The subcutaneous adipose transcriptome identifies a molecular signature of insulin resistance shared with visceral adipose.

OBJECTIVE: The objective of this study was to identify the transcriptional landscape of insulin resistance (IR) in subcutaneous adipose tissue (SAT) in humans across the spectrum of obesity. METHODS: We used SAT RNA sequencing in 220 individuals with metabolic phenotyping. RESULTS: We identified a 35-gene signature with high predictive accuracy for homeostatic model of IR that was expressed across a variety of non-immune cell populations. We observed primarily "protective" IR associations for adipocyte transcripts and "deleterious" associations for macrophage transcripts, as well as a high concordance between SAT and visceral adipose tissue (VAT). Multiple SAT genes exhibited dynamic expression 5 years after weight loss surgery and with insulin stimulation. Using available expression quantitative trait loci in SAT and/or VAT, we demonstrated similar genetic effect sizes of SAT and VAT on type 2 diabetes and BMI. CONCLUSIONS: SAT is conventionally viewed as a metabolic buffer for lipid deposition during positive energy balance, whereas VAT is viewed as a dominant contributor to and prime mediator of IR and cardiometabolic disease risk. Our results implicate a dynamic transcriptional architecture of IR that resides in both immune and non-immune populations in SAT and is shared with VAT, nuancing the current VAT-centric concept of IR in humans.

Cardiometabolic Characteristics of Obesity Phenotypes in Persons With HIV.

Background: In the general population, it is established that adipose tissue depots pose various risks for cardiometabolic diseases. The interaction among obesity, HIV, and antiretroviral treatment promotes even greater risk for persons with HIV (PWH). As obesity is a heterogeneous condition, determining the specific obesity phenotypes present and their characteristics is critical to personalize care in PWH. Methods: Visceral, sarcopenic, myosteatotic, hepatosteatotic, and metabolically healthy obesity phenotypes were determined by pre-established cut points after segmentation of computed tomography scans at the L3 vertebra. Multivariable linear regression modeling included anthropometrics, clinical biomarkers, and inflammatory factors while controlling for age, sex, race, and body mass index (BMI). Results: Of 187 PWH, 86% were male, and the mean ± SD age and BMI were 51.2 ± 12.3 years and 32.6 ± 6.3 kg/m2. Overall, 59% had visceral obesity, 11% sarcopenic obesity, 25% myosteatotic obesity, 9% hepatosteatotic obesity, and 32% metabolically healthy obesity. The strongest predictor of visceral obesity was an elevated triglyceride:high-density lipoprotein (HDL) ratio. Increased subcutaneous fat, waist circumference, and HDL cholesterol were predictors of sarcopenic obesity. Diabetes status and elevated interleukin 6, waist circumference, and HDL cholesterol predicted myosteatotic obesity. An increased CD4+ count and a decreased visceral:subcutaneous adipose tissue ratio predicted hepatosteatotic obesity, though accounting for only 28% of its variability. Participants with metabolically healthy obesity were on average 10 years younger, had higher HDL, lower triglyceride:HDL ratio, and reduced CD4+ counts. Conclusions: These findings show that discrete obesity phenotypes are highly prevalent in PWH and convey specific risk factors that measuring BMI alone does not capture. These clinically relevant findings can be used in risk stratification and optimization of personalized treatment regimens. This study is registered at ClinicalTrials.gov (NCT04451980).

Keeping it real: A descriptive analysis of HIV testing history, PrEP awareness, and PrEP use among Black cisgender women in Middle Tennessee, 2018.

