RESUMEN
BACKGROUND: People with human immunodeficiency virus (PWH) are at increased risk for comorbidities, and plasma interleukin 6 (IL-6) levels are among the most robust predictors of these outcomes. Tocilizumab (TCZ) blocks the receptor for IL-6, inhibiting functions of this cytokine. METHODS: This was a 40-week, placebo-controlled, crossover trial (NCT02049437) where PWH on stable antiretroviral therapy (ART) were randomized to receive 3 monthly doses of TCZ or matching placebo intravenously. Following a 10-week treatment period and a 12-week washout, participants were switched to the opposite treatment. The primary endpoints were safety and posttreatment levels of C-reactive protein (CRP) and CD4+ T-cell cycling. Secondary endpoints included changes in inflammatory indices and lipid levels. RESULTS: There were 9 treatment-related toxicities of grade 2 or greater during TCZ administration (mostly neutropenia) and 2 during placebo administration. Thirty-one of 34 participants completed the study and were included in a modified intent-to-treat analysis. TCZ reduced levels of CRP (median decrease, 1819.9 ng/mL, P < .0001; effect size, 0.87) and reduced inflammatory markers in PWH, including D-dimer, soluble CD14, and tumor necrosis factor receptors. T-cell cycling tended to decrease in all maturation subsets after TCZ administration, but was only significant among naive CD4 T cells. Lipid levels, including lipid classes that have been related to cardiovascular disease risk, increased during TCZ treatment. CONCLUSIONS: TCZ is safe and decreases inflammation in PWH; IL-6 is a key driver of the inflammatory environment that predicts morbidity and mortality in ART-treated PWH. The clinical significance of lipid elevations during TCZ treatment requires further study. Clinical Trials Registration. NCT02049437.
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Infecciones por VIH , Interleucina-6 , Humanos , Infecciones por VIH/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Interleucina-6/metabolismo , Lípidos , Estudios CruzadosRESUMEN
OBJECTIVES: Gender-affirming hormonal therapies (GAHT) and HIV increase cardiovascular risk for transgender women (TW), yet there is a paucity of data quantifying cardiometabolic changes following GAHT initiation, particularly among TW with HIV. METHODS: The Féminas study enrolled TW from October 2016 to March 2017 in Lima, Peru. Participants reported sexual activity that was high risk for HIV acquisition or transmission. All were tested for HIV/ sexually transmitted infection and were given access to GAHT (oestradiol valerate and spironolactone), HIV pre-exposure prophylaxis (PrEP) or antiretroviral therapy (ART) for 12 months. Biomarker measurement was done on stored serum, whereas fasting glucose and lipids were measured in real time. RESULTS: In all, 170 TW (32 with HIV, 138 without HIV) had median age 27 years and 70% prior GAHT use. At baseline, PCSK9, sCD14, sCD163, IL-6, sTNFRI/II, CRP and EN-RAGE levels were significantly higher in TW with HIV than in TW without HIV. High-density lipoprotein and total cholesterol were lower and insulin and glucose parameters were similar. All TW with HIV started ART, but only five achieved virological suppression at any time. No TW without HIV initiated PrEP. Over 6 months, all participants initiated GAHT and had worsening insulin, glucose and HOMA-IR. Large d-dimer decreases also occurred. Similar changes occurred in TW with and without HIV. CONCLUSIONS: In this unique cohort of TW, GAHT decreased d-dimer but worsened insulin sensitivity. Because PrEP uptake and ART adherence were very low, observed effects are primarily attributed to GAHT use. Further study is needed to better understand cardiometabolic changes in TW by HIV serostatus.
