RESUMEN
OBJECTIVE: Evaluating hepatic metabolic changes in people with HIV (PWH) with advanced disease, before and after antiretroviral therapy (ART) initiation, using [ 18 F]-fluorodeoxyglucose (FDG) PET-computed tomography (PET/CT). FDG PET/CT noninvasively quantifies glucose metabolism in organs. DESIGN/METHODS: Forty-eight viremic PWH (CD4 + cell counts <100âcells/µl) underwent FDG PET/CT at baseline and approximately 6âweeks after ART initiation (short-term). Twenty-seven PWH participants underwent follow-up scans 2âyears after treatment (long-term). FDG PET/CT scans from 20 healthy controls were used for comparison. Liver FDG uptake was quantified from the PET/CT scans. Imaging findings as well as clinical, laboratory, and immune markers were compared longitudinally and cross-sectionally to healthy controls. RESULTS: Liver FDG uptake was lower at baseline and short-term in PWH compared with controls ( P â<â0.0001). At the long-term scan, liver FDG uptake of PWH increased relative to baseline and short-term ( P â=â0.0083 and 0.0052) but remained lower than controls' values ( P â=â0.004). Changes in FDG uptake correlated negatively with levels of glucagon, myeloperoxidase, sCD14, and MCP-1 and positively with markers of recovery (BMI, albumin, and CD4 + cell counts) ( P â<â0.01). In multivariable analyses of PWH values across timepoints, BMI and glucagon were the best set of predictors for liver FDG uptake ( P â<â0.0001). CONCLUSION: Using FDG PET/CT, we found decreased liver glucose metabolism in PWH that could reflect hepatocytes/lymphocytes/myeloid cell loss and metabolic dysfunction because of inflammation. Although long-term ART seems to reverse many hepatic abnormalities, residual liver injury may still exist within 2 years of treatment initiation, especially in PWH who present with low nadir CD4 + cell counts.
Asunto(s)
Fluorodesoxiglucosa F18 , Infecciones por VIH , Glucagón , Glucosa , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Humanos , Hígado/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Tomografía de Emisión de Positrones/métodos , RadiofármacosRESUMEN
OBJECTIVE: We evaluated brain glucose metabolism in people living with HIV (PWH) with [18F]-Fluoro-Deoxyglucose (FDG) PET/computed tomography (CT) before and after antiretroviral therapy (ART) initiation. DESIGN: We conducted a longitudinal study wherein ART-naive late-presenting untreated PWH with CD4+ cell counts less than 100âcells/µl were prospectively assessed for FDG uptake at baseline and at 4-8 weeks (nâ=â22) and 19-26 months (nâ=â11) following ART initiation. METHODS: Relative uptake in the subcortical regions (caudate, putamen and thalamus) and cortical regions (frontal, parietal, temporal and occipital cortices) were compared across time and correlated with biomarkers of disease activity and inflammation, in addition to being compared with a group of uninfected individuals (nâ=â10). RESULTS: Before treatment initiation, putaminal and caudate relative FDG uptake values in PWH were significantly higher than in uninfected controls. Relative putaminal and thalamic uptake significantly decreased shortly following ART initiation, while frontal cortex values significantly increased. FDG uptake changes correlated with changes in CD4+ cell counts and viral load, and, in the thalamus, with IL-6R and sCD14. Approximately 2 years following ART initiation, there was further decrease in subcortical relative uptake values, reaching levels below those of uninfected controls. CONCLUSION: Our findings support pretreatment basal ganglia and thalamic neuroinflammatory changes in PWH, which decrease after treatment with eventual unmasking of long-term irreversible neuronal damage. Meanwhile, increased frontal cortex metabolism following ART initiation suggests reversible cortical dysfunction which improves with virologic control and increased CD4+ cell counts. Early initiation of treatment after HIV diagnosis and secondary control of inflammation are thus necessary to halt neurological damage in PWH.