INTRODUCTION: HIV disproportionately affects Black/African American women in the United States, particularly in the southern states, including Tennessee. Despite this, limited research and intervention are targeting this population, especially regarding biomedical prevention technologies such as pre-exposure prophylaxis (PrEP). This study aims to describe the HIV testing history of a sample of Black women in middle Tennessee, assess their awareness and potential for adopting modern HIV prevention technologies like PrEP, and explore the dyadic and social factors that influence their HIV prevention awareness and use. THEORY: The Precaution Adoption Process Model (PAPM) is employed to understand how individuals progress through decision-making stages when adopting new health behaviors, especially related to novel interventions. METHODS: For survey development and deployment, this cross-sectional survey study engaged the Nashville Health Disparities Coalition and the Resident Association for the Metropolitan Developmental Housing Association in Nashville. Eligible participants included African American and Black women aged 18 and above. The survey collected demographic information, HIV testing history, reasons for testing or not testing, dyadic HIV risk factors, awareness, and use of rapid HIV testing and PrEP, and social norms related to these prevention technologies. RESULTS AND DISCUSSION: Age significantly influenced HIV testing history, emphasizing the importance of regular screening, especially among older women. Dyadic factors such as concurrency and having a shared male partner were associated with differences in testing behavior. Awareness of both rapid HIV testing and PrEP was limited among participants, highlighting the need for increased education and awareness campaigns specifically highlighting benefits to Black women. Social norms, particularly recommendations from healthcare providers, played a crucial role in influencing women's willingness to adopt these prevention technologies. [Increasing routine HIV testing and awareness of PrEP, especially among women in non-monogamous relationships, is essential in reducing HIV disparities among Black women.] IMPLICATIONS: Healthcare providers play a crucial role in initiating and recommending HIV testing and PrEP among Black women, emphasizing the importance of patient-provider relationships and ongoing conversations about prevention strategies. This study underscores the importance of community-engaged research in addressing HIV disparities and highlights the potential for partnerships between medical centers and community organizations in the fight against HIV.

Weight Gain and Antiretroviral Therapy.

Antiretroviral therapy (ART) agents as a determinant of body weight in ART-naïve and ART-experienced persons with human immunodeficiency virus (HIV) (PWH) has become a major focus area in research and clinical settings. Recent studies demonstrating weight-suppressing properties of efavirenz and tenofovir disoproxil fumarate led to re-evaluation of weight gain studies, and a reassessment of whether other agents are weight promoting versus weight neutral. In this review, the authors synthesize recent literature on factors related to obesity, clinical measurements of adiposity, weight gain in ART-naïve and ART-experienced PWH, metabolic consequences of ART and weight gain, and the clinical management of weight gain in PWH.

Single-cell Analysis of Subcutaneous Fat Reveals Pro-fibrotic Cells that Correlate with Visceral Adiposity in HIV.

CONTEXT: Cardiometabolic diseases are common in persons with HIV (PWH) on antiretroviral therapy (ART), which has been attributed to preferential lipid storage in visceral adipose tissue (VAT) compared with subcutaneous adipose tissue (SAT). However, the relationship of SAT-specific cellular and molecular programs with VAT volume is poorly understood in PWH. OBJECTIVE: We characterized SAT cell-type specific composition and transcriptional programs that are associated with greater VAT volume in PWH on contemporary ART. METHODS: We enrolled PWH on long-term ART with a spectrum of metabolic health. Ninety-two participants underwent SAT biopsy for bulk RNA sequencing and 43 had single-cell RNA sequencing. Computed tomography quantified VAT volume and insulin resistance was calculated using HOMA2-IR. RESULTS: VAT volume was associated with HOMA2-IR (p < 0.001). Higher proportions of SAT intermediate macrophages (IMs), myofibroblasts, and MYOC + fibroblasts were associated with greater VAT volume using partial Spearman's correlation adjusting for age, sex, and body mass index (ρ=0.34-0.49, p < 0.05 for all). Whole SAT transcriptomics showed PWH with greater VAT volume have increased expression of extracellular matrix (ECM)- and inflammation-associated genes, and reduced expression of lipolysis- and fatty acid metabolism-associated genes. CONCLUSIONS: In PWH, greater VAT volume is associated with higher proportion of SAT IMs and fibroblasts, and a SAT ECM and inflammatory transcriptome, which is similar to findings in HIV-negative persons with obesity. These data identify SAT cell-type specific changes associated with VAT volume in PWH that could underlie the high rates of cardiometabolic diseases in PWH, though additional longitudinal studies are needed to define directionality and mechanisms.

Antiretrovirals and Weight Change: Weighing the Evidence.

