RESUMO
While CD4+ T cell depletion is key to disease progression in people living with HIV and SIV-infected macaques, the mechanisms underlying this depletion remain incompletely understood, with most cell death involving uninfected cells. In contrast, SIV infection of "natural" hosts such as sooty mangabeys does not cause CD4+ depletion and AIDS despite high-level viremia. Here, we report that the CARD8 inflammasome is activated immediately after HIV entry by the viral protease encapsulated in incoming virions. Sensing of HIV protease activity by CARD8 leads to rapid pyroptosis of quiescent cells without productive infection, while T cell activation abolishes CARD8 function and increases permissiveness to infection. In humanized mice reconstituted with CARD8-deficient cells, CD4+ depletion is delayed despite high viremia. Finally, we discovered loss-of-function mutations in CARD8 from "natural hosts," which may explain the peculiarly non-pathogenic nature of these infections. Our study suggests that CARD8 drives CD4+ T cell depletion during pathogenic HIV/SIV infections.
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Infecções por HIV , Inflamassomos , Síndrome de Imunodeficiência Adquirida dos Símios , Animais , Humanos , Camundongos , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Progressão da Doença , Infecções por HIV/patologia , Inflamassomos/metabolismo , Proteínas de Neoplasias/metabolismo , Síndrome de Imunodeficiência Adquirida dos Símios/patologia , Vírus da Imunodeficiência Símia/fisiologia , Viremia , HIV/fisiologiaRESUMO
OBJECTIVE: Neurofilament light chain protein (NfL) is a marker of neuronal injury and neurodegeneration. Typically assessed in cerebrospinal fluid, recent advances have allowed this biomarker to be more easily measured in plasma. This study assesses plasma NfL in people with HIV (PWH) compared with people without HIV (PWoH), and its relationship with cognitive impairment, cardiovascular risk, and a neuroimaging metric of brain aging [brain-age gap (BAG)]. DESIGN: One hundred and four PWH (HIV RNA <50âcopies/ml) and 42 PWoH provided blood samples and completed a cardiovascular risk score calculator, neuroimaging, and cognitive testing. METHOD: Plasma NfL was compared between PWoH and PWH and assessed for relationships with age, HIV clinical markers, cardiovascular disease risk, cognition, and BAG (difference between a brain-predicted age and chronological age). RESULTS: Plasma NfL was not significantly different between PWoH and PWH. Higher NfL related to increasing age in both groups. Plasma NfL was not associated with typical HIV disease variables. Within PWH, NfL was higher with higher cardiovascular risk, cognitive impairment and a greater BAG. CONCLUSION: Virally suppressed PWH who are cognitively normal likely do not have significant ongoing neurodegeneration, as evidenced by similar plasma NfL compared with PWoH. However, NfL may represent a biomarker of cognitive impairment and brain aging in PWH. Further research examining NfL with longitudinal cognitive decline is needed to understand this relationship more fully.
