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BACKGROUND: HIV-associated neurocognitive disorders (HAND) is hypothesized to be a result of myeloid cell-induced neuro-inflammation in the central nervous system that may be initiated in the periphery, but the contribution of peripheral T cells in HAND pathogenesis remains poorly understood. METHODS: We assessed markers of T cell activation (HLA-DR + CD38+), immunosenescence (CD57 + CD28-), and immune-exhaustion (TIM-3, PD-1 and TIGIT) as well as monocyte subsets (classical, intermediate, and non-classical) by flow cytometry in peripheral blood derived from individuals with HIV on long-term stable anti-retroviral therapy (ART). Additionally, normalized neuropsychological (NP) composite test z-scores were obtained and regional brain volumes were assessed by magnetic resonance imaging (MRI). Relationships between proportions of immune phenotypes (of T-cells and monocytes), NP z-scores, and brain volumes were analyzed using Pearson correlations and multiple linear regression models. RESULTS: Of N = 51 participants, 84.3% were male, 86.3% had undetectable HIV RNA < 50 copies/ml, median age was 52 [47, 57] years and median CD4 T cell count was 479 [376, 717] cells/uL. Higher CD4 T cells expressing PD-1 + and/or TIM-3 + were associated with lower executive function and working memory and higher CD8 T cells expressing PD-1+ and/or TIM-3+ were associated with reduced brain volumes in multiple regions (putamen, nucleus accumbens, cerebellar cortex, and subcortical gray matter). Furthermore, higher single or dual frequencies of PD-1 + and TIM-3 + expressing CD4 and CD8 T-cells correlated with higher CD16 + monocyte numbers. CONCLUSIONS: This study reinforces evidence that T cells, particularly those with immune exhaustion phenotypes, are associated with neurocognitive impairment and brain atrophy in people living with HIV on ART. Relationships revealed between T-cell immune exhaustion and inflammatory in CD16+ monocytes uncover interrelated cellular processes likely involved in the immunopathogenesis of HAND.
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Anti-CD4 IgG autoantibodies have been implicated in CD4+ T cell reconstitution failure, leaving people with HIV (PWH) at heightened risk of HIV-associated comorbidities, such as neurocognitive impairment. Seventeen PWH on stable anti-retroviral therapy (ART) and 10 HIV seronegative controls had plasma anti-CD4 IgG antibodies measured by enzyme-linked immunosorbent assay. Neuropsychological (NP) tests assessed cognitive performance, and brain volumes were measured by structural magnetic resonance imaging. Anti-CD4 IgG levels were elevated (p = 0.04) in PWH compared with controls. Anti-CD4 IgG correlated with global NP z-scores (rho = - 0.51, p = 0.04). A relationship was observed between anti-CD4 IgG and putamen (ß = - 0.39, p = 0.02), pallidum (ß = - 0.38, p = 0.03), and amygdala (ß = - 0.42, p = 0.05) regional brain volumes. The results of this study suggest the existence of an antibody-mediated relationship with neurocognitive impairment and brain abnormalities in an HIV-infected population.
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Complexo AIDS Demência/imunologia , Autoanticorpos/sangue , Antígenos CD4/imunologia , Linfócitos T CD4-Positivos/imunologia , Disfunção Cognitiva/virologia , Complexo AIDS Demência/tratamento farmacológico , Fármacos Anti-HIV/uso terapêutico , Autoantígenos/imunologia , Disfunção Cognitiva/imunologia , Feminino , Humanos , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-IdadeRESUMO
There are approximately 38 million people globally living with Human immunodeficiency virus 1 (HIV-1) and given the tremendous success of combination antiretroviral therapy (cART) this has dramatically reduced mortality and morbidity with prevention benefits. However, HIV-1 persists during cART within the human body and re-appears upon cART interruption. This HIV-1 reservoir remains a barrier to cure with cellular sites of viral persistence not fully understood. In this study we provide evidence corroborating a recently published article in STM demonstrating the role of platelets as a novel cellular disseminator of HIV-1 particles in the setting of viral suppression. Using classical transmission electron microscopy with and without immunogold labeling, we visualize HIV-1 in both platelets and monocytes in cART suppressed HIV donors. Our study suggests that due to the close proximity of platelets and monocytes an alternative life cycle of HIV-1 cycling within monocytes and platelets without the need of active replication under cART occurs. Our findings are supported by the lack of detectable HIV-1 particles in platelets derived from HIV uninfected donors or the 'Berlin' patient suggesting that platelets may serve as an underappreciated hidden bearer for HIV-1 and should be considered in HIV remission studies and trials.
