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1.
J Infect Dis ; 223(9): 1601-1611, 2021 05 20.
Artículo en Inglés | MEDLINE | ID: mdl-32157292

RESUMEN

BACKGROUND: The prevalence and mortality risk of depression in people with human immunodeficiency virus (HIV) infection receiving antiretroviral therapy (ART) is higher than in the general population, yet biomarkers for therapeutic targeting are unknown. In the current study, we aimed to identify plasma metabolites associated with depressive symptoms in people with HIV receiving ART. METHODS: This is a prospective study of ART-treated HIV-infected adults with or without depressive symptoms assessed using longitudinal Beck Depression Inventory scores. Plasma metabolite profiling was performed in 2 independent cohorts (total n = 99) using liquid and gas chromatography and tandem mass spectrometry. RESULTS: Participants with depressive symptoms had lower neuroactive steroids (dehydroepiandrosterone sulfate [DHEA-S], androstenediols, and pregnenolone sulfate) compared with those without depressive symptoms. The cortisol/DHEA-S ratio, an indicator of hypothalamic-pituitary-adrenal axis imbalance, was associated with depressive symptoms (P < .01) because of low DHEA-S levels, whereas cortisol was similar between groups. The odds of having depressive symptoms increased with higher cortisol/DHEA-S ratios (adjusted odds ratio, 2.5 per 1-unit increase in z score; 95% confidence interval, 1.3-4.7), independent of age and sex. The kynurenine-to-tryptophan ratio showed no significant associations. CONCLUSIONS: These findings suggest that altered neuroactive steroid metabolism may contribute to the pathophysiological mechanisms of depression in ART-treated HIV-infected adults, representing a potential biological pathway for therapeutic targeting.


Asunto(s)
Depresión , Infecciones por VIH , Neuroesteroides , Adulto , Deshidroepiandrosterona/sangre , Depresión/complicaciones , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/psicología , Humanos , Hidrocortisona/sangre , Sistema Hipotálamo-Hipofisario , Neuroesteroides/sangre , Sistema Hipófiso-Suprarrenal , Estudios Prospectivos
2.
BMC Immunol ; 21(1): 57, 2020 11 11.
Artículo en Inglés | MEDLINE | ID: mdl-33176710

RESUMEN

BACKGROUND: Extracellular vesicles (EVs) are nano-sized particles secreted by most cells. EVs carry nucleic acids that hold promise as potential biomarkers in various diseases. Human immunodeficiency virus type 1 (HIV) infects CD4+ T cells and induces immune dysfunction, inflammation, and EV secretion, but little is known about EV small RNA cargo in relation to immune dysregulation in HIV-infected individuals. Here, we characterize small RNA carried by circulating EVs in HIV-positive subjects on antiretroviral therapy (ART) relative to uninfected controls by next-generation RNA sequencing. RESULTS: Plasma EVs isolated from HIV-positive and HIV-negative subjects in test (n = 24) and validation (n = 16) cohorts were characterized by electron microscopy, nanoparticle tracking analysis, and immunoblotting for exosome markers. EVs were more abundant in plasma from HIV-positive compared to HIV-negative subjects. Small RNA sequencing of plasma EVs in the test cohort identified diverse small RNA species including miRNA, piRNA, snRNA, snoRNA, tRNA, and rRNA, with miRNA being the most abundant. A total of 351 different miRNAs were detected in plasma EVs, with the top 50 miRNAs accounting for 90% of all miRNA reads. miR-26a-5p was the most abundant miRNA, followed by miR-21-5p and miR-148-3p. qRT-PCR analysis showed that six miRNAs (miR-10a-5p, - 21-5p, -27b-3p, - 122-5p, -146a-5p, - 423-5p) were significantly increased in plasma EVs from HIV-positive compared to HIV-negative subjects in the validation cohort. Furthermore, miR-21-5p, -27b-3p, -146a-5p, and - 423-5p correlated positively with metabolite markers of oxidative stress and negatively with anti-inflammatory polyunsaturated fatty acids. Over-representation and pathway enrichment analyses of miRNAs and their target genes predicted functional association with oxidative stress responses, interferon gamma signaling, Toll-like receptor signaling, TGF beta signaling, and Notch signaling. CONCLUSIONS: HIV-positive individuals on ART have increased abundance of circulating EVs carrying diverse small RNAs, with miRNAs being the most abundant. Several miRNAs associated with inflammation and oxidative stress are increased in circulating EVs of HIV-positive individuals, representing potential biomarkers of targetable pathways that contribute to disease pathogenesis.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , MicroARN Circulante/genética , Vesículas Extracelulares/genética , Marcadores Genéticos/genética , Infecciones por VIH/inmunología , VIH-1/fisiología , Inflamación/genética , Adulto , Femenino , Infecciones por VIH/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Estrés Oxidativo/genética
3.
Hum Genomics ; 13(1): 59, 2019 11 28.
Artículo en Inglés | MEDLINE | ID: mdl-31779701

RESUMEN

BACKGROUND: Tobacco smoking induces immunomodulatory and pro-inflammatory effects associated with transcriptome changes in monocytes and other immune cell types. While smoking is prevalent in HIV-infected (HIV+) individuals, few studies have investigated its effects on gene expression in this population. Here, we report whole-transcriptome analyses of 125 peripheral blood monocyte samples from ART-treated HIV+ and uninfected (HIV-) men enrolled in the Multicenter AIDS Cohort Study (MACS) (n = 25 HIV+ smokers, n = 60 HIV+ non-smokers, n = 40 HIV- non-smoking controls). Gene expression profiling was performed using Illumina HumanHT-12 Expression BeadChip microarrays. Differential expression analysis was performed with weighted linear regression models using the R limma package, followed by functional enrichment and Ingenuity Pathway analyses. RESULTS: A total of 286 genes were differentially expressed in monocytes from HIV+ smokers compared with HIV- non-smokers; upregulated genes (n = 180) were enriched for immune and interferon response, chemical/stress response, mitochondria, and extracellular vesicle gene ontology (GO) terms. Expression of genes related to immune/interferon responses (AIM2, FCGR1A-B, IFI16, SP100), stress/chemical responses (APAF1, HSPD1, KLF4), and mitochondrial function (CISD1, MTHFD2, SQOR) was upregulated in HIV+ non-smokers and further increased in HIV+ smokers. Gene expression changes associated with smoking in previous studies of human monocytes were also observed (SASH1, STAB1, PID1, MMP25). Depressive symptoms (CES-D scores ≥ 16) were more prevalent in HIV+ tobacco smokers compared with HIV+ and HIV- non-smokers (50% vs. 26% and 13%, respectively; p = 0.007), and upregulation of immune/interferon response genes, including IFI35, IFNAR1, OAS1-2, STAT1, and SP100, was associated with depressive symptoms in logistic regression models adjusted for HIV status and smoking (p < 0.05). Network models linked the Stat1-mediated interferon pathway to transcriptional regulator Klf4 and smoking-associated toll-like receptor scaffolding protein Sash1, suggesting inter-relationships between smoking-associated genes, control of monocyte differentiation, and interferon-mediated inflammatory responses. CONCLUSIONS: This study characterizes immune, interferon, stress response, and mitochondrial-associated gene expression changes in monocytes from HIV+ tobacco smokers, and identifies augmented interferon and stress responses associated with depressive symptoms. These findings help to explain complex interrelationships between pro-inflammatory effects of HIV and smoking, and their combined impact on comorbidities prevalent in HIV+ individuals.