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Envelhecimento , Encéfalo , Infecções por HIV , Proteínas de Neurofilamentos , Humanos , Proteínas de Neurofilamentos/sangue , Infecções por HIV/complicações , Infecções por HIV/sangue , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Encéfalo/diagnóstico por imagem , Idoso , Biomarcadores/sangue , Cognição , PlasmaRESUMO
Importance: Cardiovascular disease (CVD) is increased in people with HIV (PWH) and is characterized by premature noncalcified coronary plaque. In the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE), pitavastatin reduced major adverse cardiovascular events (MACE) by 35% over a median of 5.1 years. Objective: To investigate the effects of pitavastatin on noncalcified coronary artery plaque by coronary computed tomography angiography (CTA) and on inflammatory biomarkers as potential mechanisms for MACE prevention. Design, Setting, and Participants: This double-blind, placebo-controlled randomized clinical trial enrolled participants from April 2015 to February 2018 at 31 US clinical research sites. PWH without known CVD who were taking antiretroviral therapy and had low to moderate 10-year CVD risk were included. Data were analyzed from April to November 2023. Intervention: Oral pitavastatin calcium, 4 mg per day. Main Outcomes and Measures: Coronary CTA and inflammatory biomarkers at baseline and 24 months. The primary outcomes were change in noncalcified coronary plaque volume and progression of noncalcified plaque. Results: Of 804 enrolled persons, 774 had at least 1 evaluable CTA. Plaque changes were assessed in 611 who completed both CT scans. Of 611 analyzed participants, 513 (84.0%) were male, the mean (SD) age was 51 (6) years, and the median (IQR) 10-year CVD risk was 4.5% (2.6-7.0). A total of 302 were included in the pitavastatin arm and 309 in the placebo arm. The mean noncalcified plaque volume decreased with pitavastatin compared with placebo (mean [SD] change, -1.7 [25.2] mm3 vs 2.6 [27.1] mm3; baseline adjusted difference, -4.3 mm3; 95% CI, -8.6 to -0.1; P = .04; 7% [95% CI, 1-12] greater reduction relative to placebo). A larger effect size was seen among the subgroup with plaque at baseline (-8.8 mm3 [95% CI, -17.9 to 0.4]). Progression of noncalcified plaque was 33% less likely with pitavastatin compared with placebo (relative risk, 0.67; 95% CI, 0.52-0.88; P = .003). Compared with placebo, the mean low-density lipoprotein cholesterol decreased with pitavastatin (mean change: pitavastatin, -28.5 mg/dL; 95% CI, -31.9 to -25.1; placebo, -0.8; 95% CI, -3.8 to 2.2). The pitavastatin arm had a reduction in both oxidized low-density lipoprotein (-29% [95% CI, -32 to -26] vs -13% [95% CI, -17 to -9]; P < .001) and lipoprotein-associated phospholipase A2 (-7% [95% CI, -11 to -4] vs 14% [95% CI, 10-18]; P < .001) compared with placebo at 24 months. Conclusions and Relevance: In PWH at low to moderate CVD risk, 24 months of pitavastatin reduced noncalcified plaque volume and progression as well as markers of lipid oxidation and arterial inflammation. These changes may contribute to the observed MACE reduction in REPRIEVE. Trial Registration: ClinicalTrials.gov Identifier: NCT02344290.
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Doenças Cardiovasculares , Doença da Artéria Coronariana , Infecções por HIV , Inibidores de Hidroximetilglutaril-CoA Redutases , Placa Aterosclerótica , Quinolinas , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Método Duplo-Cego , Placa Aterosclerótica/diagnóstico por imagem , Placa Aterosclerótica/tratamento farmacológico , Inflamação/tratamento farmacológico , Doenças Cardiovasculares/tratamento farmacológico , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Biomarcadores , Lipoproteínas LDLRESUMO
Persistent immune activation is linked to an increased risk of cardiovascular disease (CVD) in people with HIV (PWH) on antiretroviral therapy (ART). The NLRP3 inflammasome may contribute to elevated CVD risk in PWH. This study utilized peripheral blood mononuclear cells (PBMCs) from 25 PWH and 25 HIV-negative controls, as well as HIV in vitro infections. Transcriptional changes were analyzed using RNAseq and pathway analysis. Our results showed that in vitro HIV infection of macrophages and PBMCs from PWH had increased foam cell formation and expression of the NLRP3 inflammasome components and downstream cytokines (caspase-1, IL-1ß, and IL-18), which was reduced with inhibition of NLRP3 activity using MCC950. Transcriptomic analysis revealed an increased expression of multiple genes involved in lipid metabolism, cholesterol storage, coronary microcirculation disorders, ischemic events, and monocyte/macrophage differentiation and function with HIV infection and oxLDL treatment. HIV infection and NLRP3 activation increased foam cell formation and expression of proinflammatory cytokines, providing insights into the mechanisms underlying HIV-associated atherogenesis. This study suggests that HIV itself may contribute to increased CVD risk in PWH. Understanding the involvement of the inflammasome pathway in HIV atherosclerosis can help identify potential therapeutic targets to mitigate cardiovascular risks in PWH.
