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1.
AIDS ; 2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38905489

RESUMO

People with human immunodeficiency virus (HIV, PWH) face an increased risk of cardiovascular disease (CVD) compared to the general population. We previously demonstrated that people with (versus without) HIV have higher macrophage-specific arterial infiltration in relation to systemic monocyte activation. We now show that select T lymphocyte subpopulations (naïve CD4+, effector memory CD4+, and central memory CD8+) are differentially associated with macrophage-specific arterial infiltration among participants with versus without HIV, with evidence of interaction by HIV status. Our results suggest that among PWH, circulating T lymphocytes associate with macrophage-specific arterial infiltration, of relevance to atherogenesis and CVD risk. CLINICAL TRIALS REGISTRATION: NCT02542371.

2.
Artigo em Inglês | MEDLINE | ID: mdl-38787309

RESUMO

Despite antiretroviral therapy (ART), people living with HIV (PLWH) are at increased risk of developing cardiovascular disease (CVD) and HIV-associated neurocognitive disorder (HAND), among other comorbidities. Studies from ART-treated individuals identified galectin-3 (gal-3) and interleukin (IL)-18 as CVD biomarkers, galectin-9 (gal-9) as a HAND biomarker, and sCD163, a marker of monocyte/macrophage activation, as a biomarker of both. We asked if plasma gal-3, gal-9, and IL-18 are associated with an individual comorbidity or increase in both with animals that develop AIDS with both pathologies versus (CVD-path) alone or simian immunodeficiency virus encephalitis (SIVE) alone. We found that no biomarkers were selective between individual pathologies, and all biomarkers increased with co-development of CVD-path and SIVE (gal-3, p = 0.11; gal-9, p = 0.001; IL-18, p = 0.007; sCD163, p < 0.001; %BrdU p = 0.02). Although gal-3, gal-9, and IL-18 did not distinguish between pathologies, they correlated strongly with one another, with sCD163, a marker of monocyte/macrophage activation, and the %BrdU monocytes, a marker of monocyte turnover. Compared to animals with CVD-path or SIVE alone, animals that co-developed both pathologies had consistently elevated IL-18 throughout infection (p = 0.02) and increased sCD163 in late infection (p = 0.01). These data indicate that gal-3, gal-9, and IL-18 are associated with monocyte/macrophage activation by sCD163 and monocyte turnover by the %BrdU+ monocytes more so than CVD-path or SIVE.

3.
Front Immunol ; 14: 1240946, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37965349

RESUMO

Despite effective antiretroviral therapy, HIV co-morbidities remain where central nervous system (CNS) neurocognitive disorders and cardiovascular disease (CVD)-pathology that are linked with myeloid activation are most prevalent. Comorbidities such as neurocogntive dysfunction and cardiovascular disease (CVD) remain prevalent among people living with HIV. We sought to investigate if cardiac pathology (inflammation, fibrosis, cardiomyocyte damage) and CNS pathology (encephalitis) develop together during simian immunodeficiency virus (SIV) infection and if their co-development is linked with monocyte/macrophage activation. We used a cohort of SIV-infected rhesus macaques with rapid AIDS and demonstrated that SIV encephalitis (SIVE) and CVD pathology occur together more frequently than SIVE or CVD pathology alone. Their co-development correlated more strongly with activated myeloid cells, increased numbers of CD14+CD16+ monocytes, plasma CD163 and interleukin-18 (IL-18) than did SIVE or CVD pathology alone, or no pathology. Animals with both SIVE and CVD pathology had greater numbers of cardiac macrophages and increased collagen and monocyte/macrophage accumulation, which were better correlates of CVD-pathology than SIV-RNA. Animals with SIVE alone had higher levels of activated macrophage biomarkers and cardiac macrophage accumulation than SIVnoE animals. These observations were confirmed in HIV infected individuals with HIV encephalitis (HIVE) that had greater numbers of cardiac macrophages and fibrosis than HIV-infected controls without HIVE. These results underscore the notion that CNS and CVD pathologies frequently occur together in HIV and SIV infection, and demonstrate an unmet need for adjunctive therapies targeting macrophages.


Assuntos
Complexo AIDS Demência , Síndrome da Imunodeficiência Adquirida , Doenças Cardiovasculares , Encefalite , Infecções por HIV , Síndrome de Imunodeficiência Adquirida dos Símios , Vírus da Imunodeficiência Símia , Animais , Humanos , Vírus da Imunodeficiência Símia/fisiologia , Macaca mulatta , Síndrome de Imunodeficiência Adquirida dos Símios/complicações , Síndrome de Imunodeficiência Adquirida dos Símios/patologia , Fibrose
4.
J Infect Dis ; 226(10): 1823-1833, 2022 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-35856671