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Enfermedades Cardiovasculares , Infecciones por VIH , Resistencia a la Insulina , Insulinas , Personas Transgénero , Humanos , Femenino , Adulto , Proproteína Convertasa 9 , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/prevención & control , Estradiol/uso terapéutico , Glucosa , Insulinas/uso terapéuticoRESUMEN
People with HIV (PWH) are at increased risk for atherosclerotic cardiovascular disease (ASCVD). Proportions of vascular homing monocytes are enriched in PWH; however, little is known regarding monocyte-derived macrophages (MDMs) that may drive atherosclerosis in this population. We isolated PBMCs from people with and without HIV, and cultured these cells for 5 days in medium containing autologous serum to generate MDMs. Differential gene expression (DGE) analysis of MDMs from PWH identified broad alterations in innate immune signaling (IL-1ß, TLR expression, PPAR ßδ) and lipid processing (LXR/RXR, ACPP, SREBP1). Transcriptional changes aligned with the functional capabilities of these cells. Expression of activation markers and innate immune receptors (CD163, TLR4, and CD300e) was altered on MDMs from PWH, and these cells produced more TNFα, reactive oxygen species (ROS), and matrix metalloproteinases (MMPs) than did cells from people without HIV. MDMs from PWH also had greater lipid accumulation and uptake of oxidized LDL. PWH had increased serum levels of free fatty acids (FFAs) and ceramides, with enrichment of saturated FAs and a reduction in polyunsaturated FAs. Levels of lipid classes and species that are associated with CVD correlated with unique DGE signatures and altered metabolic pathway activation in MDMs from PWH. Here, we show that MDMs from PWH display a pro-atherogenic phenotype; they readily form foam cells, have altered transcriptional profiles, and produce mediators that likely contribute to accelerated ASCVD.
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Aterosclerosis/etiología , Infecciones por VIH/virología , VIH/inmunología , Lípidos/sangre , Macrófagos/patología , Modelos Cardiovasculares , Monocitos/virología , Aterosclerosis/patología , Estudios de Casos y Controles , VIH/genética , Infecciones por VIH/inmunología , Infecciones por VIH/patología , Humanos , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/virología , Monocitos/metabolismo , TranscriptomaRESUMEN
People infected with severe acute respiratory syndrome coronavirus 2 display a wide range of illness, from asymptomatic infection to severe respiratory distress resulting in death. We measured serum biomarkers in uninfected individuals and in individuals with mild, moderate, or critical coronavirus disease 2019 (COVID-19) disease. Levels of monocyte activation (soluble CD14 and fatty acid-binding protein 4) and inflammation (tumor necrosis factor receptors 1 and 2 [TNFR1 and TNFR2]) were increased in COVID-19 individuals, regardless of disease severity. Among patients with critical disease, individuals who recovered from COVID-19 had lower levels of TNFR1 and TNFR2 at hospital admission compared to these levels in patients with critical disease who ultimately died.
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COVID-19/mortalidad , Receptores de Lipopolisacáridos/sangre , Receptores Tipo II del Factor de Necrosis Tumoral/sangre , Receptores Tipo I de Factores de Necrosis Tumoral/sangre , Biomarcadores/sangre , COVID-19/sangre , Estudios Transversales , Humanos , Estudios Longitudinales , Valor Predictivo de las Pruebas , Índice de Severidad de la EnfermedadRESUMEN
The use of antiretroviral therapy (ART) as preexposure prophylaxis (PrEP) is an effective strategy for preventing HIV acquisition. The cellular consequences of PrEP exposure, however, have not been sufficiently explored to determine potential effects on health in individuals without HIV. In this study, peripheral blood mononuclear cells (PBMCs) from people without HIV were exposed to tenofovir disoproxil fumarate (TDF) or emtricitabine (FTC) overnight. Mitochondrial mass and function were measured by flow cytometry and an Agilent XFp analyzer. Monocyte-derived macrophages (MDMs) were differentiated in 20% autologous serum for 5 days in the presence or absence of TDF or FTC, and surface markers, lipid uptake, and efferocytosis were measured by flow cytometry. MDM gene expression was measured using transcriptome sequencing (RNA-seq). Plasma lipids were measured using mass spectrometry. PBMCs exposed to TDF or FTC had decreased maximal oxygen consumption rate (OCR) and reduced mitochondrial mass. Exposure to PrEP also increased reactive oxygen species (ROS) production from monocyte subsets. Compared to MDMs cultured in medium alone, cells differentiated in the presence of TDF (829 genes) or FTC (888 genes) had significant changes in gene expression. Further, PrEP-exposed MDMs had decreased mitochondrial mass and displayed increased lipid uptake and reduced efferocytosis. Plasma biomarkers and lipid levels were also altered in vivo in individuals receiving a PrEP regimen. In conclusion, exposure of leukocytes to TDF or FTC resulted in decreased mitochondrial function and altered functional and transcriptional profiles. These findings may have important implications for the metabolic and immunologic consequences of PrEP in populations at risk for HIV acquisition.