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Aterosclerose , Células Espumosas , Infecções por HIV , Humanos , Aterosclerose/imunologia , Citocinas , Células Espumosas/imunologia , Infecções por HIV/complicações , Infecções por HIV/imunologia , Inflamassomos/metabolismo , Interleucina-1beta/metabolismo , Leucócitos Mononucleares/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismoRESUMO
BACKGROUND: Cytomegalovirus (CMV) seropositivity is associated with poor outcomes, including physical function impairment, in people without HIV. We examined associations between CMV IgG titer and physical function in virologically suppressed people with HIV (PWH). METHODS: REPRIEVE is a double-blind randomized trial evaluating pitavastatin for primary prevention of atherosclerotic cardiovascular disease in PWH. This analysis focused on participants enrolled in a substudy with additional biomarker testing, imaging [coronary CT angiography], and physical function measures at entry. CMV IgG was measured using quantitative enzyme immunoassay, physical function by Short Physical Performance Battery, and muscle density and area by CT. Associations between CMV IgG (risk factor) and outcomes were evaluated using the partial Spearman correlation and linear and log-binomial regression. RESULTS: Among 717 participants, 82% male, the median CMV IgG was 2716 (Q1, Q3: 807, 6672) IU/mL, all above the limit of quantification. Among 631 participants with imaging, there was no association between CMV IgG and CT-based muscle density or area, controlling for age (r = -0.03 and r = -0.01, respectively; P ≥ 0.38). Among 161 participants with physical function data, higher CMV IgG was associated with poorer overall modified Short Physical Performance Battery score ( P = 0.02), adjusted for age, nadir CD4, and high-sensitivity C-reactive protein. CONCLUSIONS: Higher CMV IgG titer was associated with poorer physical function, not explained by previous immune compromise, inflammation, or muscle density or area. Further mechanistic studies are needed to understand this association and whether CMV-specific therapy can affect physical function in PWH.
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Infecções por Citomegalovirus , Infecções por HIV , Humanos , Masculino , Feminino , Citomegalovirus , Infecções por Citomegalovirus/complicações , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Músculos , Imunoglobulina G , Anticorpos AntiviraisRESUMO
Despite the development of antiretroviral therapy (ART), HIV-associated distal sensory polyneuropathy remains prevalent. Using SIV-infected rhesus macaques, this study examined molecular mechanisms of peripheral and central sensitization to infer chronic pain from HIV infection. Previous studies identified atrophy in nociceptive neurons during SIV infection, which was associated with monocyte infiltration into the dorsal root ganglia (DRG). However, the sensory signaling mechanism connecting this pathology to symptoms remains unclear, especially because pain persists after resolution of high viremia and inflammation with ART. We hypothesized that residual DRG and dorsal horn neuroinflammation contributes to nociceptive sensitization. Using three cohorts of macaques [uninfected (SIV-), SIV-infected (SIV+), and SIV infected with ART (SIV+/ART)], this study showed an increase in the cellular and cytokine inflammatory profiles in the DRG of SIV+/ART macaques compared with uninfected animals. It found significant increase in the expression of nociceptive ion channels, TRPV1, and TRPA1 among DRG neurons in SIV+/ART compared with uninfected animals. SIV-infected and SIV+/ART animals showed reduced innervation of the nonpeptidergic nociceptors into the dorsal horn compared with uninfected animals. Finally, there were a significantly higher number of CD68+ cells in the dorsal horn of SIV+/ART macaques compared with uninfected animals. In summary, these data demonstrate that neuroinflammation, characteristics of nociceptor sensitization, and central terminal atrophy persists in SIV+/ART animals.
