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Background: Heroin use may work synergistically with human immunodeficiency virus (HIV) infection to cause greater immune dysregulation than either factor alone. Unraveling how this affects end-organ disease is key as it may play a role in the excess mortality seen in people with HIV (PWH) who use heroin despite access to care and antiretroviral therapy., Methods: This is a prospectively enrolled, cross-sectional study of adults with and without HIV who use and do not use heroin using (18)F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) to compare tissue-specific inflammation including aortic (target-to-background ratio [TBR]), splenic, and bone marrow (standardized uptake value [SUV])., Results: A total of 120 participants were enrolled. The unadjusted mean difference in aortic TBR was 0.43 between HIV-positive [HIV+] heroin+ and HIV+ heroin-negative [heroin-] (P = .02); however, among HIV-, aortic TBR was similar regardless of heroin-use status. Further, HIV-by-heroin-use status interaction was significant (P = .02), indicating that the relationship between heroin use and higher aortic TBR depended on HIV status. On the other hand, both HIV (1.54 vs 1.68; P = .04, unadjusted estimated means for HIV+ vs HIV-) and heroin use were associated with lower bone marrow SUV, although the effect of heroin depended on sex (heroin-use-by-sex interaction, P = .03). HIV-by-heroin-use interaction was not significant for splenic or bone marrow SUV., Conclusions: Aortic inflammation was greatest in PWH who use heroin, but paradoxically, bone marrow activity was the least in this group, suggesting complex and possibly divergent pathophysiology within these different end organs., Competing Interests: Potential conflicts of interest . C. O. H. has served as consultant for Theratechnologies and Gilead and has received research grant support from Gilead. N. F. has served as consultant for Gilead. G. A. M. has served as consultant for Gilead, Merck, Theratechnologies, Janssen, and GSK/ViiV and has received research grants from Gilead, Merck, Janssen, and Theratechnologies, including payment for expert testimony from Gilead (no direct relationship with Gilead, deals with lawyer only). All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Feminizing hormonal therapy (FHT) and HIV potentially alter cardiovascular disease (CVD) risk in transgender women (TW)., Methods: TW were enrolled in Los Angeles, California and Houston, Texas and frequency-matched to Multicenter AIDS Cohort Study cisgender men (CM) on age, race, substance use, and abacavir use. Biomarkers of CVD risk and inflammation were assessed via ELISA. Wilcoxon rank sum and Fisher's exact tests compared TW and CM. Multivariable linear regression assessed factors associated with biomarker concentrations., Results: TW (HIV+ n  = 75, HIV- n  = 47) and CM (HIV+ n  = 40, HIV- n  = 40) had mean age 43-45 years; TW/CM were 90%/91% non-Hispanic Black, Hispanic, or Multiracial, 26%/53% obese, and 34%/24% current smokers; 67% of TW were on FHT. Among people with HIV (PWH), TW had higher median extracellular newly-identified receptor for advanced glycation end-products (EN-RAGE), lipoprotein-associated phospholipase A2 (LpPLA2), oxidized low-density lipoprotein (oxLDL), soluble tumor necrosis factor receptor type (sTNFR) I/II, interleukin (IL)-8 and plasminogen activator inhibitor (PAI)-1, but lower soluble CD14, von Willebrand factor (vWF) and endothelin (ET)-1 levels than CM. Findings were similar for participants without HIV (all P  < 0.05). In multivariable analysis, TW had higher EN-RAGE, IL-6, IL-8, P selectin, PAI-1, oxLDL and sTNFRI/II concentrations, and lower vWF, independent of HIV serostatus and current FHT use. Both being a TW and a PWH were associated with lower ET-1., Conclusions: Compared to matched cisgender men, trans women have altered profiles of biomarkers associated with systemic inflammation and CVD. Further work is needed to decipher the contributions of FHT to CVD risk in TW with HIV., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Transgender women (TW) are at increased risk for both human immunodeficiency virus (HIV) and cardiovascular disease (CVD). Antiretroviral therapy-treated HIV has been associated with a two-fold increased risk of CVD, potentially due to dysregulated Toll-like receptor (TLR)-induced immune activation. Use of estrogens