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Plaquetas/metabolismo , Infecções por HIV/sangue , HIV-1/patogenicidade , HumanosRESUMO
PURPOSE OF REVIEW: Gallant efforts are ongoing to achieve sustained antiretroviral therapy (ART)-free HIV remission in the HIV-infected person; however, most, if not all, current human clinical studies have primarily focused these efforts on targeting viral persistence in CD4 T cells in blood and tissue sanctuaries. The lack of myeloid centered HIV clinical trials, either as primary or secondary end points, has hindered our understanding of the contribution of myeloid cells in unsuccessful trials but may also guide successes in future HIV eradication clinical strategies. RECENT FINDINGS: Recent advances have highlighted the importance of myeloid reservoirs as sanctuaries of HIV persistence and therefore may partially be responsible for viral recrudescence following ART treatment interruption in several clinical trials where HIV was not detectable or recovered from CD4 T cells. Given these findings, novel innovative therapeutic approaches specifically focused on HIV clearance in myeloid cell populations need to be vigorously pursued if we are to achieve additional cases of sustained ART-free remission. This review will highlight new research efforts defining myeloid persistence and recent advances in HIV remission and cure trials that would be relevant in targeting this compartment and make an argument as to their clinical relevancy as we progress towards sustained ART-free HIV remission in all HIV-infected persons.
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Antirretrovirais/uso terapêutico , Linfócitos T CD4-Positivos/virologia , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Células Mieloides/virologia , Linfócitos T CD4-Positivos/imunologia , Ensaios Clínicos como Assunto , Humanos , Células Mieloides/efeitos dos fármacos , Latência Viral/efeitos dos fármacosRESUMO
HIV infection induces phenotypic and functional changes to CD8+ T cells defined by the coordinated upregulation of a series of negative checkpoint receptors that eventually result in T cell exhaustion and failure to control viral replication. We report that effector CD8+ T cells during HIV infection in blood and SIV infection in lymphoid tissue exhibit higher levels of the negative checkpoint receptor TIGIT. Increased frequencies of TIGIT+ and TIGIT+ PD-1+ CD8+ T cells correlated with parameters of HIV and SIV disease progression. TIGIT remained elevated despite viral suppression in those with either pharmacological antiretroviral control or immunologically in elite controllers. HIV and SIV-specific CD8+ T cells were dysfunctional and expressed high levels of TIGIT and PD-1. Ex-vivo single or combinational antibody blockade of TIGIT and/or PD-L1 restored viral-specific CD8+ T cell effector responses. The frequency of TIGIT+ CD4+ T cells correlated with the CD4+ T cell total HIV DNA. These findings identify TIGIT as a novel marker of dysfunctional HIV-specific T cells and suggest TIGIT along with other checkpoint receptors may be novel curative HIV targets to reverse T cell exhaustion.
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Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/imunologia , Receptores Imunológicos/imunologia , Animais , Antígeno B7-H1/imunologia , Separação Celular , DNA Viral/análise , Progressão da Doença , Citometria de Fluxo , Humanos , Ativação Linfocitária/imunologia , Macaca mulatta , RNA Viral/análise , Síndrome de Imunodeficiência Adquirida dos Símios/imunologiaRESUMO
OBJECTIVE: This study aimed to evaluate the relationship between inflammatory biomarkers and endothelial dysfunction (ED), as measured by brachial artery flow-mediated dilation (FMD). METHODS: We conducted a cross-sectional analysis utilizing baseline data of 135 participants with HIV infection on stable antiretroviral therapy (ART) in the Hawaii Aging with HIV-Cardiovascular (HAHC-CVD) study who had available baseline inflammatory biomarkers and brachial artery FMD measurements. RESULTS: We observed significant associations between brachial artery FMD and baseline brachial artery diameter, age, male gender, traditional cardiovascular disease (CVD) risk factors such as BMI, waist to hip ratio, hypertension, systolic blood pressure (BP), diastolic BP, and LDL cholesterol, and 10-year coronary heart disease (CHD) risk estimated by Framingham risk score (FRS). Of all biomarkers tested, higher level of C-reactive protein (CRP) (beta = - 0.695, P = 0.030) and serum amyloid P (SAP) (beta = - 1.318, P = 0.021) were significantly associated with lower brachial artery FMD in univariable regression analysis. After adjusting for baseline brachial artery diameter, age, and selected traditional CVD risk factors in multivariable model, SAP remained significantly associated with brachial artery FMD (beta = - 1.094, P = 0.030), while CRP was not (beta = - 0.391, P = 0.181). DISCUSSION: Serum amyloid P was independently associated with impaired brachial artery FMD and may potentially relate to ED and increased CVD risk in HIV-infected patients on stable ART.