Assuntos
Infecções por HIV , Síndrome de Imunodeficiência Adquirida dos Símios , Vírus da Imunodeficiência Símia , Animais , Infecções por HIV/patologia , Síndrome de Imunodeficiência Adquirida dos Símios/complicações , Síndrome de Imunodeficiência Adquirida dos Símios/patologia , Vírus da Imunodeficiência Símia/fisiologia , Nociceptores/patologia , Macaca mulatta , Doenças Neuroinflamatórias , Gânglios Espinais/patologia , Atrofia/patologiaRESUMO
A biologically relevant non-human primate (NHP) model of HIV persistence in the central nervous system (CNS) is necessary. Most current NHP/SIV models of HIV infection fail to recapitulate viral persistence in the CNS without encephalitis or fail to employ viruses that authentically represent the ongoing HIV-1 pandemic. Here, we demonstrate viral replication in the brain and neuropathogenesis after combination antiretroviral therapy (ART) in rhesus macaques (RMs) using novel macrophage-tropic transmitted/founder (TF) simian-human immunodeficiency virus SHIV.D.191,859 (SHIV.D). Quantitative immunohistochemistry (IHC) and DNA/RNAscope in situ hybridization (ISH) were performed on three brain regions from six SHIV.D-infected RMs; two necropsied while viremic, two during analytical treatment interruptions, and two on suppressive ART. We demonstrated myeloid-mediated neuroinflammation, viral replication, and proviral DNA in the brain in all animals. These results demonstrate that TF SHIV.D models native HIV-1 CNS replication, pathogenesis, and persistence on ART in rhesus macaques.
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Infecções por HIV , HIV-1 , Síndrome de Imunodeficiência Adquirida dos Símios , Vírus da Imunodeficiência Símia , Animais , Humanos , Macaca mulatta , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Infecções por HIV/tratamento farmacológico , Terapia Antirretroviral de Alta Atividade , Vírus da Imunodeficiência Símia/genética , Encéfalo , HIV-1/genética , Replicação Viral/fisiologia , Carga ViralRESUMO
Within arterial plaque, HIV infection creates a state of inflammation and immune activation, triggering NLRP3/caspase-1 inflammasome, tissue damage, and monocyte/macrophage infiltration. Previously, we documented that caspase-1 activation in myeloid cells was linked with HIV-associated atherosclerosis in mice and people with HIV. Here, we mechanistically examined the direct effect of caspase-1 on HIV-associated atherosclerosis. Caspase-1-deficient (Casp-1-/-) mice were crossed with HIV-1 transgenic (Tg26+/-) mice with an atherogenic ApoE-deficient (ApoE-/-) background to create global caspase-1-deficient mice (Tg26+/-/ApoE-/-/Casp-1-/-). Caspase-1-sufficient (Tg26+/-/ApoE-/-/Casp-1+/+) mice served as the controls. Next, we created chimeric hematopoietic cell-deficient mice by reconstituting irradiated ApoE-/- mice with bone marrow cells transplanted from Tg26+/-/ApoE-/-/Casp-1-/- (BMT Casp-1-/-) or Tg26+/-/ApoE-/-/Casp-1+/+ (BMT Casp-1+/+) mice. Global caspase-1 knockout in mice suppressed plaque deposition in the thoracic aorta, serum IL-18 levels, and ex vivo foam cell formation. The deficiency of caspase-1 in hematopoietic cells resulted in reduced atherosclerotic plaque burden in the whole aorta and aortic root, which was associated with reduced macrophage infiltration. Transcriptomic analyses of peripheral mononuclear cells and splenocytes indicated that caspase-1 deficiency inhibited caspase-1 pathway-related genes. These results document the critical atherogenic role of caspase-1 in chronic HIV infection and highlight the implication of this pathway and peripheral immune activation in HIV-associated atherosclerosis.
Assuntos
Aterosclerose , Infecções por HIV , HIV-1 , Placa Aterosclerótica , Animais , Camundongos , Apolipoproteínas E/genética , Aterosclerose/genética , Caspase 1/genética , Infecções por HIV/complicações , Infecções por HIV/genética , Placa Aterosclerótica/genéticaRESUMO
In this study, we demonstrate the safety and utility of CRISPR-Cas9 gene editing technology for in vivo editing of proviral DNA in ART-treated, virally controlled simian immunodeficiency virus (SIV) infected rhesus macaques, an established model for HIV infection. EBT-001 is an AAV9-based vector delivering SaCas9 and dual guide RNAs designed to target multiple regions of the SIV genome: the viral LTRs, and the Gag gene. The results presented here demonstrate that a single IV inoculation of EBT-001 at each of 3 dose levels (1.4 × 1012, 1.4 × 1013 and 1.4 × 1014 genome copies/kg) resulted in broad and functional biodistribution of AAV9-EBT-001 to known tissue reservoirs of SIV. No off-target effects or abnormal pathology were observed, and animals returned to their normal body weight after receiving EBT-001. Importantly, the macaques that received the 2 highest doses of EBT-001 showed improved absolute lymphocyte counts as compared to antiretroviral-treated controls. Taken together, these results demonstrate safety, biodistribution, and in vivo proviral DNA editing following IV administration of EBT-001, supporting the further development of CRISPR-based gene editing as a potential therapeutic approach for HIV in humans.