Body weight is influenced by an interplay of individual and environmental factors. In people with HIV (PWH), weight is also influenced by disease status with loss accompanying disease progression that is reversed with effective antiretroviral therapy (ART). Weight changes in comparative ART trials differ by regimen, with greater gains observed with the integrase strand transfer inhibitors (INSTIs) dolutegravir and bictegravir, particularly when co-administered with tenofovir alafenamide fumarate (TAF), compared to regimens that include agents such as tenofovir disoproxil fumarate (TDF) that attenuate weight gain. We review weight changes in major randomized trials of pre-exposure prophylaxis (PrEP) and initial and switch HIV therapy, highlighting the challenges to assessing the role of ART in weight change. This examination forms the basis for a model that questions assumptions regarding an association between INSTI and TAF and excessive weight gain and calls for more careful consideration of these data when making HIV treatment decisions.

Cytokine and Chemokine Receptor Profiles in Adipose Tissue Vasculature Unravel Endothelial Cell Responses in HIV.

Chronic systemic inflammation contributes to a substantially elevated risk of myocardial infarction in people living with HIV (PLWH). Endothelial cell dysfunction disrupts vascular homeostasis regulation, increasing the risk of vasoconstriction, inflammation, and thrombosis that contribute to cardiovascular disease. Our objective was to study the effects of plasma from PLWH on endothelial cell (EC) function, with the hypothesis that cytokines and chemokines are major drivers of EC activation. We first broadly phenotyped chemokine and cytokine receptor expression on arterial ECs, capillary ECs, venous ECs, and vascular smooth muscle cells (VSMCs) in adipose tissue in the subcutaneous adipose tissue of 59 PLWH using single cell transcriptomic analysis. We used CellChat to predict cell-cell interactions between ECs and other cells in the adipose tissue and Spearman correlation to measure the association between ECs and plasma cytokines. Finally, we cultured human arterial ECs (HAECs) in plasma-conditioned media from PLWH and performed bulk sequencing to study the direct effects ex-vivo. We observed that arterial and capillary ECs expressed higher interferon and tumor necrosis factor (TNF) receptors. Venous ECs had more interleukin (IL)-1R1 and ACKR1 receptors, and VSMCs had high significant IL-6R expression. CellChat predicted ligand-receptor interactions between adipose tissue immune cells as senders and capillary ECs as recipients in TNF-TNFRSF1A/B interactions. Chemokines expressed largely by capillary ECs were predicted to bind ACKR1 receptors on venous ECs. Beyond the adipose tissue, the proportion of venous ECs and VSMCs were positively plasma IL-6. In ex-vivo experiments, HAECs cultured with plasma-conditioned media from PLWH expressed transcripts that enriched for the TNF-α and reactive oxidative phosphorylation pathways. In conclusion, ECs demonstrate heterogeneity in cytokine and chemokine receptor expression. Further research is needed to fully elucidate the role of cytokines and chemokines in EC dysfunction and to develop effective therapeutic strategies.

Hormonal Contraception and Risk of Cardiometabolic Disease in Women with HIV.

Objective: We sought to determine the association of hormonal contraception (HC) and cardiometabolic outcomes among women with human immunodeficiency virus (HIV). Methods: We included women with HIV aged 18-45 years in clinical care in the Southeastern United States between 1998 and 2018. Oral and injectable HC use was captured from medication records. Our outcomes included incident cardiovascular/thrombotic disease (CVD) (atherosclerosis, hypertension, cerebrovascular disease, thrombosis, and heart failure) and incident metabolic disorders (diabetes, dyslipidemia, obesity, and non-alcoholic steatohepatitis). We excluded women with prevalent conditions. We used multivariable marginal structural models to examine time-varying current and cumulative HC use and cardiometabolic outcomes in separate analyses, adjusting for age, race, smoking, time-varying comorbidities, CD4 cell count, HIV RNA, and antiretroviral use. Women with HC exposure were compared with women without HC exposure. Results: Among the 710 women included, 201 women (28%) used HC. CVD analyses included 603 women without prevalent CVD and 93 incident events; metabolic analyses included 365 women without prevalent metabolic disease and 150 incident events. Current and cumulative oral HC use was associated with increased odds of CVD, though this was not statistically significant (adjusted odds ratio [aOR] = 2.08, [95% confidence interval (CI): 0.80-5.43] and aOR = 1.24 [95% CI: 0.96-1.60] per year of use, respectively). Oral HC was not associated with risk of incident metabolic disorders. Depot medroxyprogesterone acetate (DMPA) was not associated with risk of incident CVD. Current and cumulative DMPA use was significantly associated with decreased odds of incident metabolic disorders (aOR = 0.48 [95% CI: 0.23, 1.00] and aOR = 0.65 [95% CI: 0.42-1.00] per year of use, respectively). Conclusion: Our results suggest that cardiovascular risk should be considered when selecting contraception for women with HIV.