in feminizing hormone therapy (FHT) may enhance inflammatory responses and the risk of cardiovascular mortality in TW. Despite this, the immunomodulatory effects of estrogen use in TW with HIV have been inadequately explored., Methods: As an in vitro model for FHT, cryopreserved PBMCs (cryoPBMCs) from HIV negative (HIV-), HIV+ ART-suppressed (HIV+SP), and HIV+ ART-unsuppressed (HIV+USP) cisgender men were cultured overnight in the presence of 17-β estradiol or 17-α ethinylestradiol with and without the TLR4 agonist LPS or the TLR8 agonist ssPolyU. Monocyte activation (CD69, HLA-DR, CD38) was assessed by flow cytometry. Cytokine levels (IL-6, TNF-α, IL-1β, and IL-10) were measured in cell culture supernatants by Legendplex. Levels of phosphorylated TLR signaling molecules (JNK, MAPK p38) were assessed by Phosflow. Plasma levels of immune activation biomarkers (LPS-binding protein, monocyte activation markers sCD14 and sCD163, and inflammatory molecules IL-6 and TNF-α receptor I) were measured by ELISA., Results: PBMCs from people with HIV (PWH) produced greater levels of inflammatory cytokines following exposure to LPS or ssPolyU compared to levels from cells of HIV- individuals. While estrogen exposure alone induced mild changes in immune activation, LPS-induced TLR4 activation was elevated with estrogen in cisgender men (CM) with HIV, increasing monocyte activation and inflammatory cytokine production (IL-6, TNF-α). Interestingly, testosterone inhibited LPS-induced cytokine production in CM regardless of HIV status. Plasma markers of immune activation and microbial translocation (e.g., sCD14, sCD163, LPS-binding protein) were generally higher in PWH compared to HIV- CM, and these markers were positively associated with in vitro responsiveness to estrogen and LPS in CM with HIV., Conclusions: Our in vitro data suggest that estrogen exposure may enhance innate immune activation in PWH. Further examination is needed to fully understand the complex interactions of FHT, HIV, and CVD in TW, and determine optimal FHT regimens or supplementary treatments aimed at reducing excess immune activation., Competing Interests: NF has served as a consultant for Gilead. The remaining 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 Kettelhut, Bowman, Gabriel, Hand, Liyanage, Kulkarni, Avila-Soto, Lake and Funderburg.)

Objective: HIV infection and antiretroviral therapy (ART) have both been linked to dyslipidemia and increased cardiovascular disease (CVD). The relationships among the lipidome, immune activation, and subclinical vascular disease in children with perinatally acquired HIV (PHIV) have not been investigated., Methods: Serum lipid composition, including 13 lipid classes constituting 850 different lipid species were measured by direct infusion-tandem mass spectrometry in samples from 20 ART-treated PHIV and 20 age-matched and sex-matched HIV- Ugandan children. All participants were between 10 and 18 years of age with no other known active infections. PHIVs had HIV-1 RNA level 50 copies/ml or less. In addition, common carotid artery intima--media thickness (IMT), as well as plasma marker of systemic inflammation (hsCRP, IL6, sTNFRa I), monocyte activation (soluble CD14 and CD163), and T-cell activation (expression of CD38 and HLA-DR on CD4+ and CD8+) were evaluated., Results: Median age (Q1, Q3) of study participants was 13 years (11, 15), 37% were boys, 75% were on an NNRTI-based ART regimen. The concentrations of cholesterol ester, LCER, phosphatidylcholines, and sphingomyelin lipid classes were significantly increased in serum of PHIV compared with HIV (P≤0.04). Biomarkers associated with CVD risk including hsCRP, sCD163, and T-cell activation were directly correlated with lipid species in PHIV (P ≤ 0.04). Contents of free fatty acids including palmitic (16 : 0), stearic (18 : 0), and arachidic acid (20 : 0) were positively correlated with IMT in PHIV., Conclusion: Serum lipidome is altered in young virally suppressed PHIV on ART. A direct association between inflammation and lipid species known to be associated with CVD was observed., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The risk of cardiovascular disease (CVD) and its mechanisms in children living with perinatally acquired HIV (PHIV) in sub-Saharan Africa has been understudied., Methods: Mean common carotid artery intima-media thickness (IMT) and pulse-wave velocity (PWV) were evaluated in 101 