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BACKGROUND: Pericoronary adipose tissue (PCAT) may influence plaque development through inflammatory mechanisms. We assessed PCAT density, as a measure of pericoronary inflammation, in relationship to coronary plaque among people with human immunodeficiency virus (HIV [PWH]) and to a matched control population. METHODS: In this baseline analysis of 727 participants of the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) Mechanistic Substudy, we related computed tomography-derived PCAT density to presence and extent (Leaman score) of coronary artery disease (CAD), noncalcified plaque, coronary artery calcium (CAC), and vulnerable plaque features using multivariable logistic regression analyses. We further compared the PCAT density between PWH and age, sex, body mass index, CAC score, and statin use-matched controls from the community-based Framingham Heart Study (N = 464), adjusting for relevant clinical covariates. RESULTS: Among 727 REPRIEVE participants (age 50.8 ± 5.8 years; 83.6% [608/727] male), PCAT density was higher in those with (vs without) coronary plaque, noncalcified plaque, CAC >0, vulnerable plaque, and high CAD burden (Leaman score >5) (P < .001 for each comparison). PCAT density related to prevalent coronary plaque (adjusted odds ratio [per 10 HU]: 1.44; 95% confidence interval, 1.22-1.70; P < .001), adjusted for clinical cardiovascular risk factors, body mass index, and systemic immune/inflammatory biomarkers. Similarly, PCAT density related to CAC >0, noncalcified plaque, vulnerable plaque, and Leaman score >5 (all P ≤ .002). PCAT density was greater among REPRIEVE participants versus Framingham Heart Study (-88.2 ± 0.5 HU versus -90.6 ± 0.4 HU; P < .001). CONCLUSIONS: Among PWH in REPRIEVE, a large primary cardiovascular disease prevention cohort, increased PCAT density independently associated with prevalence and severity of coronary plaque, linking increased coronary inflammation to CAD in PWH.
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Doença da Artéria Coronariana , Infecções por HIV , Placa Aterosclerótica , Humanos , Masculino , Pessoa de Meia-Idade , Tecido Adiposo/diagnóstico por imagem , Biomarcadores , Angiografia Coronária , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/complicações , Vasos Coronários/diagnóstico por imagem , HIV , Infecções por HIV/complicações , Infecções por HIV/epidemiologia , Inflamação/complicações , Placa Aterosclerótica/diagnóstico por imagem , Placa Aterosclerótica/epidemiologia , Placa Aterosclerótica/complicaçõesRESUMO
Post-translational glycosylation of the HIV-1 envelope protein involving precursor glycan trimming by mannosyl oligosaccharide glucosidase (MOGS) is critically important for morphogenesis of virions and viral entry. Strategic editing of the MOGS gene in T lymphocytes and myeloid origin cells harboring latent proviral DNA results in the production of non-infectious particles upon treatment of cells with latency reversal agents. Controlled activation of CRISPR-MOGS by rebound HIV-1 mitigates production of infectious particles that exhibit poor ability of the virus to penetrate uninfected cells. Moreover, exclusive activation of CRISPR in cells infected with HIV-1 alleviates concern for broad off-target impact of MOGS gene ablation in uninfected cells. Combination CRISPR treatment of peripheral blood lymphocytes prepared from blood of people with HIV-1 (PWH) tailored for editing the MOGS gene (CRISPR-MOGS) and proviral HIV-1 DNA (CRISPR-HIV) revealed a cooperative impact of CRISPR treatment in inhibiting the production of infectious HIV-1 particles. Our design for genetic inactivation of MOGS by CRISPR exhibits no detectable off-target effects on host cells or any deleterious impact on cell survival and proliferation. Our findings offer the development of a new combined gene editing-based cure strategy for the diminution of HIV-1 spread after cessation of antiretroviral therapy (ART) and its elimination.
