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Hemochromatosis (HFE) Gene Variants Are Associated with Increased Mitochondrial DNA Levels During HIV-1 Infection and Antiretroviral Therapy.
Kallianpur AR, Gerschenson M, Hulgan T, Kaur H, Clifford DB, Haas DW, Murdock DG, McArthur JC, Samuels DC, Simpson DM
(2018) AIDS Res Hum Retroviruses 34: 942-949
MeSH Terms: Adult, Alleles, Anti-HIV Agents, CD4 Lymphocyte Count, Case-Control Studies, DNA Copy Number Variations, DNA, Mitochondrial, Female, Genotype, HIV Infections, HIV-1, Hemochromatosis Protein, Humans, Leukocytes, Mononuclear, Male, Middle Aged, Mitochondria, RNA, Viral
Show Abstract · Added December 11, 2019
Some HIV-associated complications involve mitochondrial dysfunction and may be less common in individuals with iron-loading HFE (hemochromatosis gene) variants. We evaluated HFE 845A and 187G alleles in relation to mitochondrial DNA (mtDNA) levels in peripheral blood mononuclear cells from 85 individuals with HIV infection on uninterrupted antiretroviral therapy (ART) for 15 or more consecutive weeks. Carriers of HFE gene variants (N = 24) had significantly higher mtDNA levels than noncarriers (N = 61), after adjusting for age, race, sex, and type of ART [adjusted β-coefficient 297, p-value < .001 for at least one HFE variant], but mtDNA declined among all individuals on study during 48 weeks on ART. Increased cellular mtDNA content may represent a compensatory response to mitochondrial stress that is influenced by iron-loading HFE variants.
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Brief Report: Circulating Markers of Immunologic Activity Reflect Adiposity in Persons With HIV on Antiretroviral Therapy.
Koethe JR, Jenkins CA, Furch BD, Lake JE, Barnett L, Hager CC, Smith R, Hulgan T, Shepherd BE, Kalams SA
(2018) J Acquir Immune Defic Syndr 79: 135-140
MeSH Terms: Absorptiometry, Photon, Adiposity, Adult, Anti-HIV Agents, Biomarkers, CD4 Lymphocyte Count, Female, HIV Infections, Humans, Male, Middle Aged
Show Abstract · Added December 11, 2019
BACKGROUND - Obesity alters adipose tissue immunology, and these changes may be reflected in circulating soluble inflammatory biomarker and T-cell subset profiles measured in HIV research studies.
METHODS - We recruited 70 adults with HIV (50% obese) on efavirenz, tenofovir, and emtricitabine, virologic suppression for >2 years, and no rheumatologic or other known inflammatory conditions. We measured fasting plasma levels of several markers of innate immunity and major CD4 and CD8 T-cell subsets. We assessed relationships between measurements of total adiposity [body mass index (BMI), dual-energy X-ray absorptiometry-quantified fat mass index (FMI), and plasma leptin] and the immunologic parameters using covariate-adjusted Spearman's rank correlations.
RESULTS - The cohort was 43% women, 54% nonwhite, and median age was 45 years. Higher BMI, FMI, and plasma leptin were consistently associated with higher C-reactive protein, serum amyloid A, and interleukin-6 (P < 0.01 for all), but lower interleukin-10 (P ≤ 0.02 for all). BMI and FMI were positively associated with soluble tumor necrosis factor-α receptor 1 levels (P ≤ 0.02 for both), and a positive correlation approached significance for all 3 body composition measurements with soluble CD163 (P ≤ 0.09 for all). Higher BMI and FMI were associated with lower CD38 expression on CD4 T cells (P ≤ 0.04 for both), but higher CD69 expression (P ≤ 0.01 for BMI and FMI, P = 0.07 for leptin).
CONCLUSIONS - Greater adiposity is associated with alterations in a limited set of circulating immune markers, potentially reflecting changes known to occur in adipose tissue with treated HIV infection. Measuring total fat mass radiographically did not yield substantively different results compared with BMI.