RESUMO

BACKGROUND: Persistent immune activation is thought to contribute to heightened atherosclerotic cardiovascular disease (ASCVD) risk among people with human immunodeficiency virus (PWH). METHODS: Participants (≥18 years) with or without human immunodeficiency virus (HIV) and without history of clinical ASCVD were enrolled. We hypothesized that increased macrophage-specific arterial infiltration would relate to plaque composition and systemic immune activation among PWH. We applied a novel targeted molecular imaging approach (technetium-99m [99mTc]-tilmanocept single photon emission computed tomography [SPECT]/CT) and comprehensive immune phenotyping. RESULTS: Aortic 99mTc-tilmanocept uptake was significantly higher among PWH (n = 20) than participants without HIV (n = 10) with similar 10-year ASCVD risk (P = .02). Among PWH, but not among participants without HIV, noncalcified aortic plaque volume related directly to aortic 99mTc-tilmanocept uptake at different uptake thresholds. An interaction (P = .001) was seen between HIV status and noncalcified plaque volume, but not calcified plaque (P = .83). Systemic levels of caspase-1 (P = .004), CD14-CD16+ (nonclassical/patrolling/homing) monocytes (P = .0004) and CD8+ T cells (P = .005) related positively and CD4+/CD8+ T-cell ratio (P = .02) inversely to aortic 99mTc-tilmanocept uptake volume. CONCLUSIONS: Macrophage-specific arterial infiltration was higher among PWH and related to noncalcified aortic plaque volume only among PWH. Key systemic markers of immune activation relating to macrophage-specific arterial infiltration may contribute to heightened ASCVD risk among PWH. CLINICAL TRIALS REGISTRATION: NCT02542371.


Assuntos
Aterosclerose , Infecções por HIV , Placa Aterosclerótica , Humanos , Placa Aterosclerótica/diagnóstico por imagem , Infecções por HIV/tratamento farmacológico , Macrófagos , HIV
5.
Viruses ; 14(2)2022 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-35216002

RESUMO

Before the antiretroviral therapy (ART) era, people living with HIV (PLWH) experienced complications due to AIDS more so than aging. With ART and the extended lifespan of PLWH, HIV comorbidities also include aging-most likely due to accelerated aging-as well as a cardiovascular, neurocognitive disorders, lung and kidney disease, and malignancies. The broad evidence suggests that HIV with ART is associated with accentuated aging, and that the age-related comorbidities occur earlier, due in part to chronic immune activation, co-infections, and possibly the effects of ART alone. Normally the immune system undergoes alterations of lymphocyte and monocyte populations with aging, that include diminished naïve T- and B-lymphocyte numbers, a reliance on memory lymphocytes, and a skewed production of myeloid cells leading to age-related inflammation, termed "inflamm-aging". Specifically, absolute numbers and relative proportions of monocytes and monocyte subpopulations are skewed with age along with myeloid mitochondrial dysfunction, resulting in increased accumulation of reactive oxygen species (ROS). Additionally, an increase in biomarkers of myeloid activation (IL-6, sCD14, and sCD163) occurs with chronic HIV infection and with age, and may contribute to immunosenescence. Chronic HIV infection accelerates aging; meanwhile, ART treatment may slow age-related acceleration, but is not sufficient to stop aging or age-related comorbidities. Overall, a better understanding of the mechanisms behind accentuated aging with HIV and the effects of myeloid activation and turnover is needed for future therapies.


Assuntos
Infecções por HIV/imunologia , Imunossenescência , Monócitos/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Animais , Biomarcadores , Infecções por HIV/patologia , HIV-1/imunologia , Humanos , Inflamação/imunologia , Monócitos/virologia , Síndrome de Imunodeficiência Adquirida dos Símios/patologia , Vírus da Imunodeficiência Símia/imunologia
6.
Front Immunol ; 12: 709962, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34691023

RESUMO

The dynamic nature of the SIV population during disease progression in the SIV/macaque model of AIDS and the factors responsible for its behavior have not been documented, largely owing to the lack of sufficient spatial and temporal sampling of both viral and host data from SIV-infected animals. In this study, we detail Bayesian coalescent inference of the changing collective intra-host viral effective population size (Ne ) from various tissues over the course of infection and its relationship with what we demonstrate is a continuously changing immune cell repertoire within the blood. Although the relative contribution of these factors varied among hosts and time points, the adaptive immune response best explained the overall periodic dynamic behavior of the effective virus population. Data exposing the nature of the relationship between the virus and immune cell populations revealed the plausibility of an eco-evolutionary mathematical model, which was able to mimic the large-scale oscillations in Ne through virus escape from relatively few, early immunodominant responses, followed by slower escape from several subdominant and weakened immune populations. The results of this study suggest that SIV diversity within the untreated host is governed by a predator-prey relationship, wherein differing phases of infection are the result of adaptation in response to varying immune responses. Previous investigations into viral population dynamics using sequence data have focused on single estimates of the effective viral population size (Ne ) or point estimates over sparse sampling data to provide insight into the precise impact of immune selection on virus adaptive behavior. Herein, we describe the use of the coalescent phylogenetic frame- work to estimate the relative changes in Ne over time in order to quantify the relationship with empirical data on the dynamic immune composition of the host. This relationship has allowed us to expand on earlier simulations to build a predator-prey model that explains the deterministic behavior of the virus over the course of disease progression. We show that sequential viral adaptation can occur in response to phases of varying immune pressure, providing a broader picture of the viral response throughout the entire course of progression to AIDS.