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BACKGROUND: While antiretroviral therapy (ART) has improved outcomes for people with HIV (PWH), brain dysfunction is still evident. Immune activation and inflammation remain elevated in PWH receiving ART, thereby contributing to morbidity and mortality. Previous studies demonstrated reduced functional and structural changes in PWH; however, underlying mechanisms remain elusive. METHODS: Our cohort consisted of PWH with ART adherence and viral suppression ( < 50 copies/mL; N = 173). Measurements included immune cell markers of overall immune health (CD4/CD8 T-cell ratio) and myeloid inflammation (CD16+ monocytes), plasma markers of inflammatory status (soluble CD163 and CD14), and structural and functional neuroimaging (volume and cerebral blood flow [CBF], respectively). RESULTS: Decreased CD4/CD8 ratios correlated with reduced brain volume, and higher levels of inflammatory CD16+ monocytes were associated with reduced brain volume in total cortex and gray matter. An increase in plasma soluble CD14-a marker of acute peripheral inflammation attributed to circulating microbial products-was associated with reduced CBF within the frontal, parietal, temporal, and occipital cortices and total gray matter. CONCLUSIONS: CD4/CD8 ratio and number of CD16+ monocytes, which are chronic immune cell markers, are associated with volumetric loss in the brain. Additionally, this study shows a potential new association between plasma soluble CD14 and CBF.
Assuntos
Infecções por HIV , Receptores de Lipopolissacarídeos , Humanos , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Inflamação , Biomarcadores , Monócitos , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismoRESUMO
BACKGROUND: Increased renin angiotensin aldosterone system (RAAS) activity may contribute to excess cardiovascular disease in people with HIV (PWH). We investigated how RAAS blockade may improve myocardial perfusion, injury, and function among well-treated PWH. METHODS: Forty PWH, on stable ART, without known heart disease were randomized to eplerenone 50 mg PO BID (n = 20) or identical placebo (n = 20) for 12 months. The primary endpoints were (1) myocardial perfusion assessed by coronary flow reserve (CFR) on cardiac PET or stress myocardial blood flow (sMBF) on cardiac MRI or (2) myocardial inflammation by extracellular mass index (ECMi) on cardiac MRI. RESULTS: Beneficial effects on myocardial perfusion were seen for sMBF by cardiac MRI (mean [SD]: 0.09 [0.56] vs -0.53 [0.68] mL/min/g; P = .03) but not CFR by cardiac PET (0.01 [0.64] vs -0.07 [0.48]; P = .72, eplerenone vs placebo). Eplerenone improved parameters of myocardial function on cardiac MRI including left ventricular end diastolic volume (-13 [28] vs 10 [26] mL; P = .03) and global circumferential strain (GCS; median [interquartile range 25th-75th]: -1.3% [-2.9%-1.0%] vs 2.3% [-0.4%-4.1%]; P = .03), eplerenone versus placebo respectively. On cardiac MRI, improvement in sMBF related to improvement in global circumferential strain (ρ = -0.65, P = .057) among those treated with eplerenone. Selecting for those with impaired myocardial perfusion (CFR <2.5 and/or sMBF <1.8), there was a treatment effect of eplerenone versus placebo to improve CFR (0.28 [0.27] vs -0.05 [0.36]; P = .04). Eplerenone prevented a small increase in troponin (0.00 [-0.13-0.00] vs 0.00 [0.00-0.74] ng/L; P = .03) without effects on ECMi (0.9 [-2.3-4.3] vs -0.7 [-2.2--0.1] g/m2; P = .38). CD4+ T-cell count (127 [-38-286] vs -6 [-168-53] cells/µL; P = .02) increased in the eplerenone- versus placebo-treated groups. CONCLUSIONS: RAAS blockade with eplerenone benefitted key indices and prevented worsening of myocardial perfusion, injury, and function among PWH with subclinical cardiac disease when compared with placebo. CLINICAL TRIALS REGISTRATION: NCT02740179 (https://clinicaltrials.gov/ct2/show/NCT02740179?term=NCT02740179&draw=2&rank=1).