PHIV and 96 HIV-negative (HIV-) children. PHIV were on ART, with HIV-1 RNA levels ≤400 copies/mL. We measured plasma and cellular markers of monocyte activation, T-cell activation, oxidized lipids, and gut integrity., Results: Overall median (interquartile range, Q1-Q3) age was 13 (11-15) years and 52% were females. Groups were similar by age, sex, and BMI. Median ART duration was 10 (8-11) years. PHIV had higher waist-hip ratio, triglycerides, and insulin resistance (P ≤ .03). Median IMT was slightly thicker in PHIVs than HIV- children (1.05 vs 1.02 mm for mean IMT and 1.25 vs 1.21 mm for max IMT; P < .05), while PWV did not differ between groups (P = .06). In univariate analyses, lower BMI and oxidized LDL, and higher waist-hip ratio, hsCRP, and zonulin correlated with thicker IMT in PHIV (P ≤ .05). After adjustment for age, BMI, sex, CD4 cell count, triglycerides, and separately adding sCD163, sCD14, and hsCRP, higher levels of intestinal permeability as measured by zonulin remained associated with IMT (β = 0.03 and 0.02, respectively; P ≤ .03)., Conclusions: Our study shows that African PHIV have evidence of CVD risk and structural vascular changes despite viral suppression. Intestinal intestinal barrier dysfunction may be involved in the pathogenesis of subclinical vascular disease in this population., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

We aimed to evaluate differences in socio-economic variables in a Ugandan cohort of children with perinatally acquired HIV (PHIVs), HIV exposed uninfected (HEU) and HIV unexposed uninfected (HIV-) children and their associations with markers of inflammation and intestinal integrity. This is a cross-sectional study in 57 PHIV, 59 HEU and 56 HIV - children aged 2-10 years old enrolled in Uganda. Mean age of all participants was 7 years and 55% were girls. Compared to HEU and HIV - children, PHIVs were more likely to have parents that only completed a primary education, live in a household without electricity and live in poverty ( p ≤0.034). PHIVs living in poverty had higher IL-6 ( p =0.006), those with lack of electricity had higher hsCRP, IL6, sTNFRII and d-dimer ( p ≤0.048) and PHIVs with an unprotected water source had higher IL6 and d-dimer ( p ≤0.016). After adjusting for demographic and HIV variables, IL-6 and d-dimer remained associated with lack of electricity and having an unprotected water source only in PHIVs ( p <0.019). Our findings suggest that addressing economic insecurity may mitigate the persistent low-level inflammation in HIV that lead to many end organ disease. Longitudinal studies are needed to better understand the impact of socioeconomic factors on HIV inflammation and comorbidities.

Introduction: The pathophysiology of immune activation and its mechanisms in children living with perinatally acquired HIV (PHIV) in sub-Saharan Africa has been understudied., Methods: We enrolled 101 children living with PHIV and 96 HIV-negative controls (HIV-). All participants were between 10 and 18 years of age with no known active infections. PHIVs were on ART with HIV-1 RNA level 400 copies/ml or less. We measured plasma and cellular markers of monocyte activation, T-cell activation (expression of CD38 and HLA-DR on CD4 and CD8), oxidized lipids, markers of gut integrity and fungal translocation. Spearman correlations and linear regression models were used., Results: Overall median (Q1; Q3) age was 13 years (11; 15) and 52% were girls. Groups were similar by age, sex and BMI. Median ART duration was 10 years (8; 11). PHIVs had higher monocyte and T-cell activation; higher sCD14 (P = 0.01) and elevated frequencies of nonclassical monocytes (P < 0.001 for both). Markers of systemic inflammation (hsCRP), fungal translocation (BDG), intestinal permeability (zonulin) and oxidized lipids (ox LDL) correlated with monocyte and T-cell activation in PHIV (≤0.05). After adjusting for age, sex, ART duration, protease inhibitor and nonnucleoside reverse transcriptase inhibitor use, a modest association between BDG and activated CD4 T cells was observed (β=0.65, P < 0.01). Oxidized LDL was inversely associated with activated T cells, inflammatory and nonclassical monocytes (P < 0.01)., Conclusion: Ugandan children with perinatally acquired HIV with viral suppression have evidence of ongoing immune activation. Intestinal barrier dysfunction and fungal translocation may be involved in chronic immune dysfunction.

Background: Selenium, zinc, and chromium are essential micronutrients. Their alterations have been associated with HIV disease progression, metabolic complications, and mortality., Methods: This is a cross-sectional study in children with perinatally acquired HIV (PHIV, n = 57), HIV-exposed uninfected (HEU, n = 59), and HIV-unexposed uninfected (HIV-, n = 56) children aged 2 to 10 years old, age- and sex-matched, enrolled in Uganda. PHIV were on stable antiretroviral therapy (ART) with undetectable viral load. We measured plasma concentrations of selenium, zinc, and chromium as well as markers of systemic inflammation, monocyte activation, and gut integrity., Results: Among PHIV children, 93% had viral load ≤20 copies/mL, median CD4 was 37%, and 77% were receiving a nonnucleotide reserve transcriptase regimen. Median age of all participants was 8 years and 55% were girls. Median selenium concentrations were higher in PHIV compared with the HEU and HIV groups (P < 0.001), 46% of children overall had low zinc status (P = 0.18 between groups). Higher selenium, but not chromium or zinc, was associated with lower IL6, sTNFRI and II, and higher beta d glucan, a marker of fungal translocation, zonulin, a marker of gut permeability, oxidized LDL and insulin resistance (P ≤ 0.01)., Conclusion: In this cohort of PHIV on ART in Uganda, there is a high prevalence of low zinc status overall. Higher plasma selenium concentrations were associated with lower systemic inflammation and higher gut integrity markers. Although our findings do not support the use of micronutrient supplementation broadly for PHIV in Uganda, further studies are warranted to assess the role of selenium supplements in attenuating heightened inflammation.

Objectives: The risk of cardiometabolic complications in children with perinatally acquired HIV infection (PHIVs) and in perinatally HIV-exposed but uninfected children (HEUs) and its relationship to systemic inflammation and markers of gut integrity are not well established. In this current study, we assed insulin resitance in PHIV compared to HEUs and HIV unexposed uninfected children and explored potential association with intestinal damage biomarkers., Methods: This was a cross-sectional study in PHIVs, HEUs and HIV-unexposed, uninfected children (HUUs) aged 2-10 years enrolled in Uganda. PHIVs were on stable antiretroviral therapy (ART) with HIV viral load  < 400 HIV-1 RNA copies/mL. Insulin resistance was estimated using the homeostasis model assessment of insulin resistance (HOMA-IR). We measured markers of systemic inflammation, monocyte activation and gut integrity. Kruskal-Wallis tests were used to compare markers by HIV status; Pearson correlation and multiple linear regressions were used to assess associations of the HOMA-IR index with biomarkers of intestinal damage and translocation., Results: Overall, 172 participants were enrolled in the study (57 PHIVs, 59 HEUs and 56 HUUs). The median age was 7.8 [interquartile range (IQR) 6.39, 8.84] years, 55% were female and the median body mass index (BMI) was 15 (IQR 14.3, 15.8) kg/m 2 . Among PHIVs, the median CD4% was 37%, and 93% had viral load ≤ 20 copies/mL. PHIVs had higher waist:hip ratio, high-density lipoprotein (HDL) cholesterol, triglycerides and HOMA-IR index than the other groups (P ≤ 0.02). Factors correlated with insulin resistance included higher BMI and HDL cholesterol and lower soluble tumour necrosis factor receptor I (sTNFRI) (P ≤ 0.02). There was no correlation between any of the other inflammatory or gut biomarkers and HOMA-IR index (P ≥ 0.05). After adjusting for age and sTNFRI, BMI remained independently associated with the HOMA-IR index (β = 0.16; P < 0.01)., Conclusions: Despite viral suppression, Ugandan PHIVs have disturbances in glucose metabolism. Higher BMI, and not immune activation or alteration of gut integrity, was associated with insulin resistance in this population., (© 2019 British HIV Association.)

Purpose of Review: Human immunodeficiency virus (HIV) infection and its treatment with antiretroviral therapy (ART) are associated with lipid abnormalities that may enhance cardiovascular disease risk (CVD)., Recent Findings: Chronic inflammation persists in HIV+ individuals, and complex relationships exist among lipids and inflammation, as immune activation may be both a cause and a consequence of lipid abnormalities in HIV infection. Advances in mass spectrometry-based techniques now allow for detailed measurements of individual lipid species; improved lipid measurement might better evaluate CVD risk compared with the prognostic value of traditional assessments. Lipidomic analyses have begun to characterize dynamic changes in lipid composition during HIV infection and following treatment with ART, and further investigation may identify novel lipid biomarkers predictive of adverse outcomes. Developing strategies to improve management of comorbidities in the HIV+ population is important, and statin therapy and lifestyle modifications, including diet and exercise, may help to improve lipid levels and mitigate CVD risk.

Background: HIV-exposed-uninfected (HEU) infants have increased infectious morbidity and mortality; little is known about their levels of inflammation and monocyte activation., Methods: Plasma samples obtained at birth and 6 months from 86 HEU mother-infant pairs enrolled in the National Institute of Child Health and Human Development cohorts in Brazil were compared with 88 HIV-unexposed mother-infant pairs. HIV-infected mothers received antiretroviral therapy during pregnancy, their infants received zidovudine prophylaxis and were not breastfed. IL-6, soluble TNFα receptor I (sTNF-RI) and II, soluble CD14, soluble CD163, IFN-γ-induced protein 10 (IP-10), vascular cell adhesion molecule, oxidized LDL, D-dimer and high-sensitivity C-reactive protein were assayed by ELISA at birth and at 6 months. sTNF-RI and IL-6 were considered coprimary endpoints., Results: Among HIV-infected mothers, 79% had HIV-RNA less than 400 copies/ml prior to delivery. Compared with HIV-unexposed, HEU infants had a lower mean gestational age (38.7 vs. 39.3 weeks) and weight (3.1 vs. 3.3 kg); and reached lower weight (5.9 vs. 8.5 kg) and height (53.6 vs. 68.8 cm) at 6 months. With the exception of vascular cell adhesion molecule, inflammatory markers were generally higher (P ≤ 0.005) in HEU at birth, but at 6 months only sTNF-RI and IL-6 remained higher. For HEU pairs, only IP-10 was associated with maternal levels at birth (P < 0.001). In HEU, elevated levels of high-sensitivity C-reactive protein and IP-10 at birth were associated with lower weight at birth (P = 0.04) and at 6 months (P = 0.04)., Conclusion: HIV-exposed infants have heightened inflammation and monocyte activation at birth, which for some markers persisted to 6 months of life and was not related to maternal inflammatory status. Inflammation may contribute to the increased HEU infectious morbidity and poor growth.

Objective: Evaluating cardiovascular disease risk in children and youth 13 to 24 years old who are facing a life time exposure to both HIV and antiretroviral therapy is a research priority. This study compares endothelial function measured by peripheral arterial tonometry in HIV-positive youth infected perinatally and behaviorally as well as HIV-negative controls., Methods: Three groups of participants aged 8-30 year were enrolled; HIV-positive perinatally infected, HIV-positive behaviorally infected on antiretroviral therapy with HIV-1 RNA less than 1000 copies/ml, and HIV-negative controls. We measured the reactive hyperemic index, a measure of endothelial function, using endoPAT (Caesarea, Israel). Markers of systemic inflammation, monocyte activation, and gut integrity were also assessed. Spearman correlations and regression analyses were used to explore relationships between endothelial function measures and other measured variables., Results: Overall, 119 participants were enrolled: 53 HIV-positive behaviorally infected, 18 HIV-positive perinatally infected, and 48 controls. Overall, 71% were men; 77% African Americans and median age was 22 years old. Median (interquartile range) reactive hyperemic index was lower in the HIV-positive perinatally infected group [1.34 (1.20, 1.42)], compared with the behaviorally infected group [1.52 (1.34, 1.75)] and the control group [1.52 (1.27, 1.80; P < 0.01)]. Soluble CD14, a marker of monocyte activation, intestinal fatty acid-binding protein, a marker of gut integrity and soluble vascular cell adhesion molecule, a marker of vascular dysfunction, were different among the three groups (P ≤ 0.01)., Conclusion: HIV-positive youth infected perinatally appear to have higher levels of endothelial dysfunction and immune activation when compared with behaviorally infected youth. Further longitudinal studies are needed to determine whether perinatally infected youth have higher risks of cardiovascular disease.