Assuntos
Evolução Molecular , Vírus da Imunodeficiência Símia/imunologia , Adaptação Fisiológica , Animais , Teorema de Bayes , Interações entre Hospedeiro e Microrganismos , Macaca mulatta , Filogenia
7.
J Neurovirol ; 27(1): 101-115, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33405206

RESUMO

Despite improvements in antiretroviral therapy, human immunodeficiency virus type 1 (HIV-1)-associated neurocognitive disorders (HAND) remain prevalent in subjects undergoing therapy. HAND significantly affects individuals' quality of life, as well as adherence to therapy, and, despite the increasing understanding of neuropathogenesis, no definitive diagnostic or prognostic marker has been identified. We investigated transcriptomic profiles in frontal cortex tissues of Simian immunodeficiency virus (SIV)-infected Rhesus macaques sacrificed at different stages of infection. Gene expression was compared among SIV-infected animals (n = 11), with or without CD8+ lymphocyte depletion, based on detectable (n = 6) or non-detectable (n = 5) presence of the virus in frontal cortex tissues. Significant enrichment in activation of monocyte and macrophage cellular pathways was found in animals with detectable brain infection, independently from CD8+ lymphocyte depletion. In addition, transcripts of four poly (ADP-ribose) polymerases (PARPs) were up-regulated in the frontal cortex, which was confirmed by real-time polymerase chain reaction. Our results shed light on involvement of PARPs in SIV infection of the brain and their role in SIV-associated neurodegenerative processes. Inhibition of PARPs may provide an effective novel therapeutic target for HIV-related neuropathology.


Assuntos
Transtornos Cognitivos/virologia , Lobo Frontal/metabolismo , Lobo Frontal/virologia , Poli(ADP-Ribose) Polimerases/metabolismo , Síndrome de Imunodeficiência Adquirida dos Símios/metabolismo , Animais , Transtornos Cognitivos/metabolismo , Macaca mulatta , Masculino , Síndrome de Imunodeficiência Adquirida dos Símios/virologia
8.
Virus Evol ; 6(1): veaa005, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32355568

RESUMO

Human immunodeficiency virus (HIV) is a rapidly evolving virus, allowing its genetic sequence to act as a fingerprint for epidemiological processes among, as well as within, individual infected hosts. Though primarily infecting the CD4+ T-cell population, HIV can also be found in monocytes, an immune cell population that differs in several aspects from the canonical T-cell viral target. Using single genome viral sequencing and statistical phylogenetic inference, we investigated the viral RNA diversity and relative contribution of each of these immune cell types to the viral population within the peripheral blood. Results provide evidence of an increased prevalence of circulating monocytes harboring virus in individuals with high viral load in the absence of suppressive antiretroviral therapy. Bayesian phyloanatomic analysis of three of these individuals demonstrated a measurable role for these cells, but not the circulating T-cell population, as a source of cell-free virus in the plasma, supporting the hypothesis that these cells can act as an additional conduit of virus spread.

9.
Am Heart J ; 212: 1-12, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30928823

RESUMO

BACKGROUND: People with HIV (PWH) have increased cardiovascular events, inflammation, and high-risk coronary atherosclerosis. Statin therapy has been shown to lower the risk of cardiovascular disease (CVD) in the general population, but whether this results from reductions in coronary atherosclerosis and is mediated by decreased inflammation remains unknown. METHODS: REPRIEVE is a randomized, placebo-controlled trial of pitavastatin calcium (4 mg/day) vs. placebo enrolling at least 7500 PWH between 40-75 years, on antiretroviral therapy (ART), with low to moderate traditional CVD risk. The Mechanistic Substudy of REPRIEVE (A5333s) is co-enrolling 800 participants from 31 US sites. These participants undergo serial contrast enhanced coronary computed tomography angiography (CCTA) and measurements of biomarkers of inflammation and immune activation at baseline and after 2 years of follow-up. The primary objectives are to determine the effects of pitavastatin on noncalcified coronary atherosclerotic plaque (NCP) volume, low attenuation plaque, and positive remodeling and on changes in immune activation and inflammation and to assess relationships between the two. Changes in CAD will be assessed in a standardized fashion by a core lab with expert readers blinded to time points and participant information; immune activation and inflammation assessment is also performed centrally. RESULTS: To date the Mechanistic Substudy has completed planned enrollment, with 805 participants. CONCLUSION: This study represents the first large, randomized, CCTA-based assessment of the effects of a primary prevention strategy for CVD on high-risk CAD, immune activation and inflammation among PWH. The study will assess pitavastatin's effects on coronary plaque, and the interrelationship of these changes with biomarkers of immune activation and inflammation in PWH to determine mechanisms of CVD prevention and improved outcomes in this population.