A prognostic molecular signature of hepatic steatosis is spatially heterogeneous and dynamic in human liver.

Metabolic dysfunction-associated steatotic liver disease (MASLD) prevalence is increasing in parallel with an obesity pandemic, calling for novel strategies for prevention and treatment. We defined a circulating proteome of human MASLD across ≈7000 proteins in ≈5000 individuals from diverse, at-risk populations across the metabolic health spectrum, demonstrating reproducible diagnostic performance and specifying both known and novel metabolic pathways relevant to MASLD (central carbon and amino acid metabolism, hepatocyte regeneration, inflammation, fibrosis, insulin sensitivity). A parsimonious proteomic signature of MASLD was associated with a protection from MASLD and its related multi-system metabolic consequences in >26000 free-living individuals, with an additive effect to polygenic risk. The MASLD proteome was encoded by genes that demonstrated transcriptional enrichment in liver, with spatial transcriptional activity in areas of steatosis in human liver biopsy and dynamicity for select targets in human liver across stages of steatosis. We replicated several top relations from proteomics and spatial tissue transcriptomics in a humanized "liver-on-a-chip" model of MASLD, highlighting the power of a full translational approach to discovery in MASLD. Collectively, these results underscore utility of blood-based proteomics as a dynamic "liquid biopsy" of human liver relevant to clinical biomarker and mechanistic applications.

Pharmacogenetics of weight gain following switch from efavirenz- to integrase inhibitor-containing regimens.

BACKGROUND: Excessive weight gain affects some persons with HIV after switching to integrase strand transfer inhibitor (INSTI)-containing antiretroviral therapy (ART). We studied associations between CYP2B6 genotype and weight gain after ART switch among ACTG A5001 and A5322 participants. METHODS: Eligible participants switched from efavirenz- to INSTI-containing ART, had genotype data, and had weight data at least once from 4 weeks to 2 years post-switch. Multivariable linear mixed effects models adjusted for race/ethnicity, CD4, age, BMI and INSTI type assessed relationships between CYP2B6 genotype and estimated differences in weight change. RESULTS: A total of 159 eligible participants switched ART from 2007 to 2019, of whom 138 had plasma HIV-1 RNA < 200 copies/mL (65 CYP2B6 normal, 56 intermediate, 17 poor metabolizers). Among participants with switch HIV-1 RNA < 200 copies/mL, weight increased in all 3 CYP2B6 groups. The rate of weight gain was greater in CYP2B6 poor than in CYP2B6 normal metabolizers overall, and within 9 subgroups (male, female, White, Black, Hispanic, dolutegravir, elvitegravir, raltegravir, and TDF in the pre-switch regimen); only in Hispanic and elvitegravir subgroups were these associations statistically significant ( P  < 0.05). Compared to normal metabolizers, CYP2B6 intermediate status was not consistently associated with weight gain. CONCLUSION: CYP2B6 poor metabolizer genotype was associated with greater weight gain after switch from efavirenz- to INSTI-containing ART, but results were inconsistent. Weight gain in this setting is likely complex and multifactorial.

The pathogenesis of obesity in people living with HIV.