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Infecciones por VIH , Encéfalo/diagnóstico por imagen , Recuento de Linfocito CD4 , Glucosa , Infecciones por VIH/tratamiento farmacológico , Humanos , Estudios LongitudinalesRESUMEN
Plasmacytoid dendritic cells (PDCs) and their production of interferon-alpha (IFN-α) are believed to play an important role in human immunodeficiency virus, type I (HIV-1) pathogenesis. PDCs produce IFN-α and other proinflammatory cytokines through stimulation of Toll-like receptor 7 (TLR7) and TLR9 present in endosomal compartments. TLR7 recognizes single-stranded viral RNA, while TLR9 recognizes unmethylated DNA. In this study, we examined the mechanisms that may underlie variations in IFN-α production in response to HIV, and the impact of these variations on HIV pathogenesis. In four distinct cohorts, we examined PDC production of IFN-α upon stimulation with inactivated HIV-1 particles and unmethylated DNA. The signaling cascade of TLR7 bifurcates at the myeloid differentiation protein 88 (MyD88) adaptor protein to induce expression of either IFN-α or TNF-α. To determine whether variations in IFN-α production are modulated at the level of the receptor complex or downstream of it, we correlated production of IFN-α and TNF-α following stimulation of TLR7 or TLR9 receptors. Flow cytometry detection of intracellular cytokines showed strong, direct correlations between IFN-α and TNF-α expression in all four cohorts, suggesting that variations in IFN-α production are not due to variations downstream of the receptor complex. We then investigated the events upstream of TLR binding by using lipid-like vesicles to deliver TLR ligands directly to the TLR receptors, bypassing the need for CD4 binding and endocytosis. Similar tight correlations were found in IFN-α and TNF-α production in response to the TLR ligands. Taken together, these results strongly suggest that differences in IFN-α production depend on the regulatory processes at the level of the TLR7 receptor complex. Additionally, we found no association between IFN-α production before HIV infection and disease progression.
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Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Células Dendríticas/metabolismo , Células Dendríticas/virología , VIH-1/fisiología , Interferón-alfa/biosíntesis , Receptor Toll-Like 7/metabolismo , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/metabolismo , Estudios de Cohortes , Células Dendríticas/efectos de los fármacos , Progresión de la Enfermedad , Ácidos Grasos Monoinsaturados/farmacología , Femenino , Infecciones por VIH/metabolismo , Infecciones por VIH/virología , Humanos , Interferón-alfa/metabolismo , Masculino , Factor 88 de Diferenciación Mieloide/metabolismo , Compuestos de Amonio Cuaternario/farmacología , Transducción de Señal/efectos de los fármacos , Receptor Toll-Like 7/antagonistas & inhibidores , Receptor Toll-Like 9/antagonistas & inhibidores , Receptor Toll-Like 9/metabolismo , Factor de Necrosis Tumoral alfa/biosíntesis , Carga Viral/efectos de los fármacosRESUMEN
Paradoxical inflammatory reactions associated with treatment of neurotuberculosis can lead to severe morbidity and mortality and may not be controlled by steroids alone. We report the use of the Janus kinase inhibitor ruxolitinib to treat a steroid-refractory neurotuberculosis paradoxical reaction.
RESUMEN
Increases in inflammation, coagulation, and CD8+ T-cell numbers are associated with an elevated cardiovascular disease (CVD) risk in human immunodeficiency virus (HIV)-infected antiretroviral therapy (ART) recipients. Circulating memory CD8+ T cells that express the vascular endothelium-homing receptor CX3CR1 (fractalkine receptor) are enriched in HIV-infected ART recipients. Thrombin-activated receptor (PAR-1) expression is increased in HIV-infected ART recipients and is particularly elevated on CX3CR1+ CD8+ T cells, suggesting that these cells could interact with coagulation elements. Indeed, thrombin directly enhanced T-cell receptor-mediated interferon γ production by purified CD8+ T cells but was attenuated by thrombin-induced release of transforming growth factor ß by platelets. We have therefore identified a population of circulating memory CD8+ T cells in HIV infection that may home to endothelium, can be activated by clot-forming elements, and are susceptible to platelet-mediated regulation. Complex interactions between inflammatory elements and coagulation at endothelial surfaces may play an important role in CVD risk in HIV-infected ART recipients.