Assuntos
Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/prevenção & controle , Infecções por HIV/complicações , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Inflamação/prevenção & controle , Quinolinas/uso terapêutico , Adulto , Idoso , Fármacos Anti-HIV/uso terapêutico , Biomarcadores/sangue , Angiografia por Tomografia Computadorizada , Angiografia Coronária , Doença da Artéria Coronariana/imunologia , Método Duplo-Cego , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Placa Aterosclerótica/diagnóstico por imagem , Placa Aterosclerótica/prevenção & controle , Prevenção Primária , Estudos Prospectivos , Fatores de Risco
10.
Comp Med ; 68(3): 227-232, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29776458

RESUMO

Dextrans have been used extensively as medical therapies and labeling agents in biomedical research to investigate the blood-brain barrier and CSF flow and absorption. Adverse effects from dextrans include anaphylactic reaction and dilation of the cerebral ventricles due to administration into the subarachnoid space. This retrospective study describes 51 rhesus macaques (Macaca mulatta) that received dextran intrathecally. The purpose of intrathecal administration was to enable detection of long-lived, dextran-labeled macrophages and to study monocyte-macrophage turnover in the CNS of SIV- or SHIV- infected and uninfected animals by using immunofluorescence. Of the 51 dextran-treated macaques, 8 that received dextran diluted in saline developed hydrocephalus; 6 of these 8 animals exhibited neurologic signs. In contrast, none of the macaques that received intrathecal dextran diluted in PBS developed hydrocephalus. These data suggest the use of saline diluent and the duration of dextran exposure as potential factors contributing to hydrocephalus after intrathecal dextran in rhesus macaques.


Assuntos
Dextranos/efeitos adversos , Hidrocefalia/etiologia , Injeções Espinhais/veterinária , Macaca mulatta , Solução Salina/efeitos adversos , Animais , Sistema Nervoso Central/citologia , Sistema Nervoso Central/efeitos dos fármacos , Dextranos/administração & dosagem , Dextranos/uso terapêutico , Injeções Espinhais/efeitos adversos , Macrófagos/fisiologia , Estudos Retrospectivos , Solução Salina/administração & dosagem , Fatores de Tempo
11.
PLoS One ; 13(5): e0196949, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29750804

RESUMO

Despite the advent of highly active anti-retroviral therapy HIV-associated neurocognitive disorders (HAND) continue to be a significant problem. Furthermore, the precise pathogenesis of this neurodegeneration is still unclear. The objective of this study was to examine the relationship between infection by the simian immunodeficiency virus (SIV) and neuronal injury in the rhesus macaque using in vivo and postmortem sampling techniques. The effect of SIV infection in 23 adult rhesus macaques was investigated using an accelerated NeuroAIDS model. Disease progression was modulated either with combination anti-retroviral therapy (cART, 4 animals) or minocycline (7 animals). Twelve animals remained untreated. Viral loads were monitored in the blood and cerebral spinal fluid, as were levels of activated monocytes in the blood. Neuronal injury was monitored in vivo using magnetic resonance spectroscopy. Viral RNA was quantified in brain tissue of each animal postmortem using reverse transcription polymerase chain reaction (RT-PCR), and neuronal injury was assessed by immunohistochemistry. Without treatment, viral RNA in plasma, cerebral spinal fluid, and brain tissue appears to reach a plateau. Neuronal injury was highly correlated both to plasma viral levels and a subset of infected/activated monocytes (CD14+CD16+), which are known to traffic the virus into the brain. Treatment with either cART or minocycline decreased brain viral levels and partially reversed alterations in in vivo and immunohistochemical markers for neuronal injury. These findings suggest there is significant turnover of replicating virus within the brain and the severity of neuronal injury is directly related to the brain viral load.


Assuntos
Síndrome da Imunodeficiência Adquirida , Antirretrovirais/farmacologia , Imageamento por Ressonância Magnética , Neurônios/virologia , RNA Viral , Síndrome de Imunodeficiência Adquirida dos Símios , Vírus da Imunodeficiência Símia , Síndrome da Imunodeficiência Adquirida/sangue , Síndrome da Imunodeficiência Adquirida/líquido cefalorraquidiano , Síndrome da Imunodeficiência Adquirida/diagnóstico por imagem , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Animais , Modelos Animais de Doenças , Macaca mulatta , Minociclina , RNA Viral/sangue , RNA Viral/líquido cefalorraquidiano , Síndrome de Imunodeficiência Adquirida dos Símios/sangue , Síndrome de Imunodeficiência Adquirida dos Símios/líquido cefalorraquidiano , Síndrome de Imunodeficiência Adquirida dos Símios/diagnóstico por imagem , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico
12.
Handb Clin Neurol ; 152: 41-53, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29604983