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Fármacos Anti-HIV/uso terapêutico , Artéria Braquial/fisiologia , Infecções por HIV/complicações , Componente Amiloide P Sérico/metabolismo , Vasodilatação/fisiologia , Biomarcadores , Doença Crônica , Estudos Transversais , Feminino , Infecções por HIV/tratamento farmacológico , HIV-1 , Humanos , Inflamação , Masculino , Pessoa de Meia-Idade , RNA ViralRESUMO
Chronic HIV infection has long been associated with an increased risk for cardiovascular diseases. The metabolites of the renin−angiotensin system (RAS) such as angiotensin II (AngII) play an important role in regulating blood pressure and fluid dynamics. Cross-sectional analysis of HIV-positive individuals (n = 71, age > 40 years, stable ART > 3 months with HIV viral load < 50 copies/mL) were compared to a similar HIV seronegative group (n = 72). High-resolution B-mode ultrasound images of the right carotid bifurcation (RBIF) and right common carotid artery (RCCA) were conducted to measure the extent of carotid atherosclerotic vascular disease. Plasma RAS peptide levels were quantified using a liquid chromatography-mass spectrometry-based metabolomics assay. RAS peptide concentrations were compared between persons with HIV and persons without HIV, correlating their association with clinical and cardiac measures. Median precursor peptides (Ang(1-12) and AngI) were significantly higher in the HIV-positive group compared to the HIV-negative. Analyses of the patient subgroup not on antihypertensive medication revealed circulating levels of AngII to be four-fold higher in the HIV-positive subgroup. AngII and TNF-alpha levels were found to have a positive association with RCCA, and AngI/Ang(1-12) ratio and TNF-alpha levels were found to have a positive association with RBIF. In both predictive models, AngIII had a negative association with either RCCA or RBIF, which may be attributed to its ability to bind onto AT2R and thus oppose pro-inflammatory events. These results reveal systemic alterations in RAS as a result of chronic HIV infection, which may lead to the activation of inflammatory pathways associated with carotid thickening. RAS peptide levels and cytokine markers were associated with RCCA and RBIF measurements.
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[This corrects the article DOI: 10.1371/journal.pone.0231761.].
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BACKGROUND: Cellular immunometabolism among people living with HIV (PLWH) on antiretroviral therapy (ART) remains under investigated. We assessed the relationships between mitochondrial oxidative phosphorylation (OXPHOS) in peripheral blood mononuclear cells (PBMCs) and blood parameters associated with HIV immune dysregulation. METHODS: PLWH ≥40 years old and on stable ART ≥3 months were enrolled (N = 149). OXPHOS complex I (CI, NADH dehydrogenase) and complex IV (CIV, cytochrome c oxidase) protein levels in PBMCs were quantified using immunoassays. Monocyte subsets and markers of T-cell activation, senescence, and exhaustion were measured on PBMC by flow cytometry. Plasma inflammatory mediators were quantified using a multiplex assay. HIV-uninfected group (N = 44) of similar age, gender, and ethnicity had available OXPHOS levels. RESULTS: PLWH had a median age of 51 years. Majority were male (88.6%), Caucasian (57.7%), and with undetectable plasma HIV RNA <50 copies/mL (84.6%). Median CI level was lower in PLWH compared with the HIV-seronegative group (65.5 vs 155.0 optical density/µg protein x 103, p <0.0001). There was no significant difference in median CIV levels. Lower OXPHOS levels correlated with lower CD4% and CD4/CD8 ratio. On multivariable linear regression adjusted for age, current use of zidovudine/didanosine, and HIV RNA (detectable versus undetectable), lower OXPHOS levels were significantly associated with higher MPO, SAA, SAP, and sVCAM, and higher frequencies of intermediate (CD14++CD16+) monocytes and TIGIT+TIM3+ CD4 T-cell (p<0.01). CONCLUSION: CI PBMC protein levels were decreased in PLWH on ART. Decreased OXPHOS correlated with disease severity and inflammation. Further studies on the relationship between immunometabolism and immune dysregulation in HIV are warranted.