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Infecções por HIV , Espironolactona , Humanos , Eplerenona/farmacologia , HIV , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Perfusão , Espironolactona/farmacologiaRESUMO
BACKGROUND: People with human immunodeficiency virus (HIV) have heightened incidence/risk of diastolic dysfunction and heart failure. Women with HIV have elevated cardiac fibrosis, and plasma osteopontin (Opn) is correlated to cardiac pathology. Therefore, this study provides mechanistic insight into the relationship between osteopontin and cardiac fibrosis during HIV infection. METHODS: Mouse embryonic fibroblasts (MEFs) modeled cardiac fibroblasts in vitro. Simian immunodeficiency virus (SIV)-infected macaques with or without antiretroviral therapy and HIV-infected humanized mice modeled HIV-associated cardiac fibrosis. RESULTS: Lipopolysaccharide-stimulated MEFs were myofibroblast-like, secreted cytokines, and produced Opn transcripts. SIV-infected animals had elevated plasma Opn at necropsy, full-length Opn in the ventricle, and ventricular interstitial fibrosis. Regression modeling identified growth differentiation factor 15, CD14+CD16+ monocytes, and CD163 expression on CD14+CD16+ monocytes as independent predictors of plasma Opn during SIV infection. HIV-infected humanized mice showed increased interstitial fibrosis compared to uninfected/untreated animals, and systemic inhibition of osteopontin by RNA aptamer reduced left ventricle fibrosis in HIV-infected humanized mice. CONCLUSIONS: Since Opn is elevated in the plasma and left ventricle during SIV infection and systemic inhibition of Opn reduced cardiac fibrosis in HIV-infected mice, Opn may be a potential target for adjunctive therapies to reduce cardiac fibrosis in people with HIV.
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Cardiomiopatias , Infecções por HIV , Síndrome de Imunodeficiência Adquirida dos Símios , Vírus da Imunodeficiência Símia , Humanos , Animais , Feminino , Camundongos , Infecções por HIV/patologia , Osteopontina/genética , Osteopontina/metabolismo , Fibroblastos , Coração , Cardiomiopatias/patologia , Vírus da Imunodeficiência Símia/fisiologia , Fibrose , Macaca/metabolismo , HIVRESUMO
Treatment of HIV-1ADA-infected CD34+ NSG-humanized mice with long-acting ester prodrugs of cabotegravir, lamivudine, and abacavir in combination with native rilpivirine was followed by dual CRISPR-Cas9 C-C chemokine receptor type five (CCR5) and HIV-1 proviral DNA gene editing. This led to sequential viral suppression, restoration of absolute human CD4+ T cell numbers, then elimination of replication-competent virus in 58% of infected mice. Dual CRISPR therapies enabled the excision of integrated proviral DNA in infected human cells contained within live infected animals. Highly sensitive nucleic acid nested and droplet digital PCR, RNAscope, and viral outgrowth assays affirmed viral elimination. HIV-1 was not detected in the blood, spleen, lung, kidney, liver, gut, bone marrow, and brain of virus-free animals. Progeny virus from adoptively transferred and CRISPR-treated virus-free mice was neither detected nor recovered. Residual HIV-1 DNA fragments were easily seen in untreated and viral-rebounded animals. No evidence of off-target toxicities was recorded in any of the treated animals. Importantly, the dual CRISPR therapy demonstrated statistically significant improvements in HIV-1 cure percentages compared to single treatments. Taken together, these observations underscore a pivotal role of combinatorial CRISPR gene editing in achieving the elimination of HIV-1 infection.
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Infecções por HIV , Soropositividade para HIV , Camundongos , Animais , Humanos , Antirretrovirais/uso terapêutico , Edição de Genes , Provírus/genética , Receptores CCR5RESUMO
People with human immunodeficiency virus have an increased risk of developing cardiovascular disease. RNA-Seq was performed on hearts from simian immunodeficiency virus (SIV)-infected rhesus macaques with or without antiretroviral therapy (ART). SIV infection led to high plasma viral load with very little myocardial viral RNA. SIV infection promoted an inflammatory environment in the heart through interferon and pathogen signaling, in the absence of myocardial viral RNA. While ART dampened interferon and cytokine response in the heart, SIV-infected animals receiving ART had deficits in the expression of genes directly involved in fatty acid metabolism relative to SIV-uninfected animals.
