novo lipogenesis (DNL) and promotion of lipid beta-oxidation, and GH also appears to have anti-inflammatory actions. Physiologic actions of IGF-1 include suppression of inflammatory and fibrogenic pathways important in the evolution from steatosis to steatohepatitis and fibrosis. Rodent models of impaired hepatic GH signaling show the development of steatosis, sometimes accompanied by inflammation, hepatocellular damage, and fibrosis, and these changes are ameliorated by treatment with GH and/or IGF-1. In humans, individuals with GH deficiency and GH resistance demonstrate an increased prevalence of NAFLD compared to controls, with improvement in hepatic lipid, steatohepatitis, and fibrosis following GH replacement. As a corollary, individuals with GH excess demonstrate lower hepatic lipid compared to controls along with increased hepatic lipid following treatment to normalize GH levels. Clinical trials demonstrate that augmentation of GH reduces hepatic lipid content in individuals with NAFLD and may also ameliorate steatohepatitis and fibrosis. Taken together, evidence supports an important role for perturbations in the GH/IGF-1 axis as one of the pathogenic mechanisms of NAFLD and suggests that further study is needed to assess whether augmentation of GH and/or IGF-1 may be a safe and effective therapeutic strategy for NAFLD.

The Neurobiology of Eating Behavior in Obesity: Mechanisms and Therapeutic Targets: A Report from the 23rd Annual Harvard Nutrition Obesity Symposium.

Obesity is increasing at an alarming rate. The effectiveness of currently available strategies for the treatment of obesity (including pharmacologic, surgical, and behavioral interventions) is limited. Understanding the neurobiology of appetite and the important drivers of energy intake (EI) can lead to the development of more effective strategies for the prevention and treatment of obesity. Appetite regulation is complex and is influenced by genetic, social, and environmental factors. It is intricately regulated by a complex interplay of endocrine, gastrointestinal, and neural systems. Hormonal and neural signals generated in response to the energy state of the organism and the quality of food eaten are communicated by paracrine, endocrine, and gastrointestinal signals to the nervous system. The central nervous system integrates homeostatic and hedonic signals to regulate appetite. Although there has been an enormous amount of research over many decades regarding the regulation of EI and body weight, research is only now yielding potentially effective treatment strategies for obesity. The purpose of this article is to summarize the key findings presented in June 2022 at the 23rd annual Harvard Nutrition Obesity Symposium entitled "The Neurobiology of Eating Behavior in Obesity: Mechanisms and Therapeutic Targets." Findings presented at the symposium, sponsored by NIH P30 Nutrition Obesity Research Center at Harvard, enhance our current understanding of appetite biology, including innovative techniques used to assess and systematically manipulate critical hedonic processes, which will shape future research and the development of therapeutics for obesity prevention and treatment.

Accelerated Longitudinal Weight Gain Among Infants With In Utero COVID-19 Exposure.

CONTEXT: Since the initial outbreak of coronavirus disease 2019 (COVID-19), a novel population of children with in utero exposure to maternal infection has emerged whose health outcomes are largely unknown. OBJECTIVE: To compare longitudinal growth trajectories among infants with vs without in utero COVID-19 exposure. METHODS: We conducted a longitudinal cohort study leveraging a prospectively enrolled perinatal biorepository among 149 infants with in utero COVID-19 exposure and 127 unexposed controls. Weight, length, and body mass index (BMI) were abstracted from health records at 0, 2, 6, and 12 months and standardized using World Health Organization growth charts. Analyses were adjusted for maternal age, ethnicity, parity, insurance, and BMI as well as infant sex, birthdate, and breastfeeding. RESULTS: Infants with in utero COVID-19 exposure vs controls exhibited differential trajectories of weight and BMI, but not length, z-score over the first year of life (study group × time interaction, P < .0001 for weight and BMI). Infants born to mothers with prenatal COVID-19 had lower BMI z-score at birth (effect size: -0.35, 95% CI -0.66 to -0.03) and greater gain in BMI z-score from birth to 12 months (effect size: 0.53, 95% CI 0.06 to 0.99). Birth weight z-score mediated a significant proportion of the relationship between COVID-19 exposure and postnatal growth (estimate ± SE, 32 ± 14%, P = .02). CONCLUSION: Infants with in utero COVID-19 exposure exhibited lower birth weight and accelerated weight gain in the first year of life, which may be harbingers of downstream cardiometabolic pathology. Further studies are needed to delineate cardiometabolic sequelae among this emerging global population.