RESUMO

It is difficult to study the pathogenesis of human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) in living patients because central nervous system (CNS) tissues are only available post mortem. Rodent and nonhuman primate (NHP) models of HAND allow for longitudinal analysis of HIV-associated CNS pathology and efficacy studies of novel therapeutics. Rodent models of HAND allow for studies with large sample sizes, short duration, and relatively low cost. These models include humanized mice used to study HIV-associated neuropathogenesis and transgenic mice used to study neurotoxic effects of viral proteins without infection. Simian immunodeficiency virus (SIV)-infected NHP are the premier model of neuroAIDS; SIV-associated CNS pathology is similar to HIV-associated CNS pathology with HAND. Additionally, the size, lifespan of NHP, and time to acquired immune deficiency syndrome (AIDS) progression make SIV-infected NHP models optimal for studies of viral latency and reservoirs, and assessing novel therapeutics for neuroAIDS. NHP models of neuroAIDS generally include conventional progressors (AIDS within 2-3 years) and those that have rapid disease (AIDS within 150 days). Rapid AIDS models are achieved by immune modulation and/or infection with neurovirulent and neurosuppressive viral strains and result in a high incidence of SIV-associated encephalitis. In this chapter, we briefly review rodent and NHP models of neuroAIDS, including contributions made using these models to our understanding of HIV-associated CNS disease.


Assuntos
Encéfalo/patologia , Modelos Animais de Doenças , Infecções por HIV/diagnóstico , Doenças do Sistema Nervoso/diagnóstico , Complexo AIDS Demência/diagnóstico , Complexo AIDS Demência/imunologia , Animais , Animais Geneticamente Modificados , Encéfalo/imunologia , Encéfalo/virologia , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/patologia , Sistema Nervoso Central/virologia , Infecções por HIV/imunologia , Humanos , Doenças do Sistema Nervoso/imunologia , Doenças do Sistema Nervoso/virologia , Vírus da Imunodeficiência Símia/imunologia
13.
AIDS ; 32(7): 927-932, 2018 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-29424780

RESUMO

OBJECTIVE: Monocyte/macrophage activation is increased among people with HIV, and may contribute to the heightened risk of atherosclerosis and neurocognitive dysfunction in this population. Insulin-like growth factor 1 (IGF-1) has been shown to attenuate the innate immune response in animal models of atherosclerosis and inflammatory bowel disease. We investigated, for the first time, relationships of circulating IGF-1 with monocyte/macrophage-specific indices among HIV-infected individuals and uninfected controls. DESIGN: Observational. METHODS: One hundred and thirty-one HIV-infected patients and 65 well matched controls without known cardiac disease or viral hepatitis were recruited previously. IGF-1, expressed as a z-score relative to the age-adjusted and sex-adjusted population mean, was related to log-transformed inflammatory markers within HIV and non-HIV groups. RESULTS: In HIV, IGF-1 inversely related to sCD163 (r = -0.28, P = 0.002), sCD14 (r = -0.29, P = 0.002), and high-sensitivity IL-6 (r = -0.27, P = 0.006). There was no association of IGF-1 with high-sensitivity CRP, MCP-1, IL-18, or LPS in HIV, or between IGF-1 and any inflammatory marker in controls. Relationships of IGF-1 with sCD163 and sCD14 remained significant in HIV after controlling for age, sex, smoking, BMI, visceral fat, statin use, viral load, and antiretroviral therapy. For every one-unit decline in IGF-1 z-score, sCD163 and sCD14 increased by 14% (95% CI, 0.23-29%) and 29% (95% CI, 1.4-63%), respectively. CONCLUSION: Low IGF-1 was robustly associated with high sCD163 and sCD14 in HIV. Prospective studies are needed to investigate augmentation of IGF-1 as a novel strategy to reduce monocyte/macrophage activation in this population.


Assuntos
Antígenos CD/sangue , Antígenos de Diferenciação Mielomonocítica/sangue , Infecções por HIV/patologia , Fator de Crescimento Insulin-Like I/análise , Receptores de Lipopolissacarídeos/sangue , Ativação de Macrófagos , Monócitos/imunologia , Receptores de Superfície Celular/sangue , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Carga Viral
14.
J Leukoc Biol ; 103(1): 141-155, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29345061

RESUMO

The progression to AIDS is influenced by changes in the biology of heterogeneous monocyte subsets. Classical (CD14++CD16-), intermediate (CD14++CD16+), and nonclassical (CD14+CD16++) monocytes may represent progressive stages of monocyte maturation or disparate myeloid lineages with different turnover rates and function. To investigate the relationship between monocyte subsets and the response to SIV infection, we performed microarray analysis of monocyte subsets in rhesus macaques at three time points: prior to SIV infection, 26 days postinfection, and necropsy with AIDS. Genes with a 2-fold change between monocyte subsets (2023 genes) or infection time points (424 genes) were selected. We identify 172 genes differentially expressed among monocyte subsets in both uninfected and SIV-infected animals. Classical monocytes express genes associated with inflammatory responses and cell proliferation. Nonclassical monocytes express genes associated with activation, immune effector functions, and cell cycle inhibition. The classical and intermediate subsets are most similar at all time points, and transcriptional similarity between intermediate and nonclassical monocytes increases with AIDS. Cytosolic sensors of nucleic acids, restriction factors, and IFN-stimulated genes are induced in all three subsets with AIDS. We conclude that SIV infection alters the transcriptional relationship between monocyte subsets and that the innate immune response to SIV infection is conserved across monocyte subsets.