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Infecções por HIV , Miocardite , Síndrome de Imunodeficiência Adquirida dos Símios , Vírus da Imunodeficiência Símia , Animais , Humanos , Vírus da Imunodeficiência Símia/fisiologia , Síndrome de Imunodeficiência Adquirida dos Símios/complicações , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Macaca mulatta , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Interferons , RNA Viral , Inflamação , Carga ViralRESUMO
Despite viral suppression with antiretroviral therapy (ART), people with human immunodeficiency virus (HIV) continue to experience central nervous system (CNS) complications, primarily in the form of mild cognitive impairment and mental health disorders (eg, depression, anxiety, other neuropsychiatric problems). The multifactorial pathogenesis and heterogeneity of mechanisms likely underlying CNS complications must be addressed in the development of preventive interventions and effective treatments. The biotyping approach has previously been useful to define phenotypes of other CNS diseases based on underlying mechanisms and could be translated to the field of neuroHIV. The purpose of the Biotype Workshop series, and the Virology, Immunology and Neuropathology Working Group in particular, is to capitalize on current and new technologies and guide future research efforts using the wealth of available immunological, virologic, and neuropathological data collected from people with HIV on and off ART.
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Doenças do Sistema Nervoso Central , Disfunção Cognitiva , Infecções por HIV , HIV-1 , Humanos , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Doenças do Sistema Nervoso Central/etiologia , Sistema Nervoso CentralRESUMO
Background: Inflammasome activation is increased in people with human immunodeficiency virus (PWH), but its relationship with coronary plaque is poorly understood in this setting. Methods: In a large human immunodeficiency virus cardiovascular prevention cohort, relationships between caspase-1, interleukin (IL)-1ß, and IL-18 and coronary plaque indices were assessed by multivariate logistic regression. Results: Higher IL-18 and IL-1ß were associated with Leaman score, an integrative measure of plaque burden and composition. Conclusions: As Leaman score >5 is associated with cardiovascular events in the general population, future work is needed to determine how the inflammasome relates to events and whether strategies to reduce its activation affect events or plaque progression among PWH.
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OBJECTIVE: To investigate relationships between Life's Simple 7 (LS7), an assessment of cardiovascular health (CVH), and coronary plaque among people with HIV (PWH). DESIGN: Cross-sectional. METHODS: Coronary computed tomography angiography, immune/inflammatory biomarkers, and characterization of LS7 were collected among a subset of ART-treated PWH enrolled in REPRIEVE, a primary prevention trial. Analyses adjusted for cardiovascular disease risk (ASCVD score). RESULTS: Median age of the 735 participants was 51(±6) years, 16% female, and median (Q1-Q3) CVD risk was 4.5% (2.6-6.9). Forty percent had poor (≤2 ideal components), 51% had intermediate (three or four ideal components), and only 9% had ideal CVH (≥5). Coronary plaque was present in 357 (49%); 167 (23%) had one or more vulnerable plaque features, 293 (40%) had noncalcified plaque, and 242 (35%) had a coronary artery calcium score >0. All three phenotypes were increasingly more prevalent with poorer CVH and these relationships remained after adjusting for ASCVD risk. Poor CVH was associated with higher high-sensitivity C-reactive protein, oxidized low-density cholesterol, and interleukin-6. The relationship of LS7 to plaque remained after adjusting for these biomarkers. CONCLUSIONS: Among PWH, poor CVH as measured by LS7 was associated with coronary plaque presence, vulnerable features, and calcification. LS7 was also associated with selected biomarkers; adjustment for these and ASCVD score reduced but did not eliminate LS7's association with plaque, suggesting the possibility of additional protective mechanisms against atherogenesis and plaque remodeling. Clinical use of LS7 and further exploration of its relationships with coronary artery disease may enhance efforts to reduce cardiovascular morbidity and mortality in PWH. CLINICAL TRIALS REGISTRATION: NCT02344290.