BMI-adjusted adipose tissue volumes exhibit depot-specific and divergent associations with cardiometabolic diseases.

For any given body mass index (BMI), individuals vary substantially in fat distribution, and this variation may have important implications for cardiometabolic risk. Here, we study disease associations with BMI-independent variation in visceral (VAT), abdominal subcutaneous (ASAT), and gluteofemoral (GFAT) fat depots in 40,032 individuals of the UK Biobank with body MRI. We apply deep learning models based on two-dimensional body MRI projections to enable near-perfect estimation of fat depot volumes (R2 in heldout dataset = 0.978-0.991 for VAT, ASAT, and GFAT). Next, we derive BMI-adjusted metrics for each fat depot (e.g. VAT adjusted for BMI, VATadjBMI) to quantify local adiposity burden. VATadjBMI is associated with increased risk of type 2 diabetes and coronary artery disease, ASATadjBMI is largely neutral, and GFATadjBMI is associated with reduced risk. These results - describing three metabolically distinct fat depots at scale - clarify the cardiometabolic impact of BMI-independent differences in body fat distribution.

Plasma osteopontin relates to myocardial fibrosis and steatosis and to immune activation among women with HIV.

OBJECTIVE: Women with HIV (WWH) have heightened heart failure risk. Plasma OPN (osteopontin) is a powerful predictor of heart failure outcomes in the general population. Limited data exist on relationships between plasma OPN and surrogates of HIV-associated heart failure risk. DESIGN: Prospective, cross-sectional. METHODS: We analyzed relationships between plasma OPN and cardiac structure/function (assessed using cardiovascular magnetic resonance imaging) and immune activation (biomarkers and flow cytometry) among 20 WWH and 14 women without HIV (WWOH). RESULTS: Plasma OPN did not differ between groups. Among WWH, plasma OPN related directly to the markers of cardiac fibrosis, growth differentiation factor-15 (ρ = 0.51, P = 0.02) and soluble interleukin 1 receptor-like 1 (ρ = 0.45, P = 0.0459). Among WWH (but not among WWOH or the whole group), plasma OPN related directly to both myocardial fibrosis (ρ = 0.49, P = 0.03) and myocardial steatosis (ρ = 0.46, P = 0.0487). Among the whole group and WWH (and not among WWOH), plasma OPN related directly to the surface expression of C-X3-C motif chemokine receptor 1 (CX3CR1) on nonclassical (CD14-CD16+) monocytes (whole group: ρ = 0.36, P = 0.04; WWH: ρ = 0.46, P = 0.04). Further, among WWH and WWOH (and not among the whole group), plasma OPN related directly to the surface expression of CC motif chemokine receptor 2 (CCR2) on inflammatory (CD14+CD16+) monocytes (WWH: ρ = 0.54, P = 0.01; WWOH: ρ = 0.60, P = 0.03), and in WWH, this held even after controlling for HIV-specific parameters. CONCLUSION: Among WWH, plasma OPN, a powerful predictor of heart failure outcomes, related to myocardial fibrosis and steatosis and the expression of CCR2 and CX3CR1 on select monocyte subpopulations. OPN may play a role in heart failure pathogenesis among WWH. CLINICALTRIALSGOV REGISTRATION: NCT02874703.

Proteomic Analysis of Hepatic Fibrosis in Human Immunodeficiency Virus-Associated Nonalcoholic Fatty Liver Disease Demonstrates Up-regulation of Immune Response and Tissue Repair Pathways.