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Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/imunologia , HIV-1/imunologia , Leucócitos Mononucleares/imunologia , Mitocôndrias/metabolismo , Fosforilação Oxidativa , Relação CD4-CD8 , Estudos Transversais , Feminino , Infecções por HIV/diagnóstico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/genética , HIV-1/isolamento & purificação , Havaí , Interações Hospedeiro-Patógeno/imunologia , Humanos , Leucócitos Mononucleares/citologia , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Mitocôndrias/imunologia , RNA Viral/isolamento & purificação , Índice de Gravidade de DoençaRESUMO
Despite long term antiretroviral therapy (ART), insulin resistance (IR) is common among people living with HIV/AIDS (PLWHA) exposing this population to a greater risk of cardiometabolic complications when compared to their uninfected counterparts. We previously identified an expansion in monocyte subpopulations in blood that were linked to the degree of IR in persons with HIV on stable ART. In this study, we directly assessed monocyte inflammatory functional properties from PLWHA on ART (n = 33) and HIV-uninfected controls (n = 14) of similar age, gender, and cardiovascular disease risk and determined the relationship with IR (homeostatic model assessment-insulin resistance (HOMA-IR)), calculated from fasting blood glucose and insulin measurements. Peripheral blood mononuclear cells were stimulated with oxidized low-density lipoproteins (oxLDL) and polyfunctional monocyte cytokine responses (IL-1ß, IL-6, IL-8, or TNF-α) were determined by flow cytometry. Higher monocyte IL-1ß and IL-8 responses to oxLDL were associated with higher IR in PLWHA but not in the control group. We observed that higher basal monocyte cytokine responses were associated with both duration since HIV diagnosis and ART initiation. In the management of IR in chronic HIV, strategies lowering monocyte IL-1ß and IL-8 responses should be considered in addition to ART in order to limit adverse cardio-metabolic outcomes.
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Infecções por HIV/complicações , Resistência à Insulina , Lipoproteínas LDL/metabolismo , Monócitos/metabolismo , Antirreumáticos/uso terapêutico , Glicemia , Fatores de Risco Cardiometabólico , Citocinas/metabolismo , Jejum , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Leucócitos Mononucleares , Masculino , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Maximum carotid plaque thickness (MCPT) measures the largest plaque thickness in the carotid artery and reflects atherosclerosis plaque burden. MCPT may be a better predictor of cardiovascular disease than carotid artery intima-media thickness (cIMT) because it identifies potential unstable arterial atherosclerosis plaques. We assessed the relationships of monocyte and T cell populations and plasma soluble mediators with MCPT measures. We performed a cross-sectional and small follow-up analysis in people living with HIV (PLWH) aged >40 years on stable antiretroviral therapy (ART) >6 months. MCPT was acquired by high-resolution B-mode ultrasound. Existing monocyte subsets and T cell activation frequencies were determined by flow cytometry and plasma mediators of inflammation and apolipoproteins were measured by Luminex assay. One hundred twenty-five ART-treated PLWH, 88% male, 55% Caucasian, with a median age of 51 years, median CD4 count of 477 cells/µL (Q1: 325, Q3: 612), 84% undetectable plasma HIV RNA (<50 copies/mL). Twenty-five PLWH had detectable carotid plaque. MCPT correlated with monocyte chemoattractant protein-1 (MCP-1; r = 0.487, p = .016), tumor necrosis factor-α (TNF-α; r = 0.474 p = .019), soluble vascular cell adhesion molecule-1 (sVCAM-1; r = 0.472, p = .020), apolipoprotein B6 (ApoB6; r = -0.473, p = .019), and interleukin-6 (IL-6; r = 0.455, p = .025). In a multivariable regression model, MCP-1, TNF-α, and sVCAM-1 remained significant after adjustment for age. Carotid plaque burden was associated with increased inflammatory, monocyte, and endothelial measures, including MCP-1, TNF-α, and sVCAM-1 levels. Further investigation on the evolution or severity of plaque burden in this population is warranted.