Asunto(s)
Terapia Antirretroviral Altamente Activa , Depresión/psicología , Perfilación de la Expresión Génica , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/genética , Interferones/genética , Fumar/psicología , Estrés Psicológico/genética , Adulto , Anciano , Depresión/sangre , Regulación de la Expresión Génica , Ontología de Genes , Redes Reguladoras de Genes , Infecciones por VIH/sangre , Infecciones por VIH/psicología , Seropositividad para VIH/tratamiento farmacológico , Seropositividad para VIH/genética , Seropositividad para VIH/psicología , Humanos , Interferones/metabolismo , Factor 4 Similar a Kruppel , Masculino , Persona de Mediana Edad , Transducción de Señal/genética , Fumar/genética
4.
J Neuroinflammation ; 16(1): 254, 2019 Dec 05.
Artículo en Inglés | MEDLINE | ID: mdl-31805958

RESUMEN

BACKGROUND: Extracellular vesicles (EVs) are nano-sized particles present in most body fluids including cerebrospinal fluid (CSF). Little is known about CSF EV proteins in HIV+ individuals. Here, we characterize the CSF EV proteome in HIV+ subjects and its relationship to neuroinflammation, stress responses, and HIV-associated neurocognitive disorders (HAND). METHODS: CSF EVs isolated from 20 HIV+ subjects with (n = 10) or without (n = 10) cognitive impairment were characterized by electron microscopy, nanoparticle tracking analysis, immunoblotting, and untargeted LC/MS/MS mass spectrometry. Functional annotation was performed by gene ontology (GO) mapping and expression annotation using Biobase Transfac and PANTHER software. Cultured astrocytic U87 cells were treated with hydrogen peroxide for 4 h to induce oxidative stress and EVs isolated by ultracentrifugation. Selected markers of astrocytes (GFAP, GLUL), inflammation (CRP), and stress responses (PRDX2, PARK7, HSP70) were evaluated in EVs released by U87 cells following induction of oxidative stress and in CSF EVs from HIV+ patients by immunoblotting. RESULTS: Mass spectrometry identified 2727 and 1626 proteins in EV fractions and EV-depleted CSF samples, respectively. CSF EV fractions were enriched with exosomal markers including Alix, syntenin, tetraspanins, and heat-shock proteins and a subset of neuronal, astrocyte, oligodendrocyte, and choroid plexus markers, in comparison to EV-depleted CSF. Proteins related to synapses, immune/inflammatory responses, stress responses, metabolic processes, mitochondrial functions, and blood-brain barrier were also identified in CSF EV fractions by GO mapping. HAND subjects had higher abundance of CSF EVs and proteins mapping to GO terms for synapses, glial cells, inflammation, and stress responses compared to those without HAND. GFAP, GLUL, CRP, PRDX2, PARK7, and HSP70 were confirmed by immunoblotting of CSF EVs from subjects with HAND and were also detected in EVs released by U87 cells under oxidative stress. CONCLUSIONS: These findings suggest that CSF EVs derived from neurons, glial cells, and choroid plexus carry synaptic, immune/inflammation-related, and stress response proteins in HIV+ individuals with cognitive impairment, representing a valuable source for biomarker discovery.


Asunto(s)
Disfunción Cognitiva/líquido cefalorraquídeo , Vesículas Extracelulares/metabolismo , Infecciones por VIH/líquido cefalorraquídeo , Estrés Oxidativo/fisiología , Proteómica/métodos , Sinapsis/metabolismo , Línea Celular Tumoral , Disfunción Cognitiva/genética , Disfunción Cognitiva/psicología , Vesículas Extracelulares/genética , Femenino , Infecciones por VIH/genética , Infecciones por VIH/psicología , Humanos , Inflamación/líquido cefalorraquídeo , Inflamación/genética , Inflamación/psicología , Masculino , Persona de Mediana Edad , Sinapsis/genética
5.
Clin Infect Dis ; 67(8): 1182-1190, 2018 09 28.
Artículo en Inglés | MEDLINE | ID: mdl-29617912

RESUMEN

Background: Cerebrospinal fluid (CSF) viral escape occurs in 4%-20% of human immunodeficiency virus (HIV)-infected adults, yet the impact of antiretroviral therapy (ART) on CSF escape is unclear. Methods: A prospective study of 1063 participants with baseline plasma viral load (VL) ≤400 copies/mL between 2005 and 2016. The odds ratio (OR) for ART regimens (protease inhibitor with nucleoside reverse transcriptase inhibitor [PI + NRTI] vs other ART) and CSF escape was estimated using mixed-effects models. Results: Baseline mean age was 46 years, median plasma VL, and CD4 count were 50 copies/mL, and 424 cells/µL, respectively. During median follow-up of 4.4 years, CSF escape occurred in 77 participants (7.2%). PI + NRTI use was an independent predictor of CSF escape (OR, 3.1; 95% confidence interval, 1.8-5.0) in adjusted analyses and models restricted to plasma VL ≤50 copies/mL (P < .001). Regimens that contained atazanavir (ATV) were a stronger predictor of CSF viral escape than non-ATV PI + NRTI regimens. Plasma and CSF M184V/I combined with thymidine-analog mutations were more frequent in CSF escape vs no escape (23% vs 2.3%). Genotypic susceptibility score-adjusted central nervous system (CNS) penetration-effectiveness (CPE) values were calculated for CSF escape with M184V/I mutations (n = 34). Adjusted CPE values were low (<5) for CSF in 27 (79%), indicating suboptimal CNS drug availability. Conclusions: PI + NRTI regimens are independent predictors of CSF escape in HIV-infected adults. Reduced CNS ART bioavailability may predispose to CSF escape in patients with M184V/I mutations.


Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/líquido cefalorraquídeo , Infecciones por VIH/tratamiento farmacológico , VIH/efectos de los fármacos , Adulto , Anciano , Recuento de Linfocito CD4 , Farmacorresistencia Viral/genética , Femenino , Genotipo , VIH/genética , Infecciones por VIH/epidemiología , VIH-1 , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , ARN Viral/sangre , Estados Unidos/epidemiología , Carga Viral , Adulto Joven
6.
AIDS Behav ; 21(7): 1985-1995, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-28550378

RESUMEN

Cocaine use is prevalent among HIV-infected individuals. While cross-sectional studies suggest that cocaine users may be at increased risk for depression, long-term effects of cocaine on depressive symptoms remain unclear. This is a longitudinal study of 341 HIV-infected and uninfected men (135 cocaine users and 206 controls) ages 30-60 enrolled in the Multicenter AIDS Cohort Study during 1996-2009. The median baseline age was 41; 73% were African-American. In mixed-effects models over a median of 4.8 years of observation, cocaine use was associated with higher depressive symptoms independent of age, education level, and smoking (n = 288; p = 0.02); HIV infection modified this association (p = 0.03). Latent class mixed models were used to empirically identify distinct depressive trajectories (n = 160). In adjusted models, cocaine use was associated with threefold increased odds of membership in the class with persistent high depressive symptoms (95% confidence interval (CI) 1.38-6.69) and eightfold increased odds (95% CI (2.73-25.83) when tested among HIV-infected subjects only. Cocaine use is a risk factor for chronic depressive symptoms, particularly among HIV-infected men, highlighting the importance of integrating mental health and substance use treatments to address barriers to well-being and successful HIV-care.


Asunto(s)
Trastornos Relacionados con Cocaína/psicología , Cocaína Crack , Depresión/psicología , Trastorno Depresivo/psicología , Infecciones por VIH/psicología , Adulto , Negro o Afroamericano , Trastornos Relacionados con Cocaína/complicaciones , Cognición , Depresión/complicaciones , Trastorno Depresivo/complicaciones , Progresión de la Enfermedad , Femenino , Infecciones por VIH/complicaciones , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Factores de Riesgo , Trastornos Relacionados con Sustancias/complicaciones , Trastornos Relacionados con Sustancias/psicología
7.
BMC Infect Dis ; 17(1): 151, 2017 02 17.
Artículo en Inglés | MEDLINE | ID: mdl-28212619

RESUMEN

BACKGROUND: HIV+ patients on highly active antiretroviral therapy (HAART) with suppressed viral loads have a low incidence of HIV-associated dementia, but increased prevalence of milder forms of HIV-associated neurocognitive disorders (HAND). These milder forms of HAND are often associated with minimal histological abnormalities, and their pathophysiology is unclear. Comorbidities, altered amyloid metabolism, accelerated brain aging, and activated interferon responses are suspected to play a role in HAND pathogenesis in HAART-treated persons. METHODS: To investigate associations between liver disease, accelerated brain aging, and HAND in HIV+ patients in the late HAART era (2002-2015), we studied liver and brain autopsy tissues from 53 older subjects evaluated at UCLA and BWH using histopathological stains, a sensitive fluorescent amyloid stain (AmyloGlo), and targeted gene expression profiling (NanoString). RESULTS: The majority of HIV+ subjects (median age 56) were on HAART (89.3%) with last pre-mortem plasma viral load <400 copies/mL (81.5%); 50% had CD4+ counts <200 cells/µL. Compared to HIV- controls (median age 65), HIV+ subjects had more cancer (p = 0.04), illicit drug use (p <0.00001), and HCV co-infection (p = 0.002), less cardiovascular disease (p = 0.03), and similar prevalence of cerebrovascular disease (~40%), hypertension, hyperlipidemia, and diabetes. Deep frontal white matter showed increased gliosis in HIV+ subjects vs. HIV- controls (p = 0.09), but no significant differences in myelin loss, blood vessel thickening, or inflammation. Liver showed more severe fibrosis/cirrhosis (p = 0.02) and less steatosis (p = 0.03) in HIV+ subjects, but no significant differences in inflammation, blood vessel thickness, or pigment deposition. There were no significant associations between liver and brain pathologies. AmyloGlo staining detected large amyloid deposits in only one HIV+ case (age 69 with Alzheimer's disease pathology) and two HIV- controls (ages 66 and 74). White matter from HIV+ cases vs. HIV- seronegative controls showed a trend (p = 0.06) towards increased interferon response gene expression (ISG15, MX1, IFIT1, IFIT2, and IFITM1). CONCLUSIONS: Gliosis and cerebrovascular disease, but not accelerated amyloid deposition, are common brain pathologies among older HIV+ patients in the late HAART era. Although HIV+ subjects had more cirrhosis, liver pathology was not associated with any consistent pattern of brain pathology. Cerebrovascular disease, interferon responses, and neuroinflammation are likely factors contributing to brain aging and HAND in older HIV+ patients on current HAART regimens.