BACKGROUND: Human immunodeficiency virus (HIV)-associated nonalcoholic fatty liver disease (NAFLD) is characterized by a high prevalence of hepatic fibrosis as a strong clinical predictor of all-cause and liver-specific mortality risk. METHODS: We leveraged data from an earlier clinical trial to define the circulating proteomic signature of hepatic fibrosis in HIV-associated NAFLD. A total of 183 plasma proteins within 2 high-multiplex panels were quantified at baseline and at 12 months (Olink Cardiovascular III; Immuno-Oncology). RESULTS: Twenty proteins were up-regulated at baseline among participants with fibrosis stages 2-3 versus 0-1. Proteins most differentially expressed included matrix metalloproteinase 2 (P < .001), insulin-like growth factor-binding protein 7 (P = .001), and collagen α1(I) chain (P = .001). Proteins were enriched within pathways including response to tumor necrosis factor and aminopeptidase activity. Key proteins correlated directly with visceral adiposity and glucose intolerance and inversely with CD4+ T-cell count. Within the placebo-treated arm, 11 proteins differentially increased among individuals with hepatic fibrosis progression over a 12-month period (P < .05). CONCLUSIONS: Among individuals with HIV-associated NAFLD, hepatic fibrosis was associated with a distinct proteomic signature involving up-regulation of tissue repair and immune response pathways. These findings enhance our understanding of potential mechanisms and biomarkers of hepatic fibrosis in HIV.

Facilitating the transition from paediatric to adult care in endocrinology: a focus on growth disorders.

PURPOSE OF REVIEW: Many childhood-onset growth disorders (COGDs) require continued care into adulthood, and the time of transition between paediatric and adult providers carries a high risk for interruptions in medical care and consequent worsening of disease management. RECENT FINDINGS: Research into best practices for healthcare transition (HCT) describes three distinct stages. Stage 1, transition planning and preparation, begins in the paediatric setting during early adolescence and ensures that the patient has adequate medical knowledge, self-management skills, and readiness for transition. Stage 2, transfer to adult care, occurs with variable timing depending on transition readiness and is best facilitated by warm hand-offs and, when possible, joint visits with the paediatric and adult provider(s) and/or involvement of a care coordinator. Stage 3, intake and integration into adult care, entails retaining the patient in the adult setting, ideally through the involvement of a multidisciplinary approach. SUMMARY: This review covers general principles for ensuring smooth transition of adolescents and young adults (AYA) with COGD, disease-specific medical considerations for paediatric and adult endocrinologists during the transition process, and general and disease-specific resources to assess transition readiness and facilitate transition.

Cardiac strain is lower among women with HIV in relation to monocyte activation.

BACKGROUND: Women with HIV (WWH) face heightened risks of heart failure; however, insights on immune/inflammatory pathways potentially contributing to left ventricular (LV) systolic dysfunction among WWH remain limited. SETTING: Massachusetts General Hospital, Boston, Massachusetts. METHODS: Global longitudinal strain (GLS) is a sensitive measure of LV systolic function, with lower cardiac strain predicting incident heart failure and adverse heart failure outcomes. We analyzed relationships between GLS (cardiovascular magnetic resonance imaging) and monocyte activation (flow cytometry) among 20 WWH and 14 women without HIV. RESULTS: WWH had lower GLS compared to women without HIV (WWH vs. women without HIV: 19.4±3.0 vs. 23.1±1.9%, P<0.0001). Among the whole group, HIV status was an independent predictor of lower GLS. Among WWH (but not among women without HIV), lower GLS related to a higher density of expression of HLA-DR on the surface of CD14+CD16+ monocytes (ρ = -0.45, P = 0.0475). Further, among WWH, inflammatory monocyte activation predicted lower GLS, even after controlling for CD4+ T-cell count and HIV viral load. CONCLUSIONS: Additional studies among WWH are needed to examine the role of inflammatory monocyte activation in the pathogenesis of lower GLS and to determine whether targeting this immune pathway may mitigate risks of heart failure and/or adverse heart failure outcomes. TRIAL REGISTRATION: Clinical trials.gov registration: NCT02874703.