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Fármacos Anti-VIH , Infecciones por VIH , Profilaxis Pre-Exposición , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , Emtricitabina/farmacología , Emtricitabina/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/prevención & control , Humanos , Leucocitos Mononucleares , Mitocondrias , TranscriptomaRESUMEN
Latent infection by Epstein-Barr virus (EBV) is highly associated with the endemic form of Burkitt lymphoma (eBL), which typically limits expression of EBV proteins to EBNA-1 (Latency I). Interestingly, a subset of eBLs maintain a variant program of EBV latency - Wp-restricted latency (Wp-R) - that includes expression of the EBNA-3 proteins (3A, 3B and 3C), in addition to EBNA-1. In xenograft assays, Wp-R BL cell lines were notably more tumorigenic than their counterparts that maintain Latency I, suggesting that the additional latency-associated proteins expressed in Wp-R influence cell proliferation and/or survival. Here, we evaluated the contribution of EBNA-3A. Consistent with the enhanced tumorigenic potential of Wp-R BLs, knockdown of EBNA-3A expression resulted in abrupt cell-cycle arrest in G0/G1 that was concomitant with conversion of retinoblastoma protein (Rb) to its hypophosphorylated state, followed by a loss of Rb protein. Comparable results were seen in EBV-immortalized B lymphoblastoid cell lines (LCLs), consistent with the previous observation that EBNA-3A is essential for sustained growth of these cells. In agreement with the known ability of EBNA-3A and EBNA-3C to cooperatively repress p14(ARF) and p16(INK4a) expression, knockdown of EBNA-3A in LCLs resulted in rapid elevation of p14(ARF) and p16I(NK4a). By contrast, p16(INK4a) was not detectably expressed in Wp-R BL and the low-level expression of p14(ARF) was unchanged by EBNA-3A knockdown. Amongst other G1/S regulatory proteins, only p21(WAF1/CIP1), a potent inducer of G1 arrest, was upregulated following knockdown of EBNA-3A in Wp-R BL Sal cells and LCLs, coincident with hypophosphorylation and destabilization of Rb and growth arrest. Furthermore, knockdown of p21(WAF1/CIP1) expression in Wp-R BL correlated with an increase in cellular proliferation. This novel function of EBNA-3A is distinct from the functions previously described that are shared with EBNA-3C, and likely contributes to the proliferation of Wp-R BL cells and LCLs.
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Antígenos Virales/metabolismo , Linfoma de Burkitt/virología , Proliferación Celular , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Animales , Línea Celular , Proliferación Celular/fisiología , Quinasas Ciclina-Dependientes/genética , Quinasas Ciclina-Dependientes/metabolismo , Antígenos Nucleares del Virus de Epstein-Barr/metabolismo , Humanos , RatonesRESUMEN
Recent studies link early rhinovirus (RV) infections to later asthma development. We hypothesized that neonatal RV infection leads to an IL-13-driven asthma-like phenotype in mice. BALB/c mice were inoculated with RV1B or sham on day 7 of life. Viral RNA persisted in the neonatal lung up to 7 d postinfection. Within this time frame, IFN-α, -ß, and -γ peaked 1 d postinfection, whereas IFN-λ levels persisted. Next, we examined mice on day 35 of life, 28 d after initial infection. Compared with sham-treated controls, virus-inoculated mice demonstrated airways hyperresponsiveness. Lungs from RV-infected mice showed increases in several immune cell populations, as well as the percentages of CD4-positive T cells expressing IFN-γ and of NKp46/CD335(+), TCR-ß(+) cells expressing IL-13. Periodic acid-Schiff and immunohistochemical staining revealed mucous cell metaplasia and muc5AC expression in RV1B- but not sham-inoculated lungs. Mucous metaplasia was accompanied by induction of gob-5, MUC5AC, MUC5B, and IL-13 mRNA. By comparison, adult mice infected with RV1B showed no change in IL-13 expression, mucus production, or airways responsiveness 28 d postinfection. Intraperitoneal administration of anti-IL-13 neutralizing Ab attenuated RV-induced mucous metaplasia and methacholine responses, and IL-4R null mice failed to show RV-induced mucous metaplasia. Finally, neonatal RV increased the inflammatory response to subsequent allergic sensitization and challenge. We conclude that neonatal RV1B infection leads to persistent airways inflammation, mucous metaplasia, and hyperresponsiveness, which are mediated, at least in part, by IL-13.