Asunto(s)
Complejo SIDA Demencia/metabolismo , Complejo SIDA Demencia/patología , Amiloide/metabolismo , Terapia Antirretroviral Altamente Activa , Encéfalo/patología , Interferones/inmunología , Cirrosis Hepática/patología , Complejo SIDA Demencia/inmunología , Anciano , Encéfalo/metabolismo , Recuento de Linfocito CD4 , Trastornos Cerebrovasculares/metabolismo , Trastornos Cerebrovasculares/patología , Femenino , Gliosis/metabolismo , Gliosis/patología , Humanos , Interferones/metabolismo , Cirrosis Hepática/metabolismo , Masculino , Persona de Mediana Edad , Transcriptoma , Carga Viral
8.
J Biol Chem ; 290(16): 10504-17, 2015 Apr 17.
Artículo en Inglés | MEDLINE | ID: mdl-25724652

RESUMEN

APOBEC3G (A3G) is a cellular cytidine deaminase that restricts HIV-1 replication by inducing G-to-A hypermutation in viral DNA and by deamination-independent mechanisms. HIV-1 Vif binds to A3G, resulting in its degradation via the 26 S proteasome. Therefore, this interaction represents a potential therapeutic target. To identify compounds that inhibit interaction between A3G and HIV-1 Vif in a high throughput format, we developed a homogeneous time-resolved fluorescence resonance energy transfer assay. A 307,520 compound library from the NIH Molecular Libraries Small Molecule Repository was screened. Secondary screens to evaluate dose-response performance and off-target effects, cell-based assays to identify compounds that attenuate Vif-dependent degradation of A3G, and assays testing antiviral activity in peripheral blood mononuclear cells and T cells were employed. One compound, N.41, showed potent antiviral activity in A3G(+) but not in A3G(-) T cells and had an IC50 as low as 8.4 µM and a TC50 of >100 µM when tested against HIV-1Ba-L replication in peripheral blood mononuclear cells. N.41 inhibited the Vif-A3G interaction and increased cellular A3G levels and incorporation of A3G into virions, thereby attenuating virus infectivity in a Vif-dependent manner. N.41 activity was also species- and Vif-dependent. Preliminary structure-activity relationship studies suggest that a hydroxyl moiety located at a phenylamino group is critical for N.41 anti-HIV activity and identified N.41 analogs with better potency (IC50 as low as 4.2 µM). These findings identify a new lead compound that attenuates HIV replication by liberating A3G from Vif regulation and increasing its innate antiviral activity.


Asunto(s)
Fármacos Anti-VIH/farmacología , Citidina Desaminasa/genética , VIH-1/efectos de los fármacos , Leucocitos Mononucleares/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/farmacología , Linfocitos T/efectos de los fármacos , Productos del Gen vif del Virus de la Inmunodeficiencia Humana/genética , Desaminasa APOBEC-3G , Fármacos Anti-VIH/química , Bioensayo , Línea Celular , Citidina Desaminasa/metabolismo , Transferencia Resonante de Energía de Fluorescencia , Regulación de la Expresión Génica , Células HEK293 , VIH-1/genética , VIH-1/metabolismo , Interacciones Huésped-Patógeno , Humanos , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/virología , Cultivo Primario de Células , Complejo de la Endopetidasa Proteasomal/efectos de los fármacos , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteolisis , Transducción de Señal , Bibliotecas de Moléculas Pequeñas/química , Relación Estructura-Actividad , Linfocitos T/metabolismo , Linfocitos T/virología , Replicación Viral/efectos de los fármacos , Productos del Gen vif del Virus de la Inmunodeficiencia Humana/antagonistas & inhibidores , Productos del Gen vif del Virus de la Inmunodeficiencia Humana/metabolismo
9.
Clin Infect Dis ; 63(8): 1130-1139, 2016 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-27448678

RESUMEN

BACKGROUND: Dyslipidemia and apolipoprotein E4 (APOE ϵ4) allele are risk factors for age-related cognitive decline, but how these risks are modified by human immunodeficiency virus (HIV) infection is unclear. METHODS: In a longitudinal nested study from the Multicenter AIDS Cohort Study, 273 HIV type 1-infected (HIV(+)) men aged 50-65 years with baseline HIV RNA <400 copies/mL and on continuous antiretroviral therapy (ART) in ≥95% of follow-up visits were matched by sociodemographic variables to 516 HIV-uninfected (HIV(-)) controls. The association between lipid markers (total cholesterol, low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], and triglycerides), APOE genotype, and cognitive decline in HIV infection was examined using mixed-effects models. RESULTS: The median baseline age of participants was 51, 81% were white, and 89% had education >12 years. HIV(+) men had similar baseline total cholesterol and LDL-C, but lower HDL-C and higher triglycerides than controls (P < .001). Higher total cholesterol and LDL-C were associated with faster rates of cognitive decline (P < .01), whereas higher HDL-C attenuated decline (P = .02) in HIV(+) men. In HIV(+) men with elevated cholesterol, statin use was associated with a slower estimated rate of decline (P = .02). APOE ϵ4 genotype accelerated cognitive decline in HIV(+) but not HIV(-) men (P = .01), with trajectories diverging from HIV(-) ε4 carriers after age 50. Total cholesterol levels did not modify the association of ϵ4 genotype with decline (P = .9). CONCLUSIONS: Elevated cholesterol and APOE ϵ4 genotype are independent risk factors for cognitive decline in ART-adherent HIV(+) men aged >50 years. Treatment of dyslipidemia may be an effective strategy to reduce cognitive decline in older HIV(+) individuals.


Asunto(s)
Alelos , Apolipoproteína E4/genética , Disfunción Cognitiva/sangre , Disfunción Cognitiva/etiología , Infecciones por VIH/complicaciones , Infecciones por VIH/genética , Lípidos/sangre , Factores de Edad , Anciano , Terapia Antirretroviral Altamente Activa , Biomarcadores , Disfunción Cognitiva/diagnóstico , Susceptibilidad a Enfermedades , Femenino , Estudios de Seguimiento , Genotipo , Infecciones por VIH/tratamiento farmacológico , Humanos , Masculino , Pruebas de Estado Mental y Demencia , Persona de Mediana Edad , Factores de Riesgo
10.
Nucleic Acids Res ; 40(17): e135, 2012 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-22645320

RESUMEN

We describe here a novel method for integrating gene and miRNA expression profiles in cancer using feed-forward loops (FFLs) consisting of transcription factors (TFs), miRNAs and their common target genes. The dChip-GemiNI (Gene and miRNA Network-based Integration) method statistically ranks computationally predicted FFLs by their explanatory power to account for differential gene and miRNA expression between two biological conditions such as normal and cancer. GemiNI integrates not only gene and miRNA expression data but also computationally derived information about TF-target gene and miRNA-mRNA interactions. Literature validation shows that the integrated modeling of expression data and FFLs better identifies cancer-related TFs and miRNAs compared to existing approaches. We have utilized GemiNI for analyzing six data sets of solid cancers (liver, kidney, prostate, lung and germ cell) and found that top-ranked FFLs account for ∼20% of transcriptome changes between normal and cancer. We have identified common FFL regulators across multiple cancer types, such as known FFLs consisting of MYC and miR-15/miR-17 families, and novel FFLs consisting of ARNT, CREB1 and their miRNA partners. The results and analysis web server are available at http://www.canevolve.org/dChip-GemiNi.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , MicroARNs/metabolismo , Factores de Transcripción/metabolismo , Transcriptoma , Retroalimentación Fisiológica , Humanos , Neoplasias/genética , Neoplasias/metabolismo
11.
BMC Infect Dis ; 13: 203, 2013 May 04.
Artículo en Inglés | MEDLINE | ID: mdl-23641933