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Doenças das Artérias Carótidas , Estenose das Carótidas , Infecções por HIV , Espessura Intima-Media Carotídea , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos , Fatores de RiscoRESUMO
Endogenous plasma levels of the immunomodulatory carbohydrate-binding protein galectin-9 (Gal-9) are elevated during HIV infection and remain elevated after antiretroviral therapy (ART) suppression. We recently reported that Gal-9 regulates HIV transcription and potently reactivates latent HIV. However, the signaling mechanisms underlying Gal-9-mediated viral transcription remain unclear. Given that galectins are known to modulate T cell receptor (TCR)-signaling, we hypothesized that Gal-9 modulates HIV transcriptional activity, at least in part, through inducing TCR signaling pathways. Gal-9 induced T cell receptor ζ chain (CD3ζ) phosphorylation (11.2 to 32.1%; P = 0.008) in the J-Lat HIV latency model. Lck inhibition reduced Gal-9-mediated viral reactivation in the J-Lat HIV latency model (16.8-0.9%; P < 0.0001) and reduced both Gal-9-mediated CD4+ T cell activation (10.3 to 1.65% CD69 and CD25 co-expression; P = 0.0006), and IL-2/TNFα secretion (P < 0.004) in primary CD4+ T cells from HIV-infected individuals on suppressive ART. Using phospho-kinase antibody arrays, we found that Gal-9 increased the phosphorylation of the TCR-downstream signaling molecules ERK1/2 (26.7-fold) and CREB (6.6-fold). ERK and CREB inhibitors significantly reduced Gal-9-mediated viral reactivation (16.8 to 2.6 or 12.6%, respectively; P < 0.0007). Given that the immunosuppressive rapamycin uncouples HIV latency reversal from cytokine-associated toxicity, we also investigated whether rapamycin could uncouple Gal-9-mediated latency reactivation from its concurrent pro-inflammatory cytokine production. Rapamycin reduced Gal-9-mediated secretion of IL-2 (4.4-fold, P = 0.001) and TNF (4-fold, P = 0.02) without impacting viral reactivation (16.8% compared to 16.1%; P = 0.2). In conclusion, Gal-9 modulates HIV transcription by activating the TCR-downstream ERK and CREB signaling pathways in an Lck-dependent manner. Our findings could have implications for understanding the role of endogenous galectin interactions in modulating TCR signaling and maintaining chronic immune activation during ART-suppressed HIV infection. In addition, uncoupling Gal-9-mediated viral reactivation from undesirable pro-inflammatory effects, using rapamycin, may increase the potential utility of recombinant Gal-9 within the reversal of HIV latency eradication framework.
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Galectinas/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Sistema de Sinalização das MAP Quinases/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T CD4-Positivos/imunologia , Linhagem Celular , Linhagem Celular Tumoral , Regulação Viral da Expressão Gênica/imunologia , Humanos , Células Jurkat , Ativação Linfocitária/imunologia , Transdução de Sinais/imunologia , Transcrição Gênica/imunologia , Fator de Necrose Tumoral alfa/imunologia , Ativação Viral/imunologia , Latência Viral/imunologia , Replicação Viral/imunologiaRESUMO
BACKGROUND: Compared to healthy individuals, those with stably repressed HIV experience a higher risk of developing insulin resistance, a hallmark of pre-diabetes and a major determinant for cardiometabolic diseases. Although epigenetic processes, including in particular DNA methylation, appear to be dysregulated in individuals with insulin resistance, little is known about where these occur in the genomes of immune cells and the origins of these alterations in HIV-infected individuals. Here, we examined the genome-wide DNA methylation states of monocytes in HIV-infected individuals (n = 37) with varying levels of insulin sensitivity measured by the homeostatic model assessment of insulin resistance (HOMA-IR). RESULTS: By profiling DNA methylation at single-nucleotide resolution using the Illumina Infinium HumanMethylation450 BeadChip in monocytes from insulin-resistant (IR; HOMA-IR ≥ 2.0; n = 14) and insulin-sensitive (IS; HOMA-IR < 2.0; n = 23) individuals, we identified 123 CpGs with significantly different DNA methylation levels. These CpGs were enriched at genes involved in pathways relating to glucose metabolism, immune activation, and insulin-relevant signaling, with the majority (86.2%) being hypomethylated in IR relative to IS individuals. Using a stepwise multiple logistic regression analysis, we observed 4 CpGs (cg27655935, cg02000426, cg10184328, and cg23085143) whose methylation levels independently predicted the insulin-resistant state at a higher confidence than that of clinical risk factors typically associated with insulin resistance (i.e., fasting glucose, 120-min oral glucose tolerance test, Framingham Risk Score, and Total to HDL cholesterol ratio). Interestingly, 79 of the 123 CpGs (64%) exhibited remarkably similar levels of methylation as that of hematopoietic stem cells (HSC) in monocytes from IR individuals, implicating epigenetic defects in myeloid differentiation as a possible origin for the methylation landscape underlying the insulin resistance phenotype. In support of this, gene ontology analysis of these 79 CpGs revealed overrepresentation of these CpGs at genes relevant to HSC function, including involvement in stem cell pluripotency, differentiation, and Wnt signaling pathways. CONCLUSION: Altogether, our data suggests a possible role for DNA methylation in regulating monocyte activity that may associate with the insulin-resistant phenotype. The methylomic landscape of insulin resistance in monocytes could originate from epigenetic dysregulation during HSC differentiation through the myeloid lineage. Understanding the factors involved with changes in the myeloid trajectory may provide further insight into the development of insulin resistance. Furthermore, regulation of specific genes that were implicated in our analysis reveal possible targets for modulating immune activity to ameliorate insulin resistance.
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Metilação de DNA , Epigenômica/métodos , Marcadores Genéticos , Infecções por HIV/virologia , Resistência à Insulina , Estudos de Casos e Controles , Ilhas de CpG , Feminino , Redes Reguladoras de Genes , Infecções por HIV/genética , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Monócitos/química , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Sequenciamento Completo do GenomaRESUMO
Incidences of cardiovascular diseases (CVD) are high among virologically suppressed HIV-infected individuals. Monocyte activation and trafficking are key mechanisms in the evolution of CVD. We studied the ability of cenicriviroc (CVC), a dual C-C chemokine receptor type 2 (CCR2) and CCR5 antagonist, to influence the migration of monocytes from HIV-infected individuals on antiretroviral therapy (ART). Monocytes were derived from 23 ART-suppressed HIV-infected and 16 HIV-uninfected donors. In a trans-endothelial migration model, monocytes, and human aortic endothelial cells (HAoECs) were exposed to cenicriviroc and migrated monocytes, quantified. Expression of CCR2 and CCR5 on monocytes and adhesion molecules (E-selectin, ICAM-1, VCAM-1, PECAM-1, and CD99) on HAoECs were measured. The single antagonists, BMS-22 (CCR2), and maraviroc (CCR5), served as controls. When both HAoECs and monocytes together were exposed to the antagonists, cenicriviroc led to a greater decrease in monocyte migration compared to BMS-22 or vehicle in both HIV-infected and HIV-uninfected groups (P < 0.05), with maraviroc having no inhibitory effect. Cenicriviroc treatment of HAoECs alone decreased monocyte migration in the HIV-infected group when compared to vehicle (P < 0.01). Inhibition of migration was not evident when monocytes alone were exposed to cenicriviroc, BMS-22 or maraviroc. Incubation of HAoECs with cenicriviroc decreased E-selectin expression (P = 0.045) but had limited effects on the other adhesion molecules. Cenicriviroc inhibits monocyte trans-endothelial migration more effectively than single chemokine receptor blockade, which may be mediated via disruption of monocyte-endothelial tethering through reduced E-selectin expression. Cenicriviroc should be considered as a therapeutic intervention to reduce detrimental monocyte trafficking.
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Antagonistas dos Receptores CCR5/farmacologia , Selectina E/biossíntese , Imidazóis/farmacologia , Monócitos/efeitos dos fármacos , Migração Transendotelial e Transepitelial/efeitos dos fármacos , Antígeno 12E7/fisiologia , Adulto , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Aorta , Aterosclerose/etiologia , Aterosclerose/imunologia , Moléculas de Adesão Celular/fisiologia , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos , Selectina E/genética , Células Endoteliais , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Humanos , Masculino , Maraviroc/farmacologia , Pessoa de Meia-Idade , Monócitos/fisiologia , Receptores CCR2/antagonistas & inibidores , Receptores CCR2/fisiologia , Receptores CCR5/fisiologia , SulfóxidosRESUMO
BACKGROUND: Chronic inflammation and immune dysfunction occur in human immunodeficiency virus (HIV)-infection despite stable antiretroviral therapy (ART). Red blood cell distribution width (RDW) has been shown to correlate with markers of inflammation in non-HIV conditions. The study objective was to determine associations between RDW with cellular markers of immune activation and immune dysfunction including soluble inflammatory mediators in ART treated HIV infection. METHODS: We performed a cross-sectional analysis of the Hawaii Aging with HIV-Cardiovascular study. RDW was defined as one standard deviation of RBC size divided by mean corpuscular volume multiplied by 100%. Correlations were analyzed between RDW, soluble inflammatory biomarkers and T cell activation (CD38 + HLA-DR+), senescence (CD28-CD57+), and immune exhaustion (PD-1, TIGIT, TIM-3 expression). RESULTS: Of 158 participants analyzed, median age was 50 years, duration of ART 12.6 years, virally suppressed 84.4%, and CD4 count 503 cells/mm3. Significant positive correlations were identified between RDW and soluble biomarkers including sICAM, IL-8, IL-6, SAA, TNF-α, sE-selection, fibrinogen, D-dimer, CRP, CD4/CD8 ratio, and frequency of multiple CD8 T-cell populations such as CD38 + HLA-DR + T-cells, single TIGIT+, and dual expressing of TIGIT + PD1+, TIGIT + TIM3+, and TIM3 + PD1+ CD8+ T-cell subsets (p < .05). Frequencies of CD38 + HLA-DR + CD8+ T-cells and TIGIT + CD8+ T-cells remained significant adjusting for baseline variables (p < .01). CONCLUSION: Our study revealed correlations between RDW with systemic inflammatory biomarkers and CD8+ T-cell populations related to immune activation and exhaustion in HIV-infected individuals on ART. Further studies are warranted to determine the utility of RDW as a marker of immune dysregulation in HIV.
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Índices de Eritrócitos , Eritrócitos/citologia , Infecções por HIV/tratamento farmacológico , Inflamação/patologia , Linfócitos T , Antirretrovirais , Biomarcadores/sangue , Estudos Transversais , Feminino , Infecções por HIV/sangue , Infecções por HIV/epidemiologia , Havaí/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Carga ViralRESUMO
OBJECTIVE: To evaluate changes in neuropsychological (NP) performance and in plasma and cell surface markers of peripheral monocyte activation/migration after treatment with cenicriviroc (CVC), a dual C-C chemokine receptor type 2 (CCR2) and type 5 (CCR5) antagonist, in treatment-experienced, HIV-infected individuals. SETTING: Single-arm, 24-week, open-label clinical trial. METHODS: HIV-infected individuals on antiretroviral therapy ≥1 year with plasma HIV RNA ≤50 copies per milliliter and below-normal cognitive performance [defined as age-, sex-, and education-adjusted NP performance (NPZ) <-0.5 in a single cognitive domain or in global performance] were enrolled. Changes over 24 weeks were assessed for global and domain-specific NPZ scores, plasma markers of monocyte/macrophage activation [neopterin, soluble (s)CD14, and sCD163] quantified by ELISA, and CCR2 and CCR5 expression on monocytes, and T cells measured by flow cytometry. RESULTS: Seventeen of 20 enrolled participants completed the study. Improvements over 24 weeks were observed in global NPZ [median change (Δ) = 0.24; P = 0.008], and in cognitive domains of attention (Δ0.23; P = 0.011) and working memory (Δ0.44; P = 0.017). Plasma levels of sCD163, sCD14 and neopterin decreased significantly (P's < 0.01). CCR2 and CCR5 monocyte expression remained unchanged; however, CCR5 levels on CD4 and CD8 T cells and CCR2 expression on CD4 T cells increased (P's < 0.01). CONCLUSIONS: CVC given over 24 weeks was associated with improved NP test performance and decreased plasma markers of monocyte immune activation in virally suppressed, HIV-infected participants. These data potentially link changes in monocyte activation to cognitive performance. Further study of CVC for HIV cognitive impairment in a randomized controlled study is warranted.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Cognição , Infecções por HIV/tratamento farmacológico , Monócitos/imunologia , Receptores CCR2/antagonistas & inibidores , Receptores CCR5/efeitos dos fármacos , Carga Viral , Feminino , Infecções por HIV/imunologia , Infecções por HIV/psicologia , Infecções por HIV/virologia , Humanos , Contagem de Leucócitos , Ativação de Macrófagos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Projetos PilotoRESUMO
Plasminogen activator inhibitor type 1 (PAI-1), a key negative regulator of fibrinolysis, has been investigated to be one of the potential mechanisms of the development of impaired insulin sensitivity, insulin resistance, and diabetes mellitus. Because chronically stable HIV-infected individuals frequently develop abnormal glucose metabolism, including insulin resistance and diabetes mellitus, we postulated that PAI-1 could be one of the multifactorial pathogenic roles in the development of impaired insulin sensitivity and insulin resistance among chronic HIV-infected individuals. From our longitudinal cohort study, we selectively recruited chronically stable HIV-infected individuals without diagnosis of diabetes mellitus at baseline (N = 62) to analyze the correlation of baseline inflammatory cytokines, including PAI-1 and whole-body insulin sensitivity, with 2-year follow-up, as measured by Matsuda Index. We found a negative correlation between baseline PAI-1 and Matsuda Index (r = -0.435, p = .001) and a negative correlation between baseline PAI-1 and Matsuda Index at 2 years (r = -0.377, p = .005). In a linear regression model that included age, total body fat mass percentage, serum amyloid A, and family history of diabetes mellitus, PAI-1 still remained significantly associated with Matsuda Index at 2-year follow-up (ß = -.397, p = .002). Our longitudinal study suggests that PAI-1 is an independent predictor of impaired insulin sensitivity among chronic HIV-infected individuals.