PURPOSE OF REVIEW: The public health challenge of overweight and obesity increasingly affects people living with HIV (PWH). These effects have also accelerated as the prevalence of antiretroviral therapy (ART) use has increased among PWH. It is therefore also critical that we examine and understand the pathogenesis of obesity among PWH.This review will aim to summarize relevant and recent literature related to the risks of weight gain and obesity associated with HIV disease progression, cardiometabolic disease, and multimorbidity among PWH. Further, we will discuss adipose tissue changes associated with weight gain and obesity and how these changes relate to metabolic complications. RECENT FINDINGS: Several observational and experimental studies in recent years have evaluated the role of contemporary ART regimens, particularly integrase strand transfer inhibitors (INSTIs) and tenofovir alafenamide (TAF), as contributors to weight gain, obesity, and cardiometabolic disease, though the mechanisms remain unclear. Metabolic dysregulation has also been linked to ectopic fat deposition and alterations in innate and adaptive immune cell populations in adipose tissue that accompany HIV and obesity. These factors continue to contribute to an increasing burden of metabolic diseases in an aging HIV population. SUMMARY: Obesity accompanies an increasing burden of metabolic disease among PWH, and understanding the role of fat partitioning and HIV and ART-related adipose tissue dysfunction may guide prevention and treatment strategies.

Obesity among women with HIV.

PURPOSE OF REVIEW: With the introduction of novel and more potent antiretroviral therapies (ART), persons with HIV (PWH) are living longer lives and experiencing higher rates of age- and weight-related comorbidities, including cardiovascular and metabolic diseases. Women with HIV (WWH) experience disproportionate rates of obesity, as evidenced by longitudinal observational cohorts both in the United States and globally. RECENT FINDINGS: In this article, we aim to review major research findings regarding WWH and obesity over the past few years. Multiple studies have evaluated geographic changes in the obesity epidemic across the globe with focus on developing countries who have seen a drastic change in obesity rates. Other new data assessed the effect of antiretroviral therapy on WWH, the cardiovascular effects of obesity in women on ART including data from the recently published REPRIEVE Trial, and issues unique to women, such as pregnancy and the effect of menopause on WWH. SUMMARY: Comorbid cardiometabolic conditions are rapidly increasing, in correlation with the obesity epidemic among PWH. WWH may be disproportionately impacted, and experience further effects of obesity, compounded by health disparities in many areas of the world. Further research on the most effective interventions to minimize weight gains and decrease obesity among WWH are urgently needed.

Consumption of Tree Nuts as Snacks Reduces Metabolic Syndrome Risk in Young Adults: A Randomized Trial.

Metabolic syndrome (MetSx) and its chronic disease consequences are major public health concerns worldwide. Between-meal snacking may be a modifiable risk factor. We hypothesized that consuming tree nuts as snacks, versus typical carbohydrate snacks, would reduce risk for MetSx in young adults. A prospective, randomized, 16-week parallel-group diet intervention trial was conducted in 84 adults aged 22-36 with BMI 24.5 to 34.9 kg/m2 and ≥1 MetSx clinical risk factor. Tree nuts snacks (TNsnack) were matched to carbohydrate snacks (CHOsnack) for energy (kcal), protein, fiber, and sodium content as part of a 7-day eucaloric menu. Difference in change between groups was tested by analysis of covariance using general linear models. Multivariable linear regression modeling assessed main effects of TNsnack treatment and interactions between TNsnack and sex on MetSx score. Age, BMI, and year of study enrollment were included variables. There was a main effect of TNsnack on reducing waist circumference in females (mean difference: -2.20 ± 0.73 cm, p = 0.004) and a trend toward reduced visceral fat (-5.27 ± 13.05 cm2, p = 0.06). TNsnack decreased blood insulin levels in males (-1.14 ± 1.41 mIU/L, p = 0.05) and multivariable modeling showed a main effect of TNsnack on insulin. Main effects of TNsnack on triglycerides and TG/HDL ratio were observed (p = 0.04 for both) with TG/HDL ratio reduced ~11%. A main effect of TNsnack (p = 0.04) and an interaction effect between TNsnack and sex (p < 0.001) on total MetSx score yielded 67% reduced MetSx score in TNsnack females and 42% reduced MetSx score in TNsnack males. To our knowledge, this is the first randomized parallel-arm study to investigate cardiometabolic responses to TNsnacks versus typical CHOsnacks among young adults at risk of MetSx. Our study suggests daily tree nut consumption reduces MetSx risk by improving waist circumference, lipid biomarkers, and/or insulin sensitivity-without requiring caloric restriction.