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Infecciones por Picornaviridae/complicaciones , Infecciones por Picornaviridae/patología , Hipersensibilidad Respiratoria/virología , Mucosa Respiratoria/patología , Animales , Animales Recién Nacidos , Separación Celular , Citocinas/biosíntesis , Citocinas/inmunología , Citometría de Flujo , Inmunohistoquímica , Inflamación/inmunología , Inflamación/patología , Inflamación/virología , Metaplasia , Ratones , Ratones Endogámicos BALB C , Infecciones por Picornaviridae/inmunología , Reacción en Cadena en Tiempo Real de la Polimerasa , Hipersensibilidad Respiratoria/inmunología , Hipersensibilidad Respiratoria/patología , Mucosa Respiratoria/inmunologíaRESUMEN
Human rhinovirus (HRV) infections lead to exacerbations of lower airways disease in asthmatic patients but not in healthy individuals. However, underlying mechanisms remain to be completely elucidated. We hypothesized that the Th2-driven allergic environment enhances HRV-induced CC chemokine production, leading to asthma exacerbations. Ovalbumin (OVA)-sensitized and -challenged mice inoculated with HRV showed significant increases in the expression of lung CC chemokine ligand (CCL)-2/monocyte chemotactic protein (MCP)-1, CCL4/macrophage inflammatory protein (MIP)-1ß, CCL7/MCP-3, CCL19/MIP-3ß, and CCL20/MIP3α compared with mice treated with OVA alone. Inhibition of CCL2 with neutralizing antibody significantly attenuated HRV-induced airways inflammation and hyperresponsiveness in OVA-treated mice. Immunohistochemical stains showed colocalization of CCL2 with HRV in epithelial cells and CD68-positive macrophages, and flow cytometry showed increased CCL2(+), CD11b(+) cells in the lungs of OVA-treated, HRV-infected mice. Compared with lung macrophages from naïve mice, macrophages from OVA-exposed mice expressed significantly more CCL2 in response to HRV infection ex vivo. Pretreatment of mouse lung macrophages and BEAS-2B human bronchial epithelial cells with interleukin (IL)-4 and IL-13 increased HRV-induced CCL2 expression, and mouse lung macrophages from IL-4 receptor knockout mice showed reduced CCL2 expression in response to HRV, suggesting that exposure to these Th2 cytokines plays a role in the altered HRV response. Finally, bronchoalveolar macrophages from children with asthma elaborated more CCL2 upon ex vivo exposure to HRV than cells from nonasthmatic patients. We conclude that CCL2 production by epithelial cells and macrophages contributes to HRV-induced airway hyperresponsiveness and inflammation in a mouse model of allergic airways disease and may play a role in HRV-induced asthma exacerbations.