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Factors Associated With Insulin Resistance in Adults With HIV Receiving Contemporary Antiretroviral Therapy: a Brief Update.
Hulgan T
(2018) Curr HIV/AIDS Rep 15: 223-232
MeSH Terms: Adult, Anti-HIV Agents, HIV, HIV Infections, HIV Integrase Inhibitors, HIV Protease Inhibitors, Humans, Hyperglycemia, Inflammation, Insulin Resistance, Mitochondria, Obesity
Show Abstract · Added December 11, 2019
PURPOSE OF REVIEW - This narrative review summarizes recent data on factors associated with insulin resistance (IR) in adults with HIV, including contemporary antiretroviral therapy (ART).
RECENT FINDINGS - IR remains common in persons with HIV, even those receiving contemporary ART. Generalized and abdominal obesity and ectopic fat are correlates of IR, and emerging data have identified associations with biomarkers of inflammation and immune activation. Small studies suggest associations between mitochondria and IR. In ART-naïve individuals, IR increased within 4 weeks of starting ART in persons receiving contemporary boosted protease inhibitors or an integrase inhibitor. The importance of IR in non-diabetic persons with HIV will continue to grow as the population ages and obesity increases. Non-invasive estimates of IR appear to perform well in persons with HIV, but clinically relevant cutoffs are uncertain. Unexpected metabolic effects of newer HIV integrase inhibitors have been reported; thus, careful observation for and studies of IR are still warranted.
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Increased non-AIDS mortality among persons with AIDS-defining events after antiretroviral therapy initiation.
Pettit AC, Giganti MJ, Ingle SM, May MT, Shepherd BE, Gill MJ, Fätkenheuer G, Abgrall S, Saag MS, Del Amo J, Justice AC, Miro JM, Cavasinni M, Dabis F, Monforte AD, Reiss P, Guest J, Moore D, Shepherd L, Obel N, Crane HM, Smith C, Teira R, Zangerle R, Sterne JA, Sterling TR, Antiretroviral Therapy Cohort Collaboration (ART-CC) investigators
(2018) J Int AIDS Soc 21:
MeSH Terms: Acquired Immunodeficiency Syndrome, Adult, Anti-HIV Agents, Cohort Studies, Female, Humans, Lymphoma, Non-Hodgkin, Male, Middle Aged, Pneumonia, Pneumocystis, Tuberculosis
Show Abstract · Added March 14, 2018
INTRODUCTION - HIV-1 infection leads to chronic inflammation and to an increased risk of non-AIDS mortality. Our objective was to determine whether AIDS-defining events (ADEs) were associated with increased overall and cause-specific non-AIDS related mortality after antiretroviral therapy (ART) initiation.
METHODS - We included HIV treatment-naïve adults from the Antiretroviral Therapy Cohort Collaboration (ART-CC) who initiated ART from 1996 to 2014. Causes of death were assigned using the Coding Causes of Death in HIV (CoDe) protocol. The adjusted hazard ratio (aHR) for overall and cause-specific non-AIDS mortality among those with an ADE (all ADEs, tuberculosis (TB), Pneumocystis jiroveci pneumonia (PJP), and non-Hodgkin's lymphoma (NHL)) compared to those without an ADE was estimated using a marginal structural model.
RESULTS - The adjusted hazard of overall non-AIDS mortality was higher among those with any ADE compared to those without any ADE (aHR 2.21, 95% confidence interval (CI) 2.00 to 2.43). The adjusted hazard of each of the cause-specific non-AIDS related deaths were higher among those with any ADE compared to those without, except metabolic deaths (malignancy aHR 2.59 (95% CI 2.13 to 3.14), accident/suicide/overdose aHR 1.37 (95% CI 1.05 to 1.79), cardiovascular aHR 1.95 (95% CI 1.54 to 2.48), infection aHR (95% CI 1.68 to 2.81), hepatic aHR 2.09 (95% CI 1.61 to 2.72), respiratory aHR 4.28 (95% CI 2.67 to 6.88), renal aHR 5.81 (95% CI 2.69 to 12.56) and central nervous aHR 1.53 (95% CI 1.18 to 5.44)). The risk of overall and cause-specific non-AIDS mortality differed depending on the specific ADE of interest (TB, PJP, NHL).