Increased Macrophage-Specific Arterial Infiltration Relates to Noncalcified Plaque and Systemic Immune Activation in People With Human Immunodeficiency Virus.

BACKGROUND: Persistent immune activation is thought to contribute to heightened atherosclerotic cardiovascular disease (ASCVD) risk among people with human immunodeficiency virus (PWH). METHODS: Participants (≥18 years) with or without human immunodeficiency virus (HIV) and without history of clinical ASCVD were enrolled. We hypothesized that increased macrophage-specific arterial infiltration would relate to plaque composition and systemic immune activation among PWH. We applied a novel targeted molecular imaging approach (technetium-99m [99mTc]-tilmanocept single photon emission computed tomography [SPECT]/CT) and comprehensive immune phenotyping. RESULTS: Aortic 99mTc-tilmanocept uptake was significantly higher among PWH (n = 20) than participants without HIV (n = 10) with similar 10-year ASCVD risk (P = .02). Among PWH, but not among participants without HIV, noncalcified aortic plaque volume related directly to aortic 99mTc-tilmanocept uptake at different uptake thresholds. An interaction (P = .001) was seen between HIV status and noncalcified plaque volume, but not calcified plaque (P = .83). Systemic levels of caspase-1 (P = .004), CD14-CD16+ (nonclassical/patrolling/homing) monocytes (P = .0004) and CD8+ T cells (P = .005) related positively and CD4+/CD8+ T-cell ratio (P = .02) inversely to aortic 99mTc-tilmanocept uptake volume. CONCLUSIONS: Macrophage-specific arterial infiltration was higher among PWH and related to noncalcified aortic plaque volume only among PWH. Key systemic markers of immune activation relating to macrophage-specific arterial infiltration may contribute to heightened ASCVD risk among PWH. CLINICAL TRIALS REGISTRATION: NCT02542371.

Racial and ethnic representation among a sample of nutrition- and obesity-focused professional organizations in the United States.

OBJECTIVE: Obesity is a chronic disease that disproportionately affects individuals from nonmajority racial/ethnic groups in the United States. Research shows that individuals from minority racial/ethnic backgrounds consider it important to have access to providers from diverse backgrounds. Health care providers and scientists from minority racial/ethnic groups are more likely than their non-Hispanic White counterparts to treat or conduct research on patients from underrepresented groups. The objective of this study was to characterize the racial/ethnic diversity of nutrition- and obesity-focused professional organizations in the United States. METHODS: This study assessed race/ethnicity data from several obesity-focused national organizations including The Obesity Society, the Academy of Nutrition and Dietetics (AND), the American Society for Nutrition, and the American Board of Obesity Medicine (ABOM). Each organization was queried via emailed survey to provide data on racial/ethnic representation among their membership in the past 5 years and among elected presidents from 2010 to 2020. RESULTS: Two of the three professional societies queried did not systematically track race/ethnicity data at the time of query. Limited tracking data available from AND show underrepresentation of Black (2.6%), Asian (3.9%), Latinx (3.1%), Native Hawaiian or Pacific Islander (1.3%), or indigenous (American Indian or Alaskan Native: 0.3%) individuals compared with the US population. Underrepresentation of racial/ethnic minorities was also reported for ABOM diplomates (Black: 6.0%, Latinx: 5.0%, Native American: 0.2%). Only AND reported having racial/ethnic diversity (20%) among the organization's presidents within the previous decade (2010-2020). CONCLUSIONS: Findings suggest that (1) standardized tracking of race and ethnicity data is needed to fully assess diversity, equity, and inclusion, and (2) work is needed to increase the diversity of membership and leadership at the presidential level within obesity- and nutrition-focused professional organizations. A diverse cadre of obesity- and nutrition-focused health care professionals is needed to further improve nutrition-related health outcomes, including obesity, cardiovascular disease, diabetes, and undernutrition, in this country.

Racial and ethnic representation among a sample of nutrition- and obesity-focused professional organizations in the United States.