Assuntos
Fatores Reguladores de Interferon/metabolismo , Interferons/farmacologia , Monócitos/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Vírus da Imunodeficiência Símia/imunologia , Transcriptoma , Animais , Células Cultivadas , Perfilação da Expressão Gênica , Fatores Reguladores de Interferon/genética , Macaca mulatta , Masculino , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Monócitos/virologia , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Síndrome de Imunodeficiência Adquirida dos Símios/metabolismo , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/efeitos dos fármacos
15.
J Virol ; 91(23)2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-28931681

RESUMO

A thorough understanding of the role of human immunodeficiency virus (HIV) intrahost evolution in AIDS pathogenesis has been limited by the need for longitudinally sampled viral sequences from the vast target space within the host, which are often difficult to obtain from human subjects. CD8+ lymphocyte-depleted macaques infected with simian immunodeficiency virus (SIV) provide an increasingly utilized model of pathogenesis due to clinical manifestations similar to those for HIV-1 infection and AIDS progression, as well as a characteristic rapid disease onset. Comparison of this model with SIV-infected non-CD8+ lymphocyte-depleted macaques also provides a unique opportunity to investigate the role of CD8+ cells in viral evolution and population dynamics throughout the duration of infection. Using several different phylogenetic methods, we analyzed viral gp120 sequences obtained from extensive longitudinal sampling of multiple tissues and enriched leukocyte populations from SIVmac251-infected macaques with or without CD8+ lymphocyte depletion. SIV evolutionary and selection patterns in non-CD8+ lymphocyte-depleted animals were characterized by sequential population turnover and continual viral adaptation, a scenario readily comparable to intrahost evolutionary patterns during human HIV infection in the absence of antiretroviral therapy. Alternatively, animals that were depleted of CD8+ lymphocytes exhibited greater variation in population dynamics among tissues and cell populations over the course of infection. Our findings highlight the major role for CD8+ lymphocytes in prolonging disease progression through continual control of SIV subpopulations from various anatomical compartments and the potential for greater independent viral evolutionary behavior among these compartments in response to immune modulation.IMPORTANCE Although developments in combined antiretroviral therapy (cART) strategies have successfully prolonged the time to AIDS onset in HIV-1-infected individuals, a functional cure has yet to be found. Improvement of drug interventions for a virus that is able to infect a wide range of tissues and cell types requires a thorough understanding of viral adaptation and infection dynamics within this target milieu. Although it is difficult to accomplish in the human host, longitudinal sampling of multiple anatomical locations is readily accessible in the SIV-infected macaque models of neuro-AIDS. The significance of our research is in identifying the impact of immune modulation, through differing immune selective pressures, on viral evolutionary behavior in a multitude of anatomical compartments. The results provide evidence encouraging the development of a more sophisticated model that considers a network of individual viral subpopulations within the host, with differing infection and transmission dynamics, which is necessary for more effective treatment strategies.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Evolução Molecular , Imunomodulação , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Síndrome da Imunodeficiência Adquirida , Animais , Progressão da Doença , Humanos , Depleção Linfocítica , Macaca , Glicoproteínas de Membrana/genética , Modelos Animais , Filogenia , Análise de Sequência de DNA , Vírus da Imunodeficiência Símia/classificação , Vírus da Imunodeficiência Símia/genética , Vírus da Imunodeficiência Símia/isolamento & purificação , Vírus da Imunodeficiência Símia/patogenicidade , Proteínas do Envelope Viral/genética , Carga Viral
16.
J Clin Endocrinol Metab ; 102(11): 4250-4259, 2017 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-28945911