Impact of a Multi-Institutional Initiative to Engage Students and Early-Stage Scholars From Underrepresented Racial and Ethnic Minority Groups in HIV Research: The Centers for AIDS Research Diversity, Equity, and Inclusion Pathway Initiative.

BACKGROUND: The Centers for AIDS Research Diversity, Equity, and Inclusion Pathway Initiative (CDEIPI) aims to establish programs to develop pathways for successful careers in HIV science among scholars from underrepresented racial and ethnic populations. This article describes cross-site evaluation outcomes during the first 18 months (July 2021-December 2022) across 15 programs. METHODS: The aims of the evaluation were to characterize participants, describe feasibility, challenges, and successes of the programs and provide a basis for the generalizability of best practices to Diversity, Equity, and Inclusion (DEI) programs in the United States. Two primary data collection methods were used: a quarterly programmatic monitoring process and a centrally managed, individual-level, participant quantitative and qualitative survey. RESULTS: During the first year of evaluation data collection, 1085 racially and ethnically diverse scholars ranging from the high school to postdoctoral levels applied for CDEIPI programs throughout the United States. Of these, 257 (23.7%) were selected to participate based on program capacity and applicant qualifications. Participants were trained by 149 mentors, teachers, and staff. Of the N = 95 participants responding to the individual-level survey, 95.7% agreed or strongly agreed with statements of satisfaction with the program, 96.8% planned to pursue further education, and 73.7% attributed increased interest in a variety of HIV science topics to the program. Qualitative findings suggest strong associations between mentorship, exposure to scientific content, and positive outcomes. CONCLUSIONS: These data provide evidence to support the feasibility and impact of novel DEI programs in HIV research to engage and encourage racially and ethnically diverse scholars to pursue careers in HIV science.

Centers for AIDS Research (CFAR) Diversity, Equity, and Inclusion Pathway Initiative (CDEIPI): Developing Career Pathways for Early-Stage Scholars From Racial and Ethnic Groups Underrepresented in HIV Science and Medicine.

BACKGROUND: There is an urgent need to increase diversity among scientific investigators in the HIV research field to be more reflective of communities highly affected by the HIV epidemic. Thus, it is critical to promote the inclusion and advancement of early-stage scholars from racial and ethnic groups underrepresented in HIV science and medicine. METHODS: To widen the HIV research career pathway for early-stage scholars from underrepresented minority groups, the National Institutes of Health supported the development of the Centers for AIDS Research (CFAR) Diversity, Equity, and Inclusion Pathway Initiative (CDEIPI). This program was created through partnerships between CFARs and Historically Black Colleges and Universities and other Minority Serving Institutions throughout the United States. RESULTS: Seventeen CFARs and more than 20 Historically Black Colleges and Universities and Minority Serving Institutions have participated in this initiative to date. Programs were designed for the high school (8), undergraduate (13), post baccalaureate (2), graduate (12), and postdoctoral (4) levels. Various pedagogical approaches were used including didactic seminar series, intensive multiday workshops, summer residential programs, and mentored research internship opportunities. During the first 18 months of the initiative, 257 student scholars participated in CDEIPI programs including 150 high school, 73 undergraduate, 3 post baccalaureate, 27 graduate, and 4 postdoctoral students. CONCLUSION: Numerous student scholars from a wide range of educational levels, geographic backgrounds, and racial and ethnic minority groups have engaged in CDEIPI programs. Timely and comprehensive program evaluation data will be critical to support a long-term commitment to this unique training initiative.

The Tennessee Center for AIDS Research HIV Research Training Program for Minority High School and Undergraduate Students: Development, Implementation, and Early Outcomes.