CONCLUSIONS - In this large multi-centre cohort collaboration with standardized assignment of causes of death, non-AIDS mortality was twice as high among patients with an ADE compared to without an ADE. However, non-AIDS related mortality after an ADE depended on the ADE of interest. Although there may be unmeasured confounders, these findings suggest that a common pathway may be independently driving both ADEs and NADE mortality. While prevention of ADEs may reduce subsequent death due to NADEs following ART initiation, modification of risk factors for NADE mortality remains important after ADE survival.
© 2018 The Authors. Journal of the International AIDS Society published by John Wiley & sons Ltd on behalf of the International AIDS Society.
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Adipose Tissue is Enriched for Activated and Late-Differentiated CD8+ T Cells and Shows Distinct CD8+ Receptor Usage, Compared With Blood in HIV-Infected Persons.
Koethe JR, McDonnell W, Kennedy A, Abana CO, Pilkinton M, Setliff I, Georgiev I, Barnett L, Hager CC, Smith R, Kalams SA, Hasty A, Mallal S
(2018) J Acquir Immune Defic Syndr 77: e14-e21
MeSH Terms: Adipose Tissue, Adult, Anti-HIV Agents, Blood Cells, CD8-Positive T-Lymphocytes, Cohort Studies, Female, HIV Infections, Humans, Male, Middle Aged, Receptors, Antigen, T-Cell, Sequence Analysis, DNA, Sustained Virologic Response, T-Lymphocyte Subsets
Show Abstract · Added March 14, 2018
BACKGROUND - Adverse viral and medication effects on adipose tissue contribute to the development of metabolic disease in HIV-infected persons, but T cells also have a central role modulating local inflammation and adipocyte function. We sought to characterize potentially proinflammatory T-cell populations in adipose tissue among persons on long-term antiretroviral therapy and assess whether adipose tissue CD8 T cells represent an expanded, oligoclonal population.
METHODS - We recruited 10 HIV-infected, non-diabetic, overweight or obese adults on efavirenz, tenofovir, and emtricitabine for >4 years with consistent viral suppression. We collected fasting blood and subcutaneous abdominal adipose tissue to measure the percentage of CD4 and CD8 T cells expressing activation, exhaustion, late differentiation/senescence, and memory surface markers. We performed T-cell receptor (TCR) sequencing on sorted CD8 cells. We compared the proportion of each T-cell subset and the TCR repertoire diversity, in blood versus adipose tissue.
RESULTS - Adipose tissue had a higher percentage of CD3CD8 T cells compared with blood (61.0% vs. 51.7%, P < 0.01) and was enriched for both activated CD8HLA-DR T cells (5.5% vs. 0.9%, P < 0.01) and late-differentiated CD8CD57 T cells (37.4% vs. 22.7%, P < 0.01). Adipose tissue CD8 T cells displayed distinct TCRβ V and J gene usage, and the Shannon Entropy index, a measure of overall TCRβ repertoire diversity, was lower compared with blood (4.39 vs. 4.46; P = 0.05).
CONCLUSIONS - Adipose tissue is enriched for activated and late-differentiated CD8 T cells with distinct TCR usage. These cells may contribute to tissue inflammation and impaired adipocyte fitness in HIV-infected persons.
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Race/Ethnicity and the Pharmacogenetics of Reported Suicidality With Efavirenz Among Clinical Trials Participants.