RESUMO

Context: In the general population, high-density lipoprotein (HDL) cholesterol efflux capacity (HCEC) relates inversely to incident cardiovascular events. Previous studies have suggested that HCEC is decreased in HIV and that antiretroviral therapy (ART) initiation might improve HCEC. Objective: To evaluate HCEC in the context of ART initiation and immune activation in HIV. Design and Outcome Measures: Baseline HCEC from 10 ART-naive HIV-infected males and 12 prospectively matched non-HIV-infected males were analyzed. In the HIV cohort, HCEC 6 months after elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (E/C/F/TDF) therapy was evaluated. HCEC served as the primary outcome and was measured by the ability of J774 mouse macrophages to efflux cholesterol. Our ex vivo assay used two cholesterol acceptors [apolipoprotein B (apoB)-depleted sera or purified HDL] and modulation of cellular efflux pathways using a liver X receptor (LXR) agonist. Results: The median age was 34 years [interquartile range (IQR), 27 to 51], and baseline HDL was 46 mg/dL (IQR, 38 to 61). HCEC was significantly greater in the non-HIV-infected subjects than in the HIV-infected subjects at baseline. HCEC, assessed using apoB-depleted sera, significantly increased after ART (no LXR agonist, baseline: median, 8.1%; IQR, 7.0% to 11.9%; after ART: median, 12.9%; IQR, 10.4% to 21.1%; P = 0.006; LXR agonist, baseline, 1.3% ± 1.3%; after ART, 2.5% ± 1.0%; P = 0.02), although not to the levels in the non-HIV-infected subjects (no LXR agonist: median, 14.9%; IQR, 11.5% to 19.1%; LXR agonist: 5.8% ± 1.3%). HCEC, assessed using purified HDL, did not significantly increase after ART. The change in HCEC with ART related inversely to the change in the percentage of CD14-CD16+ (nonclassical) monocytes (ρ = -0.74, P = 0.04) and directly to the change in the percentage of CD14+CD16- (classical) monocytes (ρ = 0.72, P = 0.045). Conclusions: Our data suggest improvement of HCEC with E/C/F/TDF and a relationship between the ART-induced decrease in immune activation and ART-induced improvement in HCEC.


Assuntos
Antirretrovirais/farmacologia , HDL-Colesterol/metabolismo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Adulto , Animais , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Antirretrovirais/uso terapêutico , Anticolesterolemiantes/farmacologia , Transporte Biológico/efeitos dos fármacos , Estudos de Casos e Controles , Células Cultivadas , HIV , Infecções por HIV/imunologia , Humanos , Hidrocarbonetos Fluorados/farmacologia , Imunidade Inata/efeitos dos fármacos , Inflamação/imunologia , Inflamação/metabolismo , Receptores X do Fígado/agonistas , Masculino , Camundongos , Pessoa de Meia-Idade , Sulfonamidas/farmacologia
17.
J Neurovirol ; 23(4): 568-576, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28462488

RESUMO

Peripheral neuropathy (PN) is a major comorbidity of HIV infection that is caused in part by chronic immune activation. HIV-PN is associated with infiltration of monocytes/macrophages to the dorsal root ganglia (DRG) causing neuronal loss and formation of Nageotte nodules. Here, we used an oral form of methylglyoxal-bis-guanylhydrazone (MGBG), a polyamine biosynthesis inhibitor, to specifically reduce activation of myeloid cells. MGBG is selectively taken up by monocyte/macrophages in vitro and inhibits HIV p24 expression and DNA viral integration in macrophages. Here, MGBG was administered to nine SIV-infected, CD8-depleted rhesus macaques at 21 days post-infection (dpi). An additional nine SIV-infected, CD8-depleted rhesus macaques were used as untreated controls. Cell traffic to tissues was measured by in vivo BrdU pulse labeling. MGBG treatment significantly diminished DRG histopathology and reduced the number of CD68+ and CD163+ macrophages in DRG tissue. The number of recently trafficked BrdU+ cells in the DRG was significantly reduced with MGBG treatment. Despite diminished DRG pathology, intraepidermal nerve fiber density (IENFD) did not recover after treatment with MGBG. These data suggest that MGBG alleviated DRG pathology and inflammation.


Assuntos
Inibidores Enzimáticos/farmacologia , Gânglios Espinais/efeitos dos fármacos , Mitoguazona/farmacologia , Monócitos/efeitos dos fármacos , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Administração Oral , Animais , Linfócitos T CD8-Positivos/virologia , Movimento Celular/efeitos dos fármacos , DNA Viral/genética , Gânglios Espinais/imunologia , Gânglios Espinais/patologia , Gânglios Espinais/virologia , Proteína do Núcleo p24 do HIV/genética , Depleção Linfocítica , Macaca mulatta , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/patologia , Macrófagos/virologia , Masculino , Monócitos/imunologia , Monócitos/patologia , Monócitos/virologia , Fibras Nervosas/efeitos dos fármacos , Fibras Nervosas/imunologia , Fibras Nervosas/patologia , Fibras Nervosas/virologia , Doenças do Sistema Nervoso Periférico/imunologia , Doenças do Sistema Nervoso Periférico/patologia , Doenças do Sistema Nervoso Periférico/virologia , Poliaminas/antagonistas & inibidores , Poliaminas/metabolismo , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/patologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Vírus da Imunodeficiência Símia/genética , Vírus da Imunodeficiência Símia/crescimento & desenvolvimento
18.
AIDS ; 31(6): 797-806, 2017 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-28252528

RESUMO

OBJECTIVE: Persistent immune activation is thought to contribute to increased cardiovascular disease risk in HIV and statins may help modulate systemic immune activation. We aimed to compare the effects of two key statins on markers of systemic immune activation and arterial inflammation in the HIV population. DESIGN: Double-blind, active-controlled, parallel-group comparative trial performed in 45 sites. METHODS: Two hundred and fifty-two antiretroviral therapy-treated HIV-infected participants with dyslipidemia were randomized (1 : 1) to pitavastatin 4 mg daily vs. pravastatin 40 mg daily in the HIV-infected patieNts and TREatment with PItavastatin vs. pravastatin for Dyslipidemia (INTREPID) trial. In this analysis of the INTREPID trial, we assessed markers of immune activation and arterial inflammation using a modified intent-to-treat population. This trial is registered with ClinicalTrials.gov (NCT01301066). RESULTS: One hundred and twenty-six participants were randomized to receive pitavastatin and 126 to pravastatin. Ninety-nine participants in the pitavastatin group and 91 participants in the pravastatin group completed the study. Median age was 50 (45, 56) years [median (interquartile range)]. Baseline, low-density lipoprotein-cholestrol (LDL-C) was 153 (135, 171) mg/dl, log HIV-1 viral load was 1.1 ±â€Š0.2 copies/ml, and CD4 cell count was 580 (439, 794) cells/µl. At week 52, the pitavastatin group had a significantly greater reduction (% change) compared with pravastatin in soluble CD14 (sCD14), (-10.0 vs. 0.6%, P = 0.02), oxidized LDL (oxLDL) (-26.9 vs. -17.5%, P = 0.02), and lipoprotein-associated phospholipase 2 (Lp-PLA2) (-26.6 vs. -15.5%, P = 0.005) (pitavastatin vs. pravastatin). CONCLUSION: Fifty-two weeks of pitavastatin 4 mg daily (vs. pravastatin 40 mg daily) led to a greater reduction in select markers of immune activation and arterial inflammation (sCD14, oxLDL, and LpPLA2) among HIV-infected participants. Further work is needed to assess whether immune-modulatory effects of pitavastatin reduce cardiovascular disease risk in HIV.


Assuntos
Arterite/patologia , Arterite/prevenção & controle , Biomarcadores/análise , Infecções por HIV/complicações , Fatores Imunológicos/uso terapêutico , Pravastatina/uso terapêutico , Quinolinas/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Método Duplo-Cego , Humanos , Resultado do Tratamento
19.
J Infect Dis ; 215(8): 1270-1274, 2017 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-28329310

RESUMO

The plasma kynurenine/tryptophan (KT) ratio, a marker of adaptive immune defects, strongly predicts mortality during treated human immunodeficiency virus (HIV) disease in Ugandans as compared to US-based populations. Here, the KT ratio and T-cell and plasma biomarkers of immune activation were measured among 535 HIV-infected Ugandans prior to ART initiation and at month 6 of viral suppression. The month 6 KT ratio (adjusted hazard ratio [aHR], 2.74), soluble CD14 level (aHR, 2.32), interleukin 6 level (aHR, 2.34), and D-dimer level (aHR, 1.95) were associated with mortality occurring ≥6 months after ART initiation. The KT ratio remained significantly predictive of mortality even after adjustment for the additional biomarkers, suggesting an independent contribution to clinical outcomes in resource-limited settings.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/mortalidade , Cinurenina/sangue , Triptofano/sangue , Adulto , Biomarcadores/sangue , Estudos de Coortes , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Humanos , Interleucina-6/sangue , Receptores de Lipopolissacarídeos/sangue , Masculino , Análise Multivariada , Prognóstico , Modelos de Riscos Proporcionais , Linfócitos T/imunologia , Uganda/epidemiologia , Carga Viral
20.
J Acquir Immune Defic Syndr ; 74(5): 583-592, 2017 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-28141779

RESUMO

BACKGROUND: Despite effective combination antiretroviral therapy, HIV-infected individuals develop comorbidities, including cardiovascular disease, where activated macrophages play a key role. To date, few therapies target activated monocytes and macrophages. METHODS: We evaluated a novel oral form of the polyamine biosynthesis inhibitor methylglyoxal-bis-guanylhydrazone (MGBG) on cardiovascular inflammation, carotid artery intima-media thickness (cIMT), and fibrosis in a simian immunodeficiency virus infection model of AIDS. Eleven simian immunodeficiency virus-infected animals received MGBG (30 mg/kg) once daily and 8 received a placebo control both beginning at 21 days postinfection (dpi). Animals were time sacrificed at 49 days post infection (dpi), when their matched placebo controls developed AIDS (63, 70, 77, 80), or at the study end-point (84 dpi). Aorta, carotid artery, and cardiac tissues were analyzed. Quantitative analyses of macrophage populations and T lymphocytes were done and correlated with cIMT and fibrosis. RESULTS: MGBG treatment resulted in 2.19-fold (CD163), 1.86-fold (CD68), 2.31-fold (CD206), and 2.12-fold (MAC387) decreases in macrophages in carotid arteries and significant 2.07-fold (CD163), 1.61-fold (CD68), 1.95-fold (MAC387), and 1.62-fold (CD206) decreases in macrophages in cardiac tissues. cIMT (1.49-fold) and fibrosis (2.05-fold) also were significