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Item Associations of Low Vitamin D and Elevated Parathyroid Hormone Concentrations With Bone Mineral Density in Perinatally HIV-Infected Children(Wolters Kluwer, 2017-09-01) Jacobson, Denise L.; Stephensen, Charles B.; Miller, Tracie L.; Patel, Kunjal; Chen, Janet S.; Van Dyke, Russell B.; Mirza, Ayesha; Schuster, Gertrud U.; Hazra, Rohan; Ellis, Angela; Brummel, Sean S.; Geffner, Mitchell E.; Silio, Margarita; Spector, Stephen A.; DiMeglio, Linda A.; Pediatrics, School of MedicineBACKGROUND: Perinatally HIV-infected (PHIV) children have, on average, lower bone mineral density (BMD) than perinatally HIV-exposed uninfected (PHEU) and healthy children. Low 25-hydroxy vitamin D [25(OH)D] and elevated parathyroid hormone (PTH) concentrations may lead to suboptimal bone accrual. METHODS: PHIV and PHEU children in the Pediatric HIV/AIDS Cohort Study had total body (TB) and lumbar spine (LS) BMD and bone mineral content (BMC) measured by dual-energy x-ray absorptiometry; BMD z-scores (BMDz) were calculated for age and sex. Low 25(OH)D was defined as ≤20 ng/mL and high PTH as >65 pg/mL. We fit linear regression models to estimate the average adjusted differences in BMD/BMC by 25(OH)D and PTH status and log binomial models to determine adjusted prevalence ratios of low 25(OH)D and high PTH in PHIV relative to PHEU children. RESULTS: PHIV children (n = 412) were older (13.0 vs. 10.8 years) and more often black (76% vs. 64%) than PHEU (n = 207). Among PHIV, children with low 25(OH)D had lower TB-BMDz [SD, -0.38; 95% confidence interval (CI), -0.60 to -0.16] and TB-BMC (SD, -59.1 g; 95% CI, -108.3 to -9.8); high PTH accompanied by low 25(OH)D was associated with lower TB-BMDz. Among PHEU, children with low 25(OH)D had lower TB-BMDz (SD, -0.34; 95% CI, -0.64 to -0.03). Prevalence of low 25(OH)D was similar by HIV status (adjusted prevalence ratio, 1.00; 95% CI, 0.81 to 1.24). High PTH was 3.17 (95% CI, 1.25 to 8.06) times more likely in PHIV children. CONCLUSIONS: PHIV and PHEU children with low 25(OH)D may have lower BMD. Vitamin D supplementation trials during critical periods of bone accrual are needed.Item BCL6 represses antiviral resistance in follicular T helper cells(Wiley, 2017-08) Amet, Tohti; Son, Young Min; Jiang, Li; Cheon, In Su; Huang, Su; Gupta, Samir K.; Dent, Alexander L.; Montaner, Luis J.; Yu, Qigui; Sun, Jie; Microbiology and Immunology, School of MedicineFollicular Th (Tfh) cells are a distinct subset of Th cells that help B cells produce class-switched antibodies. Studies have demonstrated that Tfh cells are highly prone to HIV infection and replication. However, the molecular mechanisms underlying this phenomenon are largely unclear. Here, we show that murine and human Tfh cells have diminished constitutive expression of IFN-stimulated genes (ISGs) inclusive of antiviral resistance factor MX dynamin-like GTPase 2 (MX2) and IFN-induced transmembrane 3 (IFITM3) compared with non-Tfh cells. A lower antiviral resistance in Tfh was consistent with a higher susceptibility to retroviral infections. Mechanistically, we found that BCL6, a master regulator of Tfh cell development, binds to ISG loci and inhibits the expression of MX2 and IFITM3 in Tfh cells. We demonstrate further that inhibition of the BCL6 BR-C, ttk, and bab (BTB) domain function increases the expression of ISGs and suppresses HIV infection and replication in Tfh cells. Our data reveal a regulatory role of BCL6 in inhibiting antiviral resistance factors in Tfh cells, thereby promoting the susceptibility Tfh cells to viral infections. Our results indicate that the modulation of BCL6 function in Tfh cells could be a potential strategy to enhance Tfh cell resistance to retroviral infections and potentially decrease cellular reservoirs of HIV infection.Item Depression and HIV Infection are Risk Factors for Incident Heart Failure Among Veterans: Veterans Aging Cohort Study.(AHA, 2015-10-27) White, Jessica R.; Chang, Chung-Chou H.; So-Armah, Kaku A.; Stewart, Jesse C.; Gupta, Samir Kumar; Butt, Adeel A.; Gibert, Cynthia L.; Rimland, David; Rodriguez-Barradas, Maria C.; Leaf, David A.; Bedimo, Roger J.; Gottdiener, John S.; Kop, Willem J.; Gottlieb, Stephen S.; Budoff, Matthew J.; Khambaty, Tasneem; Tindle, Hilary; Justice, Amy C.; Freiberg, Matthew S.; Department of Psychology, School of ScienceBackground: Both HIV and depression are associated with increased heart failure (HF) risk. Depression, a common comorbidity, may further increase the risk of HF among HIV+ adults. We assessed the association between HIV, depression and incident HF. Methods and Results: Veterans Aging Cohort Study (VACS) participants free from cardiovascular disease at baseline (N = 81,427; 26,908 HIV+, 54,519Item Effect of Advanced HIV Infection on the Respiratory Microbiome(ATS Journals, 2016-07-15) Twigg, Homer L., III; Knox, Kenneth S.; Zhou, Jin; Crothers, Kristina A.; Nelson, David E.; Toh, Evelyn; Day, Richard B.; Lin, Huaiying; Gao, Xiang; Dong, Qunfeng; Mi, Deming; Katz, Barry P.; Sodergren, Erica; Weinstock, George M.; Medicine, School of MedicineRATIONALE: Previous work found the lung microbiome in healthy subjects infected with HIV was similar to that in uninfected subjects. We hypothesized the lung microbiome from subjects infected with HIV with more advanced disease would differ from that of an uninfected control population. OBJECTIVES: To measure the lung microbiome in an HIV-infected population with advanced disease. METHODS: 16s RNA gene sequencing was performed on acellular bronchoalveolar lavage (BAL) fluid from 30 subjects infected with HIV with advanced disease (baseline mean CD4 count, 262 cells/mm(3)) before and up to 3 years after starting highly active antiretroviral therapy (HAART) and compared with 22 uninfected control subjects. MEASUREMENTS AND MAIN RESULTS: The lung microbiome in subjects infected with HIV with advanced disease demonstrated decreased alpha diversity (richness and diversity) and greater beta diversity compared with uninfected BAL. Differences improved with HAART, but still persisted up to 3 years after starting therapy. Population dispersion in the group infected with HIV was significantly greater than in the uninfected cohort and declined after treatment. There were differences in the relative abundance of some bacteria between the two groups at baseline and after 1 year of therapy. After 1 year on HAART, HIV BAL contained an increased abundance of Prevotella and Veillonella, bacteria previously associated with lung inflammation. CONCLUSIONS: The lung microbiome in subjects infected with HIV with advanced disease is altered compared with an uninfected population both in diversity and bacterial composition. Differences remain up to 3 years after starting HAART. We speculate an altered lung microbiome in HIV infection may contribute to chronic inflammation and lung complications seen in the HAART era.Item Feasibility of Rapid Case Ascertainment for Cancer in East Africa: An Investigation of Community-Representative Kaposi Sarcoma in the Era of Antiretroviral Therapy(Elsevier, 2021) Semeere, Aggrey; Byakwaga, Helen; Laker-Oketta, Miriam; Freeman, Esther; Busakhala, Naftali; Wenger, Megan; Kasozi, Charles; Ssemakadde, Matthew; Bwana, Mwebesa; Kanyesigye, Michael; Kadama-Makanga, Philippa; Rotich, Elyne; Kisuya, Job; Sang, Edwin; Maurer, Toby; Wools-Kaloustian, Kara; Kambugu, Andrew; Martin, Jeffrey; Medicine, School of MedicineBackground: Rapid case ascertainment (RCA) refers to the expeditious and detailed examination of patients with a potentially rapidly fatal disease shortly after diagnosis. RCA is frequently performed in resource-rich settings to facilitate cancer research. Despite its utility, RCA is rarely implemented in resource-limited settings and has not been performed for malignancies. One cancer and context that would benefit from RCA in a resource-limited setting is HIV-related Kaposi sarcoma (KS) in sub-Saharan Africa. Methods: To determine the feasibility of RCA for KS, we searched for all potential newly diagnosed KS among HIV-infected adults attending three community-based facilities in Uganda and Kenya. Searching involved querying of electronic medical records, pathology record review, and notification by clinicians. Upon identification, a team verified eligibility and attempted to locate patients to perform RCA, which included epidemiologic, clinical and laboratory measurements. Results: We identified 593 patients with suspected new KS. Of the 593, 171 were ineligible, mainly because biopsy failed to confirm KS (65%) or KS was not new (30%). Among the 422 remaining, RCA was performed within 1 month for 56% of patients and within 3 months for 65% (95% confidence interval: 59 to 70%). Reasons for not performing RCA included intervening death (47%), inability to contact (44%), refusal/unsuitable to consent (8.3%), and patient re-location (0.7%). Conclusions: We found that RCA - an important tool for cancer research in resource-rich settings - is feasible for the investigation of community-representative KS in East Africa. Feasibility of RCA for KS suggests feasibility for other cancers in Africa.Item High Rates of Viral Suppression and Care Retention among Youth Born Outside of the United States with Perinatally Acquired HIV(Wolters Kluwer, 2022-12) Desai, Neerav; Jenkins, Cathy A.; Zanoni, Brian; Nmoh, Ashley; Patel, Nehali; Shepherd, Bryan E.; Hussen, Sophia; Doraivelu, Kamini; Pierce, Leslie; Carlucci, James G.; Ahonkhai, Aima A.; Pediatrics, School of MedicineBackground: Youth born outside of the US with perinatally acquired HIV infection (YBoUS-PHIV) account for most children living with HIV in the US, but there are few data characterizing their care outcomes. Methods: We conducted a retrospective study of YBoUS-PHIV receiving care across 3 HIV clinics in the Southeastern US between October 2018 and 2019. Primary outcomes were retention in care and viral suppression defined as (1) proportion of suppressed viral loads (VLs) and (2) having all VLs suppressed (definition 1 presented in the abstract). Primary predictors were age, adoption and disclosure status (full, partial and none/unknown). Multivariable logistic regression and χ 2 tests were used to test for associations with care outcomes. Analysis of disclosure status was restricted to youth greater than or equal to 12 years. Results: The cohort included 111 YBoUS-PHIV. Median age was 14 years (interquartile range, 12-18), 59% were female, and 79% were international adoptees. Overall, 84% of patients were retained in care, and 88% were virally suppressed at each VL measurement. Adopted youth were more likely to be virally suppressed than nonadopted youth [odds ratio (OR), 7.08; P < 0.01] although the association was not statistically significant in adjusted analysis (adjusted OR, 4.26; P = 0.07). Neither age nor adoption status was significantly associated with retention. Among 89 patients greater than or equal to 12 years, 74% were fully disclosed of their HIV status, 12% were partially disclosed, and 13% had not started the disclosure process. There was no significant difference in retention or viral suppression by disclosure status. Conclusions: YBoUS-PHIV achieved high rates of retention and viral suppression. Adopted youth may be more likely to achieve viral suppression which may reflect the need for tailored interventions for nonadopted youth.Item HIV infection, antiretroviral therapy, and measures of endothelial function, inflammation, metabolism, and oxidative stress(PLOS, 2017-08-17) Dysangco, Andrew; Liu, Ziyue; Stein, James H.; Dubé, Michael P.; Gupta, Samir K.; Medicine, School of MedicineBackground HIV-infected patients have an increased risk of cardiovascular disease (CVD). Impaired endothelial function is an early risk factor for CVD in the general population. It is presumed that HIV infection is associated with impaired endothelial function, but results have been inconsistent. Objectives Our objectives were to determine the relationships between HIV infection, virologic suppression with antiretroviral therapy (ART), in vivo measures of conduit artery and microvascular endothelial function, and circulating biomarkers of pathways associated with CVD. Methods We performed a cross-sectional analysis of three prospectively enrolled groups from a single center: 28 were HIV-infected and virologically-suppressed on a regimen of FTC/TDF/EFV (HIV+ART+), 44 were HIV-infected but not on ART (HIV+ART-), and 39 were HIV-uninfected healthy volunteers (HIV-) matched to the HIV+ART- group for age, sex, smoking status, and height. None had diabetes, uncontrolled hypertension, known CVD, or other pro-inflammatory condition. Flow mediated dilation (FMD), nitroglycerin-mediated dilation (NTGMD), reactive hyperemia velocity time integral (RHVTI), and FMD/RHVTI of the brachial artery were measured, as well as circulating biomarkers of systemic inflammation, metabolism, oxidative stress, and endothelial activation. Results No significant differences were found amongst the three groups in FMD (P = 0.46), NTGMD (P = 0.42), RHVTI (P = 0.17), and FMD/RHVTI (P = 0.22) in unadjusted comparisons. Adjusted ANOVA models which included brachial artery diameter, demographics, and conventional CVD risk factors did not appreciably change these findings. In pairwise comparisons, the HIV+ART- group had significantly higher soluble tumor necrosis factor receptor II, soluble CD163, β-2 microglobulin, interferon-γ- induced protein-10, tissue inhibitor of metalloproteinase-1, and vascular cell adhesion molecule-1 compared to the other two groups (all p<0.05). Correlates of endothelial function differed between study groups. Conclusion Although untreated HIV infection was associated with elevated levels of several biomarkers of inflammation and endothelial activation, we were unable to demonstrate differences in measures of conduit artery and microvascular endothelial function in this study population.Item Isoniazid preventive therapy and tuberculosis transcriptional signatures in people with HIV(Wolters Kluwer, 2022) Valinetz, Ethan D.; Matemo, Daniel; Gersh, Jill K.; Joudeh, Lara L.; Mendelsohn, Simon C.; Scriba, Thomas J.; Hatherill, Mark; Kinuthia, John; Wald, Anna; Cangelosi, Gerard A.; Barnabas, Ruanne V.; Hawn, Thomas R.; Horne, David J.; Medicine, School of MedicineObjectives: To examine the association between isoniazid preventive therapy (IPT) or nontuberculous mycobacteria (NTM) sputum culture positivity and tuberculosis (TB) transcriptional signatures in people with HIV. Design: Cross-sectional study. Methods: We enrolled adults living with HIV who were IPT-naive or had completed IPT more than 6 months prior at HIV care clinics in western Kenya. We calculated TB signatures using gene expression data from qRT-PCR. We used multivariable linear regression to analyze the association between prior receipt of IPT or NTM sputum culture positivity with a transcriptional TB risk score, RISK6 (range 0-1). In secondary analyses, we explored the association between IPT or NTM positivity and four other TB transcriptional signatures. Results: Among 381 participants, 99.7% were receiving antiretroviral therapy and 86.6% had received IPT (completed median of 1.1 years prior). RISK6 scores were lower (mean difference 0.10; 95% confidence interval (CI): 0.06-0.15; P < 0.001) among participants who received IPT than those who did not. In a model that adjusted for age, sex, duration of ART, and plasma HIV RNA, the RISK6 score was 52.8% lower in those with a history of IPT ( P < 0.001). No significant association between year of IPT receipt and RISK6 scores was detected. There was no association between NTM sputum culture positivity and RISK6 scores. Conclusion: In people with HIV, IPT was associated with significantly lower RISK6 scores compared with persons who did not receive IPT. These data support investigations of its performance as a TB preventive therapy response biomarker.Item Markers of Bone Mineral Metabolism and Cardiac Structure and Function in Perinatally HIV-Infected and HIV-Exposed but Uninfected Children and Adolescents(Wolters Kluwer, 2020-06-01) Margossian, Renee; Williams, Paige L.; Yu, Wendy; Jacobson, Denise L.; Geffner, Mitchell E.; DiMeglio, Linda A.; Van Dyke, Russell B.; Spector, Stephen A.; Schuster, Gertrud U.; Stephensen, Charles B.; Miller, Tracie L.; Lipshultz, Steven E.; Study (PHACS) for the Pediatric HIV/AIDS Cohort; Pediatrics, School of MedicineBackground: Disordered bone mineral metabolism and low vitamin D concentrations are associated with cardiovascular abnormalities; few studies have evaluated this relationship in HIV-infected youth. Setting: Adolescent Master Protocol (AMP) is a Pediatric HIV/AIDS Cohort Study (PHACS) network study conducted across 14 United States sites. Methods: Among perinatally HIV-infected (PHIV) and HIV-exposed uninfected (PHEU) youth enrolled in AMP, we evaluated associations of vitamin D (measured as 25-hydroxyvitamin D [25OHD]), parathyroid hormone (PTH), calcium, phosphate, and fibroblast growth factor-23 (FGF-23) concentrations with echocardiographic measures of left ventricular (LV) structure, function and concentrations of NT-proBNP, a biomarker of cardiac damage. Results: Among 485 participants (305 PHIV, 180 PHEU) with echocardiograms and bone mineralization measures, low 25OHD (< 20 ng/mL) was common among all participants (48% PHIV and 44% PHEU), but elevated PTH (> 65 pg/mL) was identified more often among PHIV than PHEU participants (9% vs 3%, p=0.02). After adjusting for HIV status and demographic covariates, both low 25OHD and elevated PTH were associated with lower mean LV mass z-scores, while elevated PTH was associated with higher mean fractional shortening z-scores. Participants with low 25OHD also had slightly higher mean LV end-systolic wall stress z-scores, but differences were more pronounced in PHEU than in PHIV participants. FGF-23 was inversely related to end-diastolic septal thickness both overall and among PHIV participants. Conclusion: In this cohort of PHIV and PHEU youth, we observed associations of 25OHD, PTH, and FGF-23 with both structural and functional cardiac parameters, supporting links between bone mineral metabolism and cardiac status.