Mollan KR, Tierney C, Hellwege JN, Eron JJ, Hudgens MG, Gulick RM, Haubrich R, Sax PE, Campbell TB, Daar ES, Robertson KR, Ventura D, Ma Q, Edwards DRV, Haas DW, AIDS Clinical Trials Group
(2017) J Infect Dis 216: 554-564
MeSH Terms: Adult, Anti-HIV Agents, Benzoxazines, Continental Population Groups, Cytochrome P-450 CYP2A6, Cytochrome P-450 CYP2B6, Ethnic Groups, Female, Gene Frequency, Genotype, HIV Infections, Humans, Male, Pharmacogenetics, Polymorphism, Single Nucleotide, Proportional Hazards Models, Risk Factors, Suicidal Ideation, Suicide, Treatment Outcome
Show Abstract · Added March 3, 2020
Background - We examined associations between suicidality and genotypes that predict plasma efavirenz exposure among AIDS Clinical Trials Group study participants in the United States.
Methods - Four clinical trials randomly assigned treatment-naive participants to efavirenz-containing regimens; suicidality was defined as reported suicidal ideation or attempted or completed suicide. Genotypes that predict plasma efavirenz exposure were defined by CYP2B6 and CYP2A6 polymorphisms. Associations were evaluated with weighted Cox proportional hazards models stratified by race/ethnicity. Additional analyses adjusted for genetic ancestry and selected covariates.
Results - Among 1833 participants, suicidality was documented in 41 in exposed analyses, and 34 in on-treatment analyses. In unadjusted analyses based on 12 genotype levels, suicidality increased per level in exposed (hazard ratio, 1.11; 95% confidence interval, .96-1.27) and on-treatment 1.16; 1.01-1.34) analyses. In the on-treatment analysis, the association was strongest among white but nearly null among black participants. Considering 3 metabolizer levels (extensive, intermediate and slow), slow metabolizers were at increased risk. Results were similar after baseline covariate-adjustment for genetic ancestry, sex, age, weight, injection drug use history, and psychiatric history or recent psychoactive medication.
Conclusions - Genotypes that predict higher plasma efavirenz exposure were associated with increased risk of suicidality. Strength of association varied by race/ethnicity.
© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.
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CD4:CD8 Ratio and CD8 Count as Prognostic Markers for Mortality in Human Immunodeficiency Virus-Infected Patients on Antiretroviral Therapy: The Antiretroviral Therapy Cohort Collaboration (ART-CC).
Trickey A, May MT, Schommers P, Tate J, Ingle SM, Guest JL, Gill MJ, Zangerle R, Saag M, Reiss P, Monforte AD, Johnson M, Lima VD, Sterling TR, Cavassini M, Wittkop L, Costagliola D, Sterne JAC, Antiretroviral Therapy Cohort Collaboration (ART-CC)
(2017) Clin Infect Dis 65: 959-966
MeSH Terms: Adolescent, Adult, Aged, Anti-HIV Agents, Biomarkers, CD4-CD8 Ratio, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Cause of Death, Europe, Female, HIV Infections, Humans, Lymphocyte Count, Male, Middle Aged, North America, Prognosis, Proportional Hazards Models, Viral Load, Young Adult
Show Abstract · Added March 14, 2018
Background - We investigated whether CD4:CD8 ratio and CD8 count were prognostic for all-cause, AIDS, and non-AIDS mortality in virologically suppressed patients with high CD4 count.
Methods - We used data from 13 European and North American cohorts of human immunodeficiency virus-infected, antiretroviral therapy (ART)-naive adults who started ART during 1996-2010, who were followed from the date they had CD4 count ≥350 cells/μL and were virologically suppressed (baseline). We used stratified Cox models to estimate unadjusted and adjusted (for sex, people who inject drugs, ART initiation year, and baseline age, CD4 count, AIDS, duration of ART) all-cause and cause-specific mortality hazard ratios for tertiles of CD4:CD8 ratio (0-0.40, 0.41-0.64 [reference], >0.64) and CD8 count (0-760, 761-1138 [reference], >1138 cells/μL) and examined the shape of associations using cubic splines.