Assuntos
Infecções por HIV/complicações , Resistência à Insulina , Inibidor 1 de Ativador de Plasminogênio/sangue , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-IdadeRESUMO
Cross-sectional relationships were examined between regional brain volumes and mitochondrial DNA (mtDNA) 8-hydroxy-2-deoxyguanosine (8-oxo-dG) in peripheral blood mononuclear cells (PBMCs) of 47 HIV patients [mean age 51years; 81% with HIV RNA ≤50copies/mL] on combination antiretroviral therapy. The gene-specific DNA damage and repair assay measured mtDNA 8-oxo-dG break frequency. Magnetic resonance imaging was performed at 3T. Higher mtDNA 8-oxo-dG was associated with lateral ventricular enlargement and with decreased volumes of hippocampus, pallidum, and total subcortical gray matter, suggesting the involvement of systemic mitochondrial-specific oxidative stress in chronic HIV-related structural brain changes and cognitive difficulties. Clarification of the mechanism may provide potential therapeutic targets.
Assuntos
Atrofia/patologia , DNA Mitocondrial/química , Desoxiguanosina/análogos & derivados , Substância Cinzenta/patologia , Infecções por HIV/complicações , Hipocampo/patologia , Leucócitos Mononucleares/patologia , 8-Hidroxi-2'-Desoxiguanosina , Adulto , Atrofia/diagnóstico por imagem , Estudos Transversais , Dano ao DNA , Desoxiguanosina/análise , Feminino , Substância Cinzenta/diagnóstico por imagem , Hipocampo/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo , Espécies Reativas de Oxigênio/toxicidadeRESUMO
OBJECTIVE: High rates of albuminuria are observed among HIV-infected individuals on stable antiretroviral therapy (ART). Though pro-inflammatory and pro-fibrotic responses are described as components of albuminuria in the general population, it is unclear how these responses are associated to albuminuria in ART-treated chronic HIV. We investigated the relationship of monocyte subsets and urine inflammatory and fibrotic biomarkers to albuminuria in ART-treated HIV-infected participants. DESIGN AND METHODS: Cross-sectional analyses were performed on Hawaii Aging with HIV-cardiovascular disease study cohort participants who were required at entry to be ≥40 years old and on ART ≥3 months. Monocyte subpopulations were determined in banked peripheral blood mononuclear cells (PBMC) using multi-parametric flow-cytometry. Entry random urine samples were assessed for albumin-to-creatinine ratios (UACR). Urine samples were measured for inflammatory and fibrotic biomarkers using Luminex technology. RESULTS: Among 96 HIV-infected subjects with measured UACR (87% male, 59% Caucasian, and 89% undetectable HIV RNA with median CD4 of 495.5 cells/µL), 18 patients (19%) had albuminuria. Non-classical (CD14low/+CD16++) monocytes were significantly elevated in subjects with albuminuria (p = 0.034) and were correlated to UACR (r = 0.238, p = 0.019). Elevated non-classical monocyte counts were significant predictors of worsening albuminuria, independent of traditional- and ART-associated risk factors (ß = 0.539, p = 0.007). Urine TGF-ß1 and collagen-IV were significantly higher in albuminuric compared to non-albuminuric participants (TGF-ß1; p = 0.039 and collagen-IV; p = 0.042). Urine TGF-ß1 was significantly correlated with non-classical monocyte counts (r = 0.464, p = 0.017). CONCLUSION: Alterations in monocyte subpopulations and urine pro-fibrotic factors may play a role in kidney dysfunction during chronic HIV infection and warrants further study.