RESUMEN

BACKGROUND: Metabolic abnormalities are common in HIV-infected individuals on antiretroviral therapy (ART), but the biochemical details and underlying mechanisms of these disorders have not been defined. METHODS: Untargeted metabolomic profiling of plasma was performed for 32 HIV patients with low nadir CD4 counts (<300 cells/ul) on protease inhibitor (PI)-based ART and 20 healthy controls using liquid or gas chromatography and mass spectrometry. Effects of Hepatitis C (HCV) co-infection and relationships between altered lipid metabolites and markers of inflammation, microbial translocation, and hepatic function were examined. Unsupervised hierarchical clustering, principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), Random forest, pathway mapping, and metabolite set enrichment analysis (MSEA) were performed using dChip, Metaboanalyst, and MSEA software. RESULTS: A 35-metabolite signature mapping to lipid, amino acid, and nucleotide metabolism distinguished HIV patients with advanced disease on PI-based ART from controls regardless of HCV serostatus (p<0.05, false discovery rate (FDR)<0.1). Many altered lipids, including bile acids, sulfated steroids, polyunsaturated fatty acids, and eicosanoids, were ligands of nuclear receptors that regulate metabolism and inflammation. Distinct clusters of altered lipids correlated with markers of inflammation (interferon-α and interleukin-6), microbial translocation (lipopolysaccharide (LPS) and LPS-binding protein), and hepatic function (bilirubin) (p<0.05). Lipid alterations showed substantial overlap with those reported in non-alcoholic fatty liver disease (NALFD). Increased bile acids were associated with noninvasive markers of hepatic fibrosis (FIB-4, APRI, and YKL-40) and correlated with acylcarnitines, a marker of mitochondrial dysfunction. CONCLUSIONS: Lipid alterations in HIV patients receiving PI-based ART are linked to markers of inflammation, microbial translocation, and hepatic function, suggesting that therapeutic strategies attenuating dysregulated innate immune activation and hepatic dysfunction may be beneficial for prevention and treatment of metabolic disorders in HIV patients.


Asunto(s)
Hígado Graso/metabolismo , Infecciones por VIH/sangre , Infecciones por VIH/tratamiento farmacológico , Inflamación/metabolismo , Trastornos del Metabolismo de los Lípidos/metabolismo , Adulto , Ácidos y Sales Biliares/sangre , Biomarcadores/sangre , Biomarcadores/metabolismo , Estudios de Cohortes , Hígado Graso/sangre , Hígado Graso/virología , Femenino , Infecciones por VIH/enzimología , Hepatitis C/enzimología , Hepatitis C/metabolismo , Hepatitis C/virología , Humanos , Inflamación/sangre , Inflamación/complicaciones , Análisis de los Mínimos Cuadrados , Trastornos del Metabolismo de los Lípidos/sangre , Trastornos del Metabolismo de los Lípidos/virología , Lípidos/sangre , Masculino , Redes y Vías Metabólicas , Metaboloma , Metabolómica , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico , Análisis de Componente Principal , Inhibidores de Proteasas/uso terapéutico
12.
Viruses ; 15(9)2023 Aug 29.
Artículo en Inglés | MEDLINE | ID: mdl-37766236

RESUMEN

HIV establishes a viral reservoir in the CNS despite viral suppression in the blood on antiretroviral therapy (ART). In a minority of people with HIV (PWH), HIV RNA is detectable in CSF when HIV RNA in plasma is undetectable or HIV RNA levels are higher in CSF compared with plasma, an event termed CSF viral escape that can occur with or without neurological symptoms. Asymptomatic CSF viral escape occurs in 3-20% of PWH on ART, yet associated biomarkers are unclear. To identify biomarkers associated with asymptomatic CSF viral escape, we performed a matched group study of PWH on ART with vs. without CSF viral escape (n = 10 and n = 60, respectively, matched for age, duration of HIV infection, nadir CD4 count, and ART regimen) and 50 HIV-negative controls. PWH were on 3 or more ART drugs for >1 year, and the group with no CSF viral escape was suppressed below 50 copies/mL in plasma and CSF. Biomarkers of inflammation (IFN-γ, IL-1ß, IL-6, IL-8, IL-15, IP-10, MCP-1, VEGF), cell adhesion (ICAM-1, VCAM-1), CNS injury (NFL), and glial activation (GFAP, YKL-40) were measured in paired plasma and CSF using the Meso Scale Discovery platform. PWH with vs. without CSF viral escape had more individuals (40%) with a plasma viral load (VL) > 50 copies/mL, higher CSF VL (median 156 vs. 40 copies/mL; p < 0.0001), lower CD4 count (318 vs. 512; p = 0.045), and higher CSF WBC (median [IQR] 4 [0-22] vs. 2 [0-4] cells/µL; p = 0.15) but similar proportions with HIV-associated neurocognitive disorders (HAND) (50% vs. 47%). CSF viral escape was associated with increased IL-1ß, IFN-γ, IP-10, ICAM-1, and VCAM-1 in CSF but not plasma; IP-10 had the strongest association (p = 0.0008). CSF VL and WBC correlated with IFN-γ, IP-10, ICAM-1, and VCAM-1 (p < 0.05). Although markers of CNS injury showed no significant association with asymptomatic CSF viral escape, CSF YKL-40 correlated positively with CSF IL-1ß (p = 0.003), IFN-γ (p = 0.0008), IP-10 (p < 0.0001), and NFL (p = 0.06) and negatively with neurocognitive T scores (p = 0.02). These findings identify CSF inflammation and glial activation markers that may serve as surrogate measures of HIV persistence in the CNS for future studies on therapeutics targeting the CNS reservoir.


Asunto(s)
Enfermedades del Sistema Nervioso Central , Infecciones por VIH , Humanos , Proteína 1 Similar a Quitinasa-3 , Molécula 1 de Adhesión Intercelular , Quimiocina CXCL10 , Molécula 1 de Adhesión Celular Vascular/uso terapéutico , Inflamación , ARN Viral , Biomarcadores/líquido cefalorraquídeo , Carga Viral
13.
AIDS ; 37(14): 2137-2147, 2023 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-37503603

RESUMEN

OBJECTIVE: Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) remain prevalent despite viral suppression on antiretroviral therapy (ART). Vascular disease contributes to HAND, but peripheral markers that distinguish vascular cognitive impairment (VCI) from HIV-related etiologies remain unclear. DESIGN: Cross-sectional study of vascular injury, inflammation, and central nervous system (CNS) injury markers in relation to HAND. METHODS: Vascular injury (VCAM-1, ICAM-1, CRP), inflammation (IFN-γ, IL-1ß, IL-6, IL-8, IL-15, IP-10, MCP-1, VEGF-A), and CNS injury (NFL, total Tau, GFAP, YKL-40) markers were measured in plasma and CSF from 248 individuals (143 HIV+ on suppressive ART and 105 HIV- controls). RESULTS: Median age was 53 years, median CD4 + cell count, and duration of HIV infection were 505 cells/µl and 16 years, respectively. Vascular injury, inflammation, and CNS injury markers were increased in HIV+ compared with HIV- individuals ( P < 0.05). HAND was associated with increased plasma VCAM-1, ICAM-1, and YKL-40 ( P  < 0.01) and vascular disease ( P  = 0.004). In contrast, inflammation markers had no significant association with HAND. Vascular injury markers were associated with lower neurocognitive T scores in age-adjusted models ( P  < 0.01). Furthermore, plasma VCAM-1 correlated with NFL ( r  = 0.29, P  = 0.003). Biomarker clustering separated HAND into three clusters: two clusters with high prevalence of vascular disease, elevated VCAM-1 and NFL, and distinctive inflammation profiles (CRP/ICAM-1/YKL-40 or IL-6/IL-8/IL-15/MCP-1), and one cluster with no distinctive biomarker elevations. CONCLUSIONS: Vascular injury markers are more closely related to HAND and CNS injury in PWH on suppressive ART than inflammation markers and may help to distinguish relative contributions of VCI to HAND.


Asunto(s)
Disfunción Cognitiva , Infecciones por VIH , Lesiones del Sistema Vascular , Humanos , Persona de Mediana Edad , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , VIH , Molécula 1 de Adhesión Intercelular , Proteína 1 Similar a Quitinasa-3 , Interleucina-15 , Interleucina-8 , Interleucina-6 , Lesiones del Sistema Vascular/complicaciones , Estudios Transversales , Molécula 1 de Adhesión Celular Vascular , Disfunción Cognitiva/complicaciones , Biomarcadores , Inflamación/complicaciones
14.
Viruses ; 15(4)2023 04 20.
Artículo en Inglés | MEDLINE | ID: mdl-37112989

RESUMEN

HIV establishes a persistent viral reservoir in the brain despite viral suppression in blood to undetectable levels on antiretroviral therapy (ART). The brain viral reservoir in virally suppressed HIV+ individuals is not well-characterized. In this study, intact, defective, and total HIV proviral genomes were measured in frontal lobe white matter from 28 virally suppressed individuals on ART using the intact proviral DNA assay (IPDA). HIV gag DNA/RNA levels were measured using single-copy assays and expression of 78 genes related to inflammation and white matter integrity was measured using the NanoString platform. Intact proviral DNA was detected in brain tissues of 18 of 28 (64%) individuals on suppressive ART. The median proviral genome copy numbers in brain tissue as measured by the IPDA were: intact, 10 (IQR 1-92); 3' defective, 509 (225-858); 5' defective, 519 (273-906); and total proviruses, 1063 (501-2074) copies/106 cells. Intact proviral genomes accounted for less than 10% (median 8.3%) of total proviral genomes in the brain, while 3' and 5' defective genomes accounted for 44% and 49%, respectively. There was no significant difference in median copy number of intact, defective, or total proviruses between groups stratified by neurocognitive impairment (NCI) vs. no NCI. In contrast, there was an increasing trend in intact proviruses in brains with vs. without neuroinflammatory pathology (56 vs. 5 copies/106 cells, p = 0.1), but no significant differences in defective or total proviruses. Genes related to inflammation, stress responses, and white matter integrity were differentially expressed in brain tissues with >5 vs. +5 intact proviruses/106 cells. These findings suggest that intact HIV proviral genomes persist in the brain at levels comparable to those reported in blood and lymphoid tissues and increase CNS inflammation/immune activation despite suppressive ART, indicating the importance of targeting the CNS reservoir to achieve HIV cure.


Asunto(s)
Infecciones por VIH , Provirus , Humanos , Provirus/genética , Provirus/metabolismo , Enfermedades Neuroinflamatorias , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Linfocitos T CD4-Positivos , Encéfalo , Inflamación , ADN Viral/metabolismo , Carga Viral/genética
15.
medRxiv ; 2023 Jul 24.
Artículo en Inglés | MEDLINE | ID: mdl-37546734

RESUMEN

Objective: Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) remain prevalent despite viral suppression on antiretroviral therapy (ART). Vascular disease contributes to HAND, but peripheral markers that distinguish vascular cognitive impairment (VCI) from HIV-related etiologies remain unclear. Design: Cross-sectional study of vascular injury, inflammation, and central nervous system (CNS) injury markers in relation to HAND. Methods: Vascular injury (VCAM-1, ICAM-1, CRP), inflammation (IFN-γ, IL-1ß, IL-6, IL-8, IL-15, IP-10, MCP-1, VEGF-A), and CNS injury (NFL, total Tau, GFAP, YKL-40) markers were measured in plasma and CSF from 248 individuals (143 HIV+ on suppressive ART and 105 HIV- controls). Results: Median age was 53 years, median CD4 count, and duration of HIV infection were 505 cells/µl and 16 years, respectively. Vascular injury, inflammation, and CNS injury markers were increased in HIV+ compared with HIV- individuals (p<0.05). HAND was associated with increased plasma VCAM-1, ICAM-1, and YKL-40 (p<0.01) and vascular disease (p=0.004). In contrast, inflammation markers had no significant association with HAND. Vascular injury markers were associated with lower neurocognitive T scores in age-adjusted models (p<0.01). Furthermore, plasma VCAM-1 correlated with NFL (r=0.29, p=0.003). Biomarker clustering separated HAND into three clusters: two clusters with high prevalence of vascular disease, elevated VCAM-1 and NFL, and distinctive inflammation profiles (CRP/ICAM-1/YKL-40 or IL-6/IL-8/IL-15/MCP-1), and one cluster with no distinctive biomarker elevations. Conclusions: Vascular injury markers are more closely related to HAND and CNS injury in PWH on suppressive ART than inflammation markers and may help to distinguish relative contributions of VCI to HAND.

16.
Viruses ; 16(1)2023 12 31.
Artículo en Inglés | MEDLINE | ID: mdl-38257772

RESUMEN

HIV-associated neurocognitive disorders (HAND) remain prevalent despite viral suppression on antiretroviral therapy (ART). Older people with HIV (PWH) are also at risk for amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD). ß-amyloid (Aß) and Tau biomarkers are associated with aMCI/AD, but their relationship to HAND is unclear. Given the role of extracellular vesicles (EVs) in age-related neurological disorders, we investigated soluble and EV-associated Aß42, total Tau, NFL, GFAP, ICAM-1, VCAM-1, and CRP in relation to cognitive impairment in PWH. Plasma and CSF EVs were isolated from 184 participants (98 PWH on ART and 86 HIV- controls). Biomarkers were measured using Meso Scale Discovery assays. The median age of PWH was 53 years, and 52% were diagnosed with mild forms of HAND. PWH had increased plasma NFL (p = 0.04) and CSF Aß42 (p = 0.0003) compared with HIV- controls but no significant difference in Tau or EV-associated forms of these markers. CSF EV Aß42 was decreased (p = 0.0002) and CSF EV Tau/Aß42 ratio was increased (p = 0.001) in PWH with HAND vs. no HAND, while soluble forms of these markers showed no significant differences. Decreased CSF EV Aß42 (p < 0.0001) and an increased CSF EV Tau/Aß42 ratio (p = 0.0003) were associated with lower neurocognitive T scores in age-adjusted models; an optimal model included both CSF EV Aß42 and plasma NFL. Levels of soluble, but not EV-associated, ICAM-1, VCAM-1, and CRP were increased in PWH with HAND vs. no HAND (p < 0.05). These findings suggest that decreased Aß42 and an increased Tau/Aß42 ratio in CSF EVs are associated with cognitive impairment in older PWH, and these EV-associated biomarkers may help to distinguish aMCI/AD from HIV-related cognitive disorders in future studies.


Asunto(s)
Disfunción Cognitiva , Vesículas Extracelulares , Infecciones por VIH , Humanos , Persona de Mediana Edad , Biomarcadores , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/etiología , VIH , Infecciones por VIH/complicaciones , Molécula 1 de Adhesión Intercelular , Molécula 1 de Adhesión Celular Vascular
17.
Retrovirology ; 9: 33, 2012 Jun 22.
Artículo en Inglés | MEDLINE | ID: mdl-22534017

RESUMEN

BACKGROUND: HIV-1 Nef protein contributes to pathogenesis via multiple functions that include enhancement of viral replication and infectivity, alteration of intracellular trafficking, and modulation of cellular signaling pathways. Nef stimulates formation of tunneling nanotubes and virological synapses, and is transferred to bystander cells via these intercellular contacts and secreted microvesicles. Nef associates with and activates Pak2, a kinase that regulates T-cell signaling and actin cytoskeleton dynamics, but how Nef promotes nanotube formation is unknown. RESULTS: To identify Nef binding partners involved in Pak2-association dependent Nef functions, we employed tandem mass spectrometry analysis of Nef immunocomplexes from Jurkat cells expressing wild-type Nef or Nef mutants defective for the ability to associate with Pak2 (F85L, F89H, H191F and A72P, A75P in NL4-3). We report that wild-type, but not mutant Nef, was associated with 5 components of the exocyst complex (EXOC1, EXOC2, EXOC3, EXOC4, and EXOC6), an octameric complex that tethers vesicles at the plasma membrane, regulates polarized exocytosis, and recruits membranes and proteins required for nanotube formation. Additionally, Pak2 kinase was associated exclusively with wild-type Nef. Association of EXOC1, EXOC2, EXOC3, and EXOC4 with wild-type, but not mutant Nef, was verified by co-immunoprecipitation assays in Jurkat cells. Furthermore, shRNA-mediated depletion of EXOC2 in Jurkat cells abrogated Nef-mediated enhancement of nanotube formation. Using bioinformatic tools, we visualized protein interaction networks that reveal functional linkages between Nef, the exocyst complex, and the cellular endocytic and exocytic trafficking machinery. CONCLUSIONS: Exocyst complex proteins are likely a key effector of Nef-mediated enhancement of nanotube formation, and possibly microvesicle secretion. Linkages revealed between Nef and the exocyst complex suggest a new paradigm of exocyst involvement in polarized targeting for intercellular transfer of viral proteins and viruses.


Asunto(s)
Proteínas de Transporte Vesicular/metabolismo , Productos del Gen nef del Virus de la Inmunodeficiencia Humana/metabolismo , Línea Celular , Humanos , Modelos Biológicos , Proteínas Mutantes/metabolismo , Unión Proteica , Mapeo de Interacción de Proteínas , Mapas de Interacción de Proteínas , Proteómica , Productos del Gen nef del Virus de la Inmunodeficiencia Humana/genética , Quinasas p21 Activadas/metabolismo
18.
J Acquir Immune Defic Syndr ; 88(5): 518-527, 2021 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-34757975

RESUMEN

BACKGROUND: People with HIV (PWH) have increased frailty risk at younger ages compared with the general population. Multimorbidity is associated with frailty, yet effects of specific comorbidities on transition to frailty in PWH are unknown. SETTING: Prospective study of 219 PWH age 45 years or older in the National NeuroAIDS Tissue Consortium. METHODS: Frailty status was categorized using Fried frailty phenotype criteria. Comorbidities [bone disease, cardiovascular disease, cerebrovascular disease, liver disease, renal disease, diabetes, chronic obstructive pulmonary disease (COPD), hypertension, obesity, cancers, neuropsychiatric conditions] were assessed from longitudinal data. Associations between baseline comorbidities and transition to frailty within 30 months were analyzed using Kaplan-Meier and Cox regression models. Grip strength was assessed using mixed-effects models. RESULTS: At baseline, the median age was 61 years, 73% were male 98% were on antiretroviral therapy, 29% had ≥3 comorbidities, 27% were robust, and 73% were pre-frail. Cerebrovascular disease, diabetes, and COPD were independent predictors of transition to frailty within 30 months in models adjusted for age, sex, and multimorbidity (≥3 additional comorbidities) [hazard ratios (95% confidence intervals) 2.52 (1.29 to 4.93), 2.31 (1.12 to 4.76), and 1.82 (0.95 to 3.48), respectively]. Furthermore, cerebrovascular disease, diabetes, COPD, or liver disease co-occurring with multimorbidity was associated with substantially increased frailty hazards compared with multimorbidity alone (hazard ratios 4.75-7.46). Cerebrovascular disease was associated with decreased baseline grip strength (P = 0.0001), whereas multimorbidity, diabetes, and COPD were associated with declining grip strength (P < 0.10). CONCLUSIONS: In older PWH, cerebrovascular disease, diabetes, COPD, or liver disease co-occurring with multimorbidity is associated with substantially increased risk of becoming frail within 30 months. Interventions targeting these comorbidities may ameliorate frailty and age-related functional decline in PWH.


Asunto(s)
Anciano Frágil , Fragilidad/diagnóstico , Infecciones por VIH/complicaciones , Anciano , Envejecimiento , Terapia Antirretroviral Altamente Activa , Comorbilidad , Diabetes Mellitus/epidemiología , Femenino , Fragilidad/epidemiología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Humanos , Hepatopatías/epidemiología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Estados Unidos/epidemiología
19.
EClinicalMedicine ; 31: 100697, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33554087

RESUMEN

BACKGROUND: Marijuana smoke contains some of the same toxicants present in tobacco smoke. Marijuana smoking is prevalent among HIV+ individuals, but few studies have characterized smoke-related toxicants or associated health outcomes in exclusive marijuana users. METHODS: This longitudinal study included 245 participants over age 40 (76% HIV+). 33 plasma and 28 urine metabolites of nicotine, ∆-9-trans-tetrahydrocannabinol, polycyclic aromatic hydrocarbons, and volatile organic compounds were assayed by liquid or gas chromatography/mass spectrometry. Exposures and health outcomes were assessed from surveys and medical records. FINDINGS: At baseline, 18% of participants were marijuana-only smokers, 20% tobacco-only smokers, and 24% dual marijuana-tobacco smokers (median (IQR) age 53 (47-60) years, 78% male, 54% white race). Marijuana smoking was independently associated with elevated plasma naphthalenes, 2-hydroxyfluorene sulfate, 4-vinylphenol sulfate, and o-cresol sulfate (p<0·05) and urine acrylonitrile and acrylamide metabolites (p<0·05), but levels were lower than those associated with tobacco smoking. Acrolein metabolite N-Acetyl-S-(3-hydroxypropyl)-l-cysteine (3HPMA) was significantly elevated in plasma and urine in tobacco-only and dual but not marijuana-only smokers, and correlated with nicotine metabolites (p<0·05). The highest tertile of 3HPMA was associated with increased cardiovascular disease diagnoses independent of tobacco smoking, traditional risk factors, and HIV status (odds ratio [95% CI] 3·34 [1·31-8·57]; p = 0·012). INTERPRETATION: Smoke-related toxicants, including acrylonitrile and acrylamide metabolites, are detectable in exclusive marijuana smokers, but exposures are lower compared with tobacco or dual smokers. Acrolein exposure is increased by tobacco smoking but not exclusive marijuana smoking in HIV+ and HIV- adults, and contributes to cardiovascular disease in tobacco smokers. FUNDING: U.S. NIH.

20.
AIDS ; 35(15): 2451-2461, 2021 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-34324449

RESUMEN

OBJECTIVE: People with HIV (PWH) have increased prevalence of multimorbidity and frailty at younger ages compared with the general population. This study investigated individual and combinatorial effects of neuropsychiatric and medical comorbidities as predictors of frailty in PWH. DESIGN: Analysis of data from the National NeuroAIDS Tissue Consortium, a longitudinal observational cohort. METHODS: Five hundred and twenty-four PWH over age 40 years were classified using Fried's Frailty criteria. Twelve comorbidities were documented from longitudinal data and associations between individual and co-occurring comorbidities with frailty were assessed using weighted network and logistic regression analyses. RESULTS: At frailty assessment between 2015 and 2020, median age was 61 years, 76% were men, 94% were on antiretroviral therapy (ART), 73% had two or more comorbidities, 24% were frail, and 52% were prefrail. Among individual comorbidities, highest odds of frailty were in participants with depressive symptoms [adjusted odds ratio (aOR), 95% confidence interval (CI) 3.48 (2.22-5.46)], followed by bone disease and chronic obstructive pulmonary disease (COPD) [2.47 (1.28-4.72) and 2.13 (1.36-3.34), respectively]. Among co-occurring comorbidities, highest odds of frailty were in participants having depressive symptoms with diabetes, hypertension, or obesity [aORs (95% CIs) 5.29 (2.32-12.08), 5.21 (2.65-10.40), 4.85 (2.39-9.95), respectively], cognitive impairment with diabetes or renal disease [2.81 (1.38-5.68) and 2.53 (1.26-5.03), respectively], renal disease with cardiovascular disease [2.81 (1.32-6.01)], and diabetes with obesity [2.76 (1.39-5.45)]. CONCLUSION: Co-occurrence of depressive symptoms, cognitive impairment, diabetes, or renal disease with other medical conditions substantially increases odds of frailty in older PWH. Identifying and treating these comorbidities may help to reduce functional decline with aging in PWH.


Asunto(s)
Fragilidad , Infecciones por VIH , Adulto , Anciano , Envejecimiento , Estudios de Cohortes , Fragilidad/epidemiología , Infecciones por VIH/complicaciones , Infecciones por VIH/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Multimorbilidad
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