BACKGROUND: Obesity is a chronic disease that disproportionately affects individuals from nonmajority racial/ethnic groups in the United States. Research shows that individuals from minority racial/ethnic backgrounds consider it important to have access to providers from diverse backgrounds. Health care providers and scientists from minority racial/ethnic groups are more likely than non-Hispanic whites to treat or conduct research on patients from underrepresented groups. OBJECTIVES: To characterize the racial/ethnic diversity of nutrition- and obesity-focused professional organizations in the United States. METHODS: This study assessed race/ethnicity data from several obesity-focused national organizations including The Obesity Society, the Academy of Nutrition and Dietetics (AND), the American Society for Nutrition, and the American Board of Obesity Medicine (ABOM). Each organization was queried via emailed survey to provide data on racial/ethnic representation among their membership in the past 5 y and among elected presidents from 2010 to 2020. RESULTS: Two of the 3 professional societies queried did not systematically track race/ethnicity data at the time of query. Limited tracking data available from AND show underrepresentation of black (2.6%), Asian (3.9%), Latinx (3.1%), Native Hawaiian or Pacific Islander: (1.3%), or indigenous (American Indian or Alaskan Native: 0.3%) individuals compared with the US population. Underrepresentation of racial/ethnic minorities was also reported for ABOM diplomates (black: 6.0%, Latinx: 5.0%, Native American: 0.2%). Only AND reported having racial/ethnic diversity (20%) among the organization's presidents within the previous decade (2010-2020). CONCLUSIONS: Findings suggest that 1) standardized tracking of race and ethnicity data is needed to fully assess diversity, equity, and inclusion, and 2) work is needed to increase the diversity of membership and leadership at the presidential level within obesity- and nutrition-focused professional organizations. A diverse cadre of obesity- and nutrition-focused health care professionals is needed to further improve nutrition-related health outcomes, including obesity, cardiovascular disease, diabetes, and undernutrition, in this country.

An endocrine perspective on menstrual suppression for adolescents: achieving good suppression while optimizing bone health.

Suppression of menstruation and/or ovarian function in adolescent girls may be desired for a variety of reasons. Numerous medical options exist. The choice of the appropriate modality for an individual patient depends on several factors based on differences in the efficacy of achieving menstrual suppression as well as in their side effect profiles. Adolescence is also a period of bone mass accrual in girls, and several of these modalities may negatively influence peak bone mass. This review focuses on the efficacy of achieving menstrual suppression and the effect on bone health of the various options through an overview of the current literature and also highlights areas in need of further research.

Placental Vascular Abnormalities in Association With Prenatal and Long-Term Health Characteristics Among HIV-Exposed Uninfected Adolescents and Young Adults.

BACKGROUND: HIV-exposed uninfected (HEU) individuals are predisposed to adverse health outcomes, which in part may stem from the influence of an altered intrauterine milieu on fetal programming. The placenta serves as a readout for the effects of the maternal environment on the developing fetus and may itself contribute to the pathogenesis of disease. SETTING: US academic health system. METHODS: We leveraged a previously established registry-based cohort of HEU adolescents and young adults to identify 26 subjects for whom placental histopathology was available. We further obtained placental tissue from 29 HIV-unexposed pregnancies for comparison. We examined differences in placental histopathology between the groups and related villous vascularity in the HEU group to prenatal maternal characteristics and long-term health outcomes. RESULTS: Placentas from HEU pregnancies demonstrated a higher blood vessel count per villus as compared with controls (5.9 ± 1.0 vs. 5.4 ± 0.8; P = 0.05), which was independent of maternal prenatal age, race, body mass index, smoking status, hemoglobin, and gestational age. Furthermore, within the HEU group, lower CD4+ T-cell count during pregnancy was associated with greater placental vascularity (r = -0.44; P = 0.03). No significant relationships were observed between placental blood vessel count per villus and body mass index z-score or reactive airway disease among HEU individuals later in life. CONCLUSIONS: Placentas from HEU pregnancies demonstrated increased villous vascularity compared with HIV-unexposed controls in proportion to the severity of maternal immune dysfunction. Further studies are needed to examine intrauterine exposure to hypoxia as a potential mechanism of fetal programming in HIV.