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Plaquetas/metabolismo , Linfocitos T CD8-positivos/inmunología , Infecciones por VIH/patología , Receptores de Quimiocina/análisis , Subgrupos de Linfocitos T/inmunología , Linfocitos T CD8-positivos/química , Linfocitos T CD8-positivos/efectos de los fármacos , Receptor 1 de Quimiocinas CX3C , Infecciones por VIH/inmunología , Humanos , Subgrupos de Linfocitos T/química , Subgrupos de Linfocitos T/efectos de los fármacos , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
We describe a patient with two recent episodes of tenofovir disoproxil fumarate (TDF)-associated acute kidney injury and six-class drug-resistant HIV infection who achieved and maintained viral suppression without worsening kidney function on a regimen including tenofovir alafenamide (TAF) through 48 weeks of therapy. The safety and efficacy of TAF in patients with TDF-associated renal tubulopathy and multiple drug resistant HIV has not yet been described. TAF may represent a useful option to maximally suppress HIV in patients with these complications.
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Lesión Renal Aguda/inducido químicamente , Adenina/análogos & derivados , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Tenofovir/efectos adversos , Lesión Renal Aguda/fisiopatología , Adenina/uso terapéutico , Alanina , Farmacorresistencia Viral Múltiple/genética , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , VIH-1/genética , Humanos , Masculino , Persona de Mediana Edad , Terapia RecuperativaRESUMEN
To better understand the components of an effective immune response to human immunodeficiency virus (HIV), the CD8(+) T-cell responses to HIV, hepatitis C virus (HCV), and cytomegalovirus (CMV) were compared with regard to frequency, immunodominance, phenotype, and interleukin-2 (IL-2) responsiveness. Responses were examined in rare patients exhibiting durable immune-mediated control over HIV, termed long-term nonprogressors (LTNP) or elite controllers, and patients with progressive HIV infection (progressors). The magnitude of the virus-specific CD8(+) T-cell response targeting HIV, CMV, and HCV was not significantly different between LTNP and progressors, even though their capacity to proliferate to HIV antigens was preserved only in LTNP. In contrast to HIV-specific CD8(+) T-cell responses of LTNP, HLA B5701-restricted responses within CMV pp65 were rare and did not dominate the total CMV-specific response. Virus-specific CD8(+) T cells were predominantly CD27(+)45RO(+) for HIV and CD27(-)45RA(+) for CMV; however, these phenotypes were highly variable and heavily influenced by the degree of viremia. Although IL-2 induced significant expansions of CMV-specific CD8(+) T cells in LTNP and progressors by increasing both the numbers of cells entering the proliferating pool and the number of divisions, the proliferative capacity of a significant proportion of HIV-specific CD8(+) T cells was not restored with exogenous IL-2. These results suggest that immunodominance by HLA B5701-restricted cells is specific to HIV infection in LTNP and is not a feature of responses to other chronic viral infections. They also suggest that poor responsiveness to IL-2 is a property of HIV-specific CD8(+) T cells of progressors that is not shared with responses to other viruses over which immunologic control is maintained.
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Linfocitos T CD8-positivos/inmunología , Infecciones por Citomegalovirus/inmunología , Infecciones por VIH/inmunología , Hepatitis C/inmunología , Interleucina-2/inmunología , Linfocitos T CD8-positivos/química , Proliferación Celular , Citomegalovirus/inmunología , VIH/inmunología , Sobrevivientes de VIH a Largo Plazo , Antígenos HLA-B/inmunología , Hepacivirus/inmunología , Humanos , Antígenos Comunes de Leucocito/análisis , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/análisisRESUMEN
Induction of broadly cross-reactive neutralizing antibodies (NAb) is an important goal for a prophylactic human immunodeficiency virus type 1 (HIV-1) vaccine. Some HIV-infected patients make a NAb response that reacts with diverse strains of HIV-1, but most candidate vaccines have induced NAb only against a subset of highly sensitive isolates. To better understand the nature of broad NAb responses that arise during natural infection, we screened patients for sera able to neutralize diverse HIV strains and explored the frequency and phenotype of their peripheral Envelope-specific B cells. We screened 113 HIV-infected patients of various clinical statuses for the prevalence of broad NAb. Sera able to neutralize at least four of five viral isolates were found in over one-third of progressors and slow progressors, but much less frequently in aviremic long-term nonprogressors. Most Env-specific antibody-secreting B cells were CD27(hi) CD38(hi) plasmablasts, and the total plasmablast frequency was higher in HIV-infected patients than in uninfected donors. We found that 0.0031% of B cells and 0.047% of plasmablasts secreted Env-specific immunoglobulin G (IgG) in an enzyme-linked immunospot (ELISPOT) assay. We developed a novel staining protocol to label HIV-specific B cells with Env gp140 protein. A total of 0.09% of B cells were found to be Env-specific by this method, a frequency far higher than that indicated by ELISPOT assay. gp140-labeled B cells were predominantly CD27(+) and surface IgG(+). These data describe the breadth and titer of serum NAb and the frequency and phenotype of HIV-specific B cells in a cohort of patients with broad cross-neutralizing antibody responses that are potential goals for vaccines for HIV.