Results - During 276526 person-years, 1834 of 49865 patients died (249 AIDS-related; 1076 non-AIDS-defining; 509 unknown/unclassifiable deaths). There was little evidence that CD4:CD8 ratio was prognostic for all-cause mortality after adjustment for other factors: the adjusted hazard ratio (aHR) for lower vs middle tertile was 1.11 (95% confidence interval [CI], 1.00-1.25). The association of CD8 count with all-cause mortality was U-shaped: aHR for higher vs middle tertile was 1.13 (95% CI, 1.01-1.26). AIDS-related mortality declined with increasing CD4:CD8 ratio and decreasing CD8 count. There was little evidence that CD4:CD8 ratio or CD8 count was prognostic for non-AIDS mortality.
Conclusions - In this large cohort collaboration, the magnitude of adjusted associations of CD4:CD8 ratio or CD8 count with mortality was too small for them to be useful as independent prognostic markers in virally suppressed patients on ART.
© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.
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Shared peptide binding of HLA Class I and II alleles associate with cutaneous nevirapine hypersensitivity and identify novel risk alleles.
Pavlos R, McKinnon EJ, Ostrov DA, Peters B, Buus S, Koelle D, Chopra A, Schutte R, Rive C, Redwood A, Restrepo S, Bracey A, Kaever T, Myers P, Speers E, Malaker SA, Shabanowitz J, Jing Y, Gaudieri S, Hunt DF, Carrington M, Haas DW, Mallal S, Phillips EJ
(2017) Sci Rep 7: 8653
MeSH Terms: Alleles, Anti-HIV Agents, Case-Control Studies, Disease Susceptibility, Drug Hypersensitivity, Histocompatibility Antigens Class I, Histocompatibility Antigens Class II, Humans, Nevirapine, Odds Ratio, Peptides, Protein Binding, Risk Assessment, T-Lymphocytes
Show Abstract · Added March 30, 2020
Genes of the human leukocyte antigen (HLA) system encode cell-surface proteins involved in regulation of immune responses, and the way drugs interact with the HLA peptide binding groove is important in the immunopathogenesis of T-cell mediated drug hypersensitivity syndromes. Nevirapine (NVP), is an HIV-1 antiretroviral with treatment-limiting hypersensitivity reactions (HSRs) associated with multiple class I and II HLA alleles. Here we utilize a novel analytical approach to explore these multi-allelic associations by systematically examining HLA molecules for similarities in peptide binding specificities and binding pocket structure. We demonstrate that primary predisposition to cutaneous NVP HSR, seen across ancestral groups, can be attributed to a cluster of HLA-C alleles sharing a common binding groove F pocket with HLA-C*04:01. An independent association with a group of class II alleles which share the HLA-DRB1-P4 pocket is also observed. In contrast, NVP HSR protection is afforded by a cluster of HLA-B alleles defined by a characteristic peptide binding groove B pocket. The results suggest drug-specific interactions within the antigen binding cleft can be shared across HLA molecules with similar binding pockets. We thereby provide an explanation for multiple HLA associations with cutaneous NVP HSR and advance insight into its pathogenic mechanisms.
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cytochrome P450 46A1 (CYP46A1) activation by neuroactive compounds.