Delineating tesamorelin response pathways in HIV-associated NAFLD using a targeted proteomic and transcriptomic approach.

NAFLD is a leading comorbidity in HIV with an exaggerated course compared to the general population. Tesamorelin has been demonstrated to reduce liver fat and prevent fibrosis progression in HIV-associated NAFLD. We further showed that tesamorelin downregulated hepatic gene sets involved in inflammation, tissue repair, and cell division. Nonetheless, effects of tesamorelin on individual plasma proteins pertaining to these pathways are not known. Leveraging our prior randomized-controlled trial and transcriptomic approach, we performed a focused assessment of 9 plasma proteins corresponding to top leading edge genes within differentially modulated gene sets. Tesamorelin led to significant reductions in vascular endothelial growth factor A (VEGFA, log2-fold change - 0.20 ± 0.35 vs. 0.05 ± 0.34, P = 0.02), transforming growth factor beta 1 (TGFB1, - 0.35 ± 0.56 vs. - 0.05 ± 0.43, P = 0.05), and macrophage colony stimulating factor 1 (CSF1, - 0.17 ± 0.21 vs. 0.02 ± 0.20, P = 0.004) versus placebo. Among tesamorelin-treated participants, reductions in plasma VEGFA (r = 0.62, P = 0.006) and CSF1 (r = 0.50, P = 0.04) correlated with a decline in NAFLD activity score. Decreases in TGFB1 (r = 0.61, P = 0.009) and CSF1 (r = 0.64, P = 0.006) were associated with reduced gene-level fibrosis score. Tesamorelin suppressed key angiogenic, fibrogenic, and pro-inflammatory mediators. CSF1, a regulator of monocyte recruitment and activation, may serve as an innovative therapeutic target for NAFLD in HIV. Clinical Trials Registry Number: NCT02196831.

Growth Hormone Releasing Hormone Reduces Circulating Markers of Immune Activation in Parallel with Effects on Hepatic Immune Pathways in Individuals with HIV-infection and Nonalcoholic Fatty Liver Disease.

BACKGROUND: The growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis modulates critical metabolic pathways; however, little is known regarding effects of augmenting pulsatile GH secretion on immune function in humans. This study used proteomics and gene set enrichment analysis to assess effects of a GH releasing hormone (GHRH) analog, tesamorelin, on circulating immune markers and liver tissue in people with human immunodeficiency virus (HIV) (PWH) and nonalcoholic fatty liver disease (NAFLD). METHODS: 92 biomarkers associated with immunity, chemotaxis, and metabolism were measured in plasma samples from 61 PWH with NAFLD who participated in a double-blind, randomized trial of tesamorelin versus placebo for 12 months. Gene set enrichment analysis was performed on serial liver biopsies targeted to immune pathways. RESULTS: Tesamorelin, compared to placebo, decreased interconnected proteins related to cytotoxic T-cell and monocyte activation. Circulating concentrations of 13 proteins were significantly decreased, and no proteins increased, by tesamorelin. These included 4 chemokines (CCL3, CCL4, CCL13 [MCP4], IL8 [CXCL8]), 2 cytokines (IL-10 and CSF-1), and 4 T-cell associated molecules (CD8A, CRTAM, GZMA, ADGRG1), as well as ARG1, Gal-9, and HGF. Network analysis indicated close interaction among the gene pathways responsible for these proteins, with imputational analyses suggesting down-regulation of a closely related cluster of immune pathways. Targeted transcriptomics using liver tissue confirmed a significant end-organ signal of down-regulated immune activation pathways. CONCLUSIONS: Long-term treatment with a GHRH analog reduced markers of T-cell and monocyte/macrophage activity, suggesting that augmentation of the GH axis may ameliorate immune activation in an HIV population with metabolic dysregulation, systemic and end organ inflammation. Clinical Trials Registration. NCT02196831.