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Quimiocina CCL2/inmunología , Células Epiteliales/inmunología , Hipersensibilidad/inmunología , Pulmón/inmunología , Macrófagos/inmunología , Rhinovirus/fisiología , Animales , Anticuerpos Neutralizantes/farmacología , Antígenos CD/genética , Antígenos CD/inmunología , Antígenos de Diferenciación Mielomonocítica/genética , Antígenos de Diferenciación Mielomonocítica/inmunología , Quimiocina CCL19/genética , Quimiocina CCL19/inmunología , Quimiocina CCL2/antagonistas & inhibidores , Quimiocina CCL2/genética , Quimiocina CCL20/genética , Quimiocina CCL20/inmunología , Quimiocina CCL4/genética , Quimiocina CCL4/inmunología , Quimiocina CCL7/genética , Quimiocina CCL7/inmunología , Niño , Modelos Animales de Enfermedad , Células Epiteliales/efectos de los fármacos , Células Epiteliales/patología , Expresión Génica , Humanos , Hipersensibilidad/patología , Hipersensibilidad/virología , Inflamación/inducido químicamente , Inflamación/inmunología , Inflamación/patología , Inflamación/virología , Interleucina-13/farmacología , Interleucina-4/farmacología , Pulmón/patología , Pulmón/virología , Macrófagos/efectos de los fármacos , Macrófagos/patología , Ratones , Ovalbúmina , Rhinovirus/patogenicidad , Células Th2/inmunologíaRESUMEN
Rhinovirus (RV), a single-stranded RNA picornavirus, is the most frequent cause of asthma exacerbations. We previously demonstrated in human bronchial epithelial cells that melanoma differentiation-associated gene (MDA)-5 and the adaptor protein for Toll-like receptor (TLR)-3 are each required for maximal RV1B-induced interferon (IFN) responses. However, in vivo, the overall airway response to viral infection likely represents a coordinated response integrating both antiviral and pro-inflammatory pathways. We examined the airway responses of MDA5- and TLR3-deficient mice to infection with RV1B, a minor group virus which replicates in mouse lungs. MDA5 null mice showed a delayed type I IFN and attenuated type III IFN response to RV1B infection, leading to a transient increase in viral titer. TLR3 null mice showed normal IFN responses and unchanged viral titers. Further, RV-infected MDA5 and TLR3 null mice showed reduced lung inflammatory responses and reduced airways responsiveness. Finally, RV-infected MDA5 null mice with allergic airways disease showed lower viral titers despite deficient IFN responses, and allergic MDA5 and TLR3 null mice each showed decreased RV-induced airway inflammatory and contractile responses. These results suggest that, in the context of RV infection, binding of viral dsRNA to MDA5 and TLR3 initiates pro-inflammatory signaling pathways leading to airways inflammation and hyperresponsiveness.
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Hiperreactividad Bronquial/fisiopatología , Hiperreactividad Bronquial/virología , ARN Helicasas DEAD-box/fisiología , Inflamación/fisiopatología , Inflamación/virología , Rhinovirus/fisiología , Transducción de Señal/fisiología , Receptor Toll-Like 3/fisiología , Animales , Hiperreactividad Bronquial/metabolismo , Modelos Animales de Enfermedad , Inflamación/metabolismo , Helicasa Inducida por Interferón IFIH1 , Interferones/metabolismo , Pulmón/metabolismo , Pulmón/fisiopatología , Pulmón/virología , Enfermedades Pulmonares/metabolismo , Enfermedades Pulmonares/fisiopatología , Enfermedades Pulmonares/virología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Infecciones por Picornaviridae/metabolismo , Infecciones por Picornaviridae/fisiopatología , Infecciones por Picornaviridae/virología , ARN Bicatenario/metabolismo , ARN Viral/metabolismo , Rhinovirus/aislamiento & purificaciónRESUMEN
Human rhinovirus is responsible for the majority of virus-induced asthma exacerbations. To determine the immunologic mechanisms underlying rhinovirus (RV)-induced asthma exacerbations, we combined mouse models of allergic airways disease and human rhinovirus infection. We inoculated OVA-sensitized and challenged BALB/c mice with rhinovirus serotype 1B, a minor group strain capable of infecting mouse cells. Compared with sham-infected, OVA-treated mice, virus-infected mice showed increased lung infiltration with neutrophils, eosinophils and macrophages, airway cholinergic hyperresponsiveness, and increased lung expression of cytokines including eotaxin-1/CCL11, IL-4, IL-13, and IFN-gamma. Administration of anti-eotaxin-1 attenuated rhinovirus-induced airway eosinophilia and responsiveness. Immunohistochemical analysis showed eotaxin-1 in the lung macrophages of virus-infected, OVA-treated mice, and confocal fluorescence microscopy revealed colocalization of rhinovirus, eotaxin-1, and IL-4 in CD68-positive cells. RV inoculation of lung macrophages from OVA-treated, but not PBS-treated, mice induced expression of eotaxin-1, IL-4, and IL-13 ex vivo. Macrophages from OVA-treated mice showed increased expression of arginase-1, Ym-1, Mgl-2, and IL-10, indicating a shift in macrophage activation status. Depletion of macrophages from OVA-sensitized and -challenged mice reduced eosinophilic inflammation and airways responsiveness following RV infection. We conclude that augmented airway eosinophilic inflammation and hyperresponsiveness in RV-infected mice with allergic airways disease is directed in part by eotaxin-1. Airway macrophages from mice with allergic airways disease demonstrate a change in activation state characterized in part by altered eotaxin and IL-4 production in response to RV infection. These data provide a new paradigm to explain RV-induced asthma exacerbations.