BACKGROUND: The Southern region of the United States has the highest HIV incidence, and new infections disproportionately affect Black Americans. The Tennessee Center for AIDS Research (CFAR) Diversity, Equity, and Inclusion Pathway Initiative (CDEIPI) program supports the training of individuals from groups underrepresented in medicine and science in multiple areas of research to increase the pool of HIV-focused investigators at early educational and career stages. SETTING: The Tennessee CFAR is a partnership between Vanderbilt University Medical Center, Meharry Medical College (one of the oldest historically Black medical colleges), Tennessee Department of Health, and Nashville Community AIDS Resources, Education and Services (a sophisticated community service organization, which emphasizes research training responsive to regional and national priorities). METHODS: The Tennessee CFAR CDEIPI program leverages existing Vanderbilt University Medical Center and Meharry Medical College structured biomedical training programs for high school and undergraduate students to provide an intensive, mentored, HIV research experience augmented by CFAR resources situating this training within the broader history, scientific breadth, and societal and political aspects of the HIV epidemic. RESULTS: The first year of the Tennessee CFAR CDEIPI program trained 3 high school and 3 undergraduate students from underrepresented in medicine and science backgrounds in basic, clinical/translational, and community-focused research projects with a diverse group of 9 mentors. All students completed the program, and evaluations yielded positive feedback regarding mentoring quality and effectiveness, and continued interest in HIV-related research. CONCLUSIONS: The Tennessee CFAR CDEIPI program will continue to build upon experience from the first year to further contribute to national efforts to increase diversity in HIV-related research.

Changes in subcutaneous white adipose tissue cellular composition and molecular programs underlie glucose intolerance in persons with HIV.

Introduction: Subcutaneous adipose tissue (SAT) is a critical regulator of systemic metabolic homeostasis. Persons with HIV (PWH) have an increased risk of metabolic diseases and significant alterations in the SAT immune environment compared with the general population. Methods: We generated a comprehensive single-cell multi-omic SAT atlas to characterize cellular compositional and transcriptional changes in 59 PWH across a spectrum of metabolic health. Results: Glucose intolerance was associated with increased lipid-associated macrophages, CD4+ and CD8+ T effector memory cells, and decreased perivascular macrophages. We observed a coordinated intercellular regulatory program which enriched for genes related to inflammation and lipid-processing across multiple cell types as glucose intolerance increased. Increased CD4+ effector memory tissue-resident cells most strongly associated with altered expression of adipocyte genes critical for lipid metabolism and cellular regulation. Intercellular communication analysis demonstrated enhanced pro-inflammatory and pro-fibrotic signaling between immune cells and stromal cells in PWH with glucose intolerance compared with non-diabetic PWH. Lastly, while cell type-specific gene expression among PWH with diabetes was globally similar to HIV-negative individuals with diabetes, we observed substantially divergent intercellular communication pathways. Discussion: These findings suggest a central role of tissue-resident immune cells in regulating SAT inflammation among PWH with metabolic disease, and underscore unique mechanisms that may converge to promote metabolic disease.

Association of alpha-aminoadipic acid with cardiometabolic risk factors in healthy and high-risk individuals.

Introduction: Plasma levels of the metabolite alpha-aminoadipic acid (2-AAA) have been associated with risk of type 2 diabetes (T2D) and atherosclerosis. However, little is known about the relationship of 2-AAA to other cardiometabolic risk markers in pre-disease states, or in the setting of comorbid disease. Methods: We measured circulating 2-AAA using two methods in 1) a sample of 261 healthy individuals (2-AAA Study), and 2) in a sample of 134 persons comprising 110 individuals with treated HIV, with or without T2D, a population at high risk of metabolic disease and cardiovascular events despite suppression of circulating virus, and 24 individuals with T2D without HIV (HATIM Study). We examined associations between plasma 2-AAA and markers of cardiometabolic health within each cohort. Results and discussion: We observed differences in 2-AAA by sex and race in both cohorts, with higher levels observed in men compared with women, and in Asian compared with Black or white individuals (P<0.05). There was no significant difference in 2-AAA by HIV status within individuals with T2D in the HATIM Study. We confirmed associations between 2-AAA and dyslipidemia in both cohorts, where high 2-AAA associated with low HDL cholesterol (P<0.001) and high triglycerides (P<0.05). As expected, within the cohort of people with HIV, 2-AAA was higher in the setting of T2D compared to pre-diabetes or normoglycemia (P<0.001). 2-AAA was positively associated with body mass index (BMI) in the 2-AAA Study, and with waist circumference and measures of visceral fat volume in HATIM (all P<0.05). Further, 2-AAA associated with increased liver fat in persons with HIV (P<0.001). Our study confirms 2-AAA as a marker of cardiometabolic risk in both healthy individuals and those at high cardiometabolic risk, reveals relationships with adiposity and hepatic steatosis, and highlights important differences by sex and race. Further studies are warranted to establish molecular mechanisms linking 2-AAA to disease in other high-risk populations.

Impact of micro- and macronutrient status on the incidence of tuberculosis: An examination of an African cohort initiating antiretroviral therapy.

Macronutrient and micronutrient deficiencies are associated with tuberculosis (TB) incidence. However, evidence is limited on the impact of micronutrient (vitamins and minerals) supplementation among underweight individuals. We conducted a secondary data analysis of a randomised controlled trial of lipid nutritional supplements with and without high-dose vitamin and mineral supplementation (LNS-VM vs LNS) for underweight (Body Mass Index [BMI] <18.5 kg/m2) adults with human immunodeficiency virus (HIV) initiating antiretroviral therapy (ART) in Tanzania and Zambia (2011-2013). Incident TB disease diagnoses were extracted from trial records. We used multivariable Cox regression to estimate hazard ratios (HR) for the impact of receiving LNS-VM on TB incidence, and the dose-response relationship between baseline BMI and TB incidence. Overall, 263 (17%) of 1506 participants developed TB disease. After adjusting for age, sex, CD4 count, haemoglobin, and C-reactive protein, receiving LNS-VM was not associated with TB incidence (aHR [95%CI] = 0.93 [0.72-1.20]; p = 0.57) compared to LNS alone. There was strong evidence for an association between lower BMI and incident TB (aHR [95%CI]: 16-16.9kg/m2 = 1.15 [0.82-1.62] and <16kg/m2 = 1.70 [1.26-2.30] compared to 17-18.5kg/m2; linear trend p<0.01). There was strong evidence that the rate of developing TB was lower after initiating ART (p<0.01). In conclusion, the addition of micronutrient supplementation to LNS was not associated with lower TB incidence in this underweight ART-naive population.

Association of alpha-aminoadipic acid (2-AAA) with cardiometabolic risk factors in healthy and high-risk individuals.

Plasma levels of the metabolite alpha-aminoadipic acid (2-AAA) have been associated with risk of type 2 diabetes (T2D) and atherosclerosis. However, little is known about the relationship of 2-AAA to other cardiometabolic risk markers in pre-disease states, or in the setting of comorbid disease. We measured circulating 2-AAA using two methods in 1) a sample of 261 healthy individuals (2-AAA Study), and 2) in a sample of 134 persons comprising 110 individuals with treated HIV, with or without T2D, a population at high risk of metabolic disease and cardiovascular events despite suppression of circulating virus, and 24 individuals with T2D without HIV (HATIM Study). We examined associations between plasma 2-AAA and markers of cardiometabolic health within each cohort. We observed differences in 2-AAA by sex and race in both cohorts, with higher levels observed in men compared with women, and in Asian compared with Black or white individuals (P<0.05). There was no significant difference in 2-AAA by HIV status within individuals with T2D in the HATIM Study. We confirmed associations between 2-AAA and dyslipidemia in both cohorts where high 2-AAA associated with low HDL cholesterol (P<0.001) and high triglycerides (P<0.05). As expected, within the cohort of people with HIV, 2-AAA was higher in the setting of T2D compared to pre-diabetes or normoglycemia (P<0.001). 2-AAA was positively associated with body mass index (BMI) in the 2-AAA Study, and with waist circumference and measures of visceral fat volume in HATIM (all P<0.05). Further, 2-AAA associated with increased liver fat in persons with HIV (P<0.001). Our study confirms 2-AAA as a marker of cardiometabolic risk in both healthy individuals and those at high cardiometabolic risk, reveals relationships with adiposity and hepatic steatosis, and highlights important differences by sex and race. Further studies are warranted to establish molecular mechanisms linking 2-AAA to disease in other high-risk populations.