Mast N, Anderson KW, Johnson KM, Phan TTN, Guengerich FP, Pikuleva IA
(2017) J Biol Chem 292: 12934-12946
MeSH Terms: Acetylcholine, Allosteric Regulation, Amino Acid Substitution, Anti-HIV Agents, Aspartic Acid, Benzoxazines, Binding Sites, Biocatalysis, Cholesterol 24-Hydroxylase, Deuterium Exchange Measurement, Enzyme Activation, Glutamic Acid, Ligands, Models, Molecular, Molecular Docking Simulation, Mutagenesis, Site-Directed, Mutation, Nerve Tissue Proteins, Peptide Fragments, Protein Conformation, Recombinant Fusion Proteins, gamma-Aminobutyric Acid
Show Abstract · Added March 14, 2018
Cytochrome P450 46A1 (CYP46A1, cholesterol 24-hydroxylase) is the enzyme responsible for the majority of cholesterol elimination from the brain. Previously, we found that the anti-HIV drug efavirenz (EFV) can pharmacologically activate CYP46A1 in mice. Herein, we investigated whether CYP46A1 could also be activated by endogenous compounds, including major neurotransmitters. experiments with purified recombinant CYP46A1 indicated that CYP46A1 is activated by l-glutamate (l-Glu), l-aspartate, γ-aminobutyric acid, and acetylcholine, with l-Glu eliciting the highest increase (3-fold) in CYP46A1-mediated cholesterol 24-hydroxylation. We also found that l-Glu and other activating neurotransmitters bind to the same site on the CYP46A1 surface, which differs from the EFV-binding site. The other principal differences between EFV and l-Glu in CYP46A1 activation include an apparent lack of l-Glu binding to the P450 active site and different pathways of signal transduction from the allosteric site to the active site. EFV and l-Glu similarly increased the CYP46A1 , the rate of the "fast" phase of the enzyme reduction by the redox partner NADPH-cytochrome P450 oxidoreductase, and the amount of P450 reduced. Spectral titrations with cholesterol, in the presence of EFV or l-Glu, suggest that water displacement from the heme iron can be affected in activator-bound CYP46A1. Moreover, EFV and l-Glu synergistically activated CYP46A1. Collectively, our data, along with those from previous cell culture and studies by others, suggest that l-Glu-induced CYP46A1 activation is of physiological relevance.
© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
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An Innovative Approach to Addressing the HIV Care Continuum: Implementation of a Clinical Pharmacy Resident in a Veterans Affairs HIV Specialty Clinic.
Bagwell A, McFarland MS, Hulgan T
(2018) J Pharm Pract 31: 422-428
MeSH Terms: Adult, Aged, Ambulatory Care Facilities, Anti-HIV Agents, Cohort Studies, HIV Infections, Hospitals, Veterans, Humans, Male, Middle Aged, Organizational Innovation, Pharmacy Residencies, Pharmacy Service, Hospital, Pilot Projects, United States, United States Department of Veterans Affairs, Veterans, Viral Load
Show Abstract · Added December 11, 2019
PURPOSE - Engagement of patients in the HIV care continuum and adherence to antiretroviral therapy (ART) continue to limit successful viral suppression. Innovative practices to improve this continuum and ameliorate potential physician shortages are needed. The objective of this evaluation was to determine the clinical benefits of incorporating pharmacy resident involvement on a multidisciplinary team in caring for patients with HIV.
METHODS - A single-center pre-post cohort pilot evaluation was conducted at the Tennessee Valley Healthcare Systems VA Medical Center. Patients were enrolled in an HIV pharmacotherapy clinic implemented by an ambulatory care pharmacy resident. The primary end point of the evaluation was the percentage of patients achieving an undetectable plasma HIV viral load after enrollment. Secondary end points included change from baseline in CD4 T-cell count and self-reported adherence.
RESULTS - A total of 55 patients were seen in the HIV pharmacotherapy clinic over a 28-week evaluation period. Of those patients with detectable viral load at enrollment, 70% reached viral suppression during follow-up, with a significant 0.75 log10 decrease in the median viral load ( P < .0001 for both). The median CD4 T-cell count increased from 464 to 525 cells/mm ( P = .01). Reported adherence, assessed using the Visual Analogue adherence Scale (VAS) increased significantly ( P = .0001).
CONCLUSION - After enrollment in an HIV pharmacotherapy clinic, a significant decrease in viral load was seen, as were improvements in secondary end points of CD4 T cells and adherence. These data demonstrate the clinical benefits of pharmacy resident involvement on a multidisciplinary team in caring for patients with HIV.
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