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Quimiocina CCL11/inmunología , Macrófagos Alveolares/inmunología , Ovalbúmina/inmunología , Infecciones por Picornaviridae/inmunología , Animales , Antígenos CD/inmunología , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/inmunología , Antígenos de Diferenciación Mielomonocítica/metabolismo , Hiperreactividad Bronquial/inmunología , Hiperreactividad Bronquial/metabolismo , Quimiocina CCL11/genética , Quimiocina CCL11/metabolismo , Citocinas/genética , Citocinas/inmunología , Citocinas/metabolismo , Eosinófilos/inmunología , Eosinófilos/metabolismo , Eosinófilos/patología , Células HeLa , Humanos , Inmunohistoquímica , Inflamación/inmunología , Inflamación/metabolismo , Mediadores de Inflamación/inmunología , Mediadores de Inflamación/metabolismo , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/patología , Macrófagos Alveolares/metabolismo , Ratones , Ratones Endogámicos BALB C , Microscopía Confocal , Infecciones por Picornaviridae/virología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Rhinovirus/inmunologíaRESUMEN
PURPOSE: To improve cardiovascular disease (CVD) risk prediction by combining screening techniques and to determine whether the combination of sonographic aortic calcification quantification, measurement of aortic intimal thickness, and monocyte laboratory values provides improved diagnostic detection compared with computed tomography (CT) calcium scoring. METHODS: A pre-experimental design was used to collect imaging, demographic, and biometric data. Data were collected from a convenience sample of 11 volunteers aged 40 to 60 years, including 6 men and 5 women. Collected data included anthropometric measures, laboratory values, flow cytometry, coronary artery calcium scores, atherosclerotic cardiovascular disease (ASCVD) 10-year risk scores, and aortic intimal-medial thickness (IMT). RESULTS: Aortic IMT in the distal portion of the aorta or region 1 was related significantly to mass (r = 0.725, P = .012), body mass index (r = 0.668, P = .025), and ASCVD 10-year risk score (r = 0.747, P = .033). The aortic IMT in mid portion of the aorta or region 2 was related significantly to mass (r = 0.651, P = .030), antihypertensive medications (r = 0.682, P = .021), ASCVD 10-year risk score (r = 0.753, P = .031), and total coronary artery calcification (CAC) (r = 0.626, P = .039). In addition, the proportions of circulating CD14+CD16- (traditional) and CD14+CD16+ (inflammatory) monocytes, and the monocyte surface expression of the adhesion molecules CD11a and CD11c, were correlated with the number of calcifications in regions 1 and 2. DISCUSSION: The use of a modified grading system for sonography provided a nonionizing, noninvasive option to easily assess patients' risks of CVD in an office environment. Although CAC has been used widely as a screening mechanism for CVD, ionizing radiation use might not be justified for those who are asymptomatic. The combination of sonography with flow cytometry demonstrated a promising alternative for assessing CVD risk. CONCLUSION: tBetter quantification of inflammatory markers and atherosclerotic plaques is needed. The combination of noninvasive imaging and advanced laboratory analysis holds promise for assessing and managing CVD risk. This study provides further evidence of the need for continued research with larger sample sizes and diversified populations to improve the quality of CVD risk assessment.
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Aterosclerosis , Calcinosis , Enfermedades Cardiovasculares , Enfermedad de la Arteria Coronaria , Aorta/diagnóstico por imagen , Calcinosis/diagnóstico por imagen , Calcio , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Femenino , Citometría de Flujo , Humanos , Masculino , Proyectos Piloto , Medición de Riesgo , Factores de Riesgo , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Altered gut integrity is central to HIV-related immune activation. Opioids may promote similar changes in gut permeability and/or increase systemic inflammation, potentially augmenting processes already occurring in people with HIV (PWH). SETTING: Urban hospital systems in Cleveland, Ohio, and surrounding communities. METHODS: This is a prospectively enrolled, cross-sectional study including people with and without HIV using heroin and people with and without HIV who have never used heroin, matched by age, sex, and CD4+ T-cell count (PWH only) to compare markers of gut integrity, microbial translocation, systemic inflammation, and immune activation. RESULTS: A total of 100 participants were enrolled. Active heroin use was associated with higher concentrations of lipopolysaccharide-binding protein (LBP), beta-D-glucan (BDG), high-sensitivity C-reactive protein (hsCRP), soluble tumor necrosis factor-α-receptors I and II, soluble CD163, inflammatory monocytes, and activated CD4+ lymphocytes in adjusted models. HIV status tended to modify the effect between heroin use and LBP, BDG, hsCRP, patrolling monocytes, and activated CD4+ lymphocytes (P < 0.15 for interactions); however, it was not as expected. The effect of heroin on these markers (except patrolling monocytes) was greatest among those without HIV rather than among those with HIV. CONCLUSIONS: Heroin use is associated with heightened microbial translocation, systemic inflammation, and immune activation. Concurrent HIV infection in virologically suppressed individuals does not seem to substantially worsen the effects heroin has on these markers.
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Infecciones por VIH , Biomarcadores , Proteína C-Reactiva , Estudios Transversales , Infecciones por VIH/complicaciones , Heroína , Humanos , InflamaciónRESUMEN
Age-related comorbidities and physical function impairments in aging people with HIV (PWH) can be improved through exercise interventions. The mechanisms underlying these improvements, including lipidomic changes, are unknown. Sedentary adults (50-75 years old) with or without HIV participated in supervised endurance/resistance exercise for 24 weeks. Plasma lipid concentrations (â¼1,200 lipid species from 13 lipid classes) at baseline and week 24 were measured by mass spectrometry. Given multiple comparisons, unadjusted and Benjamini-Hochberg corrected p values are reported. Analyses are considered exploratory. Twenty-five PWH and 24 controls had paired samples at baseline and week 24. The change in total triacylglycerol (TAG) concentrations after exercise intervention differed between groups (unadj-p = 0.006, adj-p = 0.078) with concentrations increasing among controls, but not among PWH. Changes in concentrations of TAG species composed of long-chain fatty acids differed between groups (unadj-p < 0.04) with increases among controls, but not among PWH. Changes in total diacylglycerol (DAG) concentration from baseline to week 24 differed between groups (unadj-p = 0.03, adj-p = 0.2) with an increase in PWH and a nonsignificant decrease in controls. Baseline to week 24 changes in DAGs composed of palmitic acid (16:0), palmitoleic acid (16:1), and stearic acid (18:0) differed by serostatus (unadj-p = 0.009-0.03; adj-p 0.10-0.12), with nonsignificant increases and decreases in concentrations in PWH and controls, respectively. Concentrations of individual lysophosphatidylcholine (LPC) and ceramide (CER) species also differed by HIV serostatus (unadj-p < = 0.05). Although exploratory, the effects of exercise on the lipidome may differ among people with and without HIV, potentially due to underlying alterations in lipid processing and fatty acid oxidation in PWH. Clinical Trials NCT02404792.
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Infecciones por VIH , Lipidómica , Adulto , Anciano , Envejecimiento , Ejercicio Físico , Infecciones por VIH/tratamiento farmacológico , Humanos , Persona de Mediana EdadRESUMEN
Rhinovirus (RV), a ssRNA virus of the picornavirus family, is a major cause of the common cold as well as asthma and chronic obstructive pulmonary disease exacerbations. Viral dsRNA produced during replication may be recognized by the host pattern recognition receptors TLR-3, retinoic acid-inducible gene (RIG)-I, and melanoma differentiation-associated gene (MDA)-5. No study has yet identified the receptor required for sensing RV dsRNA. To examine this, BEAS-2B human bronchial epithelial cells were infected with intact RV-1B or replication-deficient UV-irradiated virus, and IFN and IFN-stimulated gene expression was determined by quantitative PCR. The separate requirements of RIG-I, MDA5, and IFN response factor (IRF)-3 were determined using their respective small interfering RNAs (siRNA). The requirement of TLR3 was determined using siRNA against the TLR3 adaptor molecule Toll/IL-1R homologous region-domain-containing adapter-inducing IFN-beta (TRIF). Intact RV-1B, but not UV-irradiated RV, induced IRF3 phosphorylation and dimerization, as well as mRNA expression of IFN-beta, IFN-lambda1, IFN-lambda2/3, IRF7, RIG-I, MDA5, 10-kDa IFN-gamma-inducible protein/CXCL10, IL-8/CXCL8, and GM-CSF. siRNA against IRF3, MDA5, and TRIF, but not RIG-I, decreased RV-1B-induced expression of IFN-beta, IFN-lambda1, IFN-lambda2/3, IRF7, RIG-I, MDA5, and inflammatory protein-10/CXCL10 but had no effect on IL-8/CXCL8 and GM-CSF. siRNAs against MDA5 and TRIF also reduced IRF3 dimerization. Finally, in primary cells, transfection with MDA5 siRNA significantly reduced IFN expression, as it did in BEAS-2B cells. These results suggest that TLR3 and MDA5, but not RIG-I, are required for maximal sensing of RV dsRNA and that TLR3 and MDA5 signal through a common downstream signaling intermediate, IRF3.
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ARN Helicasas DEAD-box/inmunología , Células Epiteliales/inmunología , Infecciones por Picornaviridae/inmunología , Mucosa Respiratoria/inmunología , Receptor Toll-Like 3/inmunología , Western Blotting , Línea Celular , Proteína 58 DEAD Box , ARN Helicasas DEAD-box/biosíntesis , ARN Helicasas DEAD-box/genética , Células Epiteliales/virología , Expresión Génica , Humanos , Helicasa Inducida por Interferón IFIH1 , ARN Bicatenario/inmunología , ARN Interferente Pequeño , Receptores Inmunológicos , Receptores de Reconocimiento de Patrones/biosíntesis , Receptores de Reconocimiento de Patrones/genética , Receptores de Reconocimiento de Patrones/inmunología , Mucosa Respiratoria/virología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Rhinovirus/inmunología , Transducción de Señal/inmunología , Receptor Toll-Like 3/biosíntesis , Receptor Toll-Like 3/genéticaRESUMEN
Background: HIV infection and antiretroviral therapy (ART) have both been linked to dyslipidemia and increased cardiovascular disease (CVD) risk. Alterations in the composition of saturated (SaFA), monounsaturated (MUFA), and polyunsaturated (PUFA) fatty acids are related to inflammation and CVD progression in HIV-uninfected (HIV-) populations. The relationships among the lipidome and markers of monocyte and immune activation in HIV-infected (HIV+) individuals are not well understood. Methods: Concentrations of serum lipids and their fatty acid composition were measured by direct infusion-tandem mass spectrometry in samples from 20 ART-treated HIV+ individuals and 20 HIV- individuals. Results: HIV+ individuals had increased levels of free fatty acids (FFAs) with enrichment of SaFAs, including palmitic acid (16:0) and stearic acid (18:0), and these levels were directly associated with markers of monocyte (CD40, HLA-DR, TLR4, CD36) and serum inflammation (LBP, CRP). PUFA levels were reduced significantly in HIV+ individuals, and many individual PUFA species levels were inversely related to markers of monocyte activation, such as tissue factor, TLR4, CD69, and SR-A. Also in HIV+ individuals, the composition of lysophosphatidylcholine (LPC) was enriched for SaFAs; LPC species containing SaFAs were directly associated with IL-6 levels and monocyte activation. We similarly observed direct relationships between levels of SaFAs and inflammation in HIV uninfected individuals. Further, SaFA exposure altered monocyte subset phenotypes and inflammatory cytokine production in vitro. Conclusions: The lipidome is altered in ART-treated HIV infection, and may contribute to inflammation and CVD progression. Detailed lipidomic analyses may better assess CVD risk in both HIV+ and HIV- individuals than does traditional lipid profiling.