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Linfocitos B/inmunología , Reacciones Cruzadas , Anticuerpos Anti-VIH/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , ADP-Ribosil Ciclasa 1/análisis , Linfocitos B/química , Anticuerpos Anti-VIH/sangre , Infecciones por VIH/virología , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Pruebas de Neutralización , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/análisis , Productos del Gen env del Virus de la Inmunodeficiencia Humana/inmunologíaRESUMEN
Human immunodeficiency virus type 1 (HIV-1) infection has been associated with perturbations of plasmacytoid dendritic cells (PDC), including diminished frequencies in the peripheral blood and reduced production of type I interferons (IFNs) in response to in vitro stimulation. However, recent data suggest a paradoxical increase in production of type 1 interferons in vivo in HIV-infected patients compared to uninfected controls. Using a flow cytometric assay to detect IFN-alpha-producing cells within unseparated peripheral blood mononuclear cells, we observed that short-term interruptions of antiretroviral therapy are sufficient to result in significantly reduced IFN-alpha production by PDC in vitro in response to CpG A ligands or inactivated HIV particles. The primary cause of diminished IFN-alpha production was reduced responsiveness of PDC to de novo stimulation, not diminished per cell IFN-alpha production or migration of cells to lymphoid organs. Real-time PCR analysis of purified PDC from patients prior to and during treatment interruptions revealed that active HIV-1 replication is associated with upregulation of type I IFN-stimulated gene expression. Treatment of hepatitis C virus-infected patients with IFN-alpha2b and ribavirin for hepatitis C virus infection resulted in a profound suppression of de novo IFN-alpha production in response to CpG A or inactivated HIV particles, similar to the response observed in HIV-infected patients. Together, these results suggest that diminished production of type I interferons in vitro by PDC from HIV-1-infected patients may not represent diminished interferon production in vivo. Rather, diminished function in vitro is likely a consequence of prior activation via type I interferons or HIV virions in vivo.
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Células Dendríticas/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , Interferón-alfa/biosíntesis , Viremia/inmunología , Células Cultivadas , Citometría de Flujo , Infecciones por VIH/complicaciones , Hepatitis C/tratamiento farmacológico , Humanos , Interferón alfa-2 , Interferón-alfa/uso terapéutico , Leucocitos Mononucleares/inmunología , Proteínas Recombinantes , Ribavirina/uso terapéuticoRESUMEN
The effect of human immunodeficiency virus (HIV) infection and high-level HIV replication on the function of monocytes was investigated. HIV-positive patients had elevated levels of spontaneous production of some or all of the monocyte proinflammatory cytokines measured (interleukin-1beta [IL-1beta], IL-6, and tumor necrosis factor alpha [TNF-alpha]) compared to uninfected controls. In patients on therapy with high frequencies of monocytes producing proinflammatory cytokines, this frequency was diminished in the context of viremia during an interruption of therapy. Diminished production of proinflammatory cytokines during viremia was restored by culture with autologous CD4(+) T cells or monocytes from an on-therapy time point or lipopolysaccharide (LPS). Microarray analysis demonstrated that diminished monocyte production of proinflammatory cytokines was correlated with elevated type I interferon-stimulated gene transcripts. The addition of exogenous alpha 2A interferon diminished the spontaneous production of IL-1beta, IL-6, and TNF-alpha but did not affect responses to LPS, recapitulating the changes observed for HIV-viremic patients. These results suggest that monocyte function is diminished during high-level HIV viremia and that this effect is mediated by chronic stimulation by type I interferons. This effect on monocytes during viremia may play a role in diminished innate or adaptive immune system functions in HIV-infected patients. In addition, the restoration of these functions may also play a role in some immune reconstitution syndromes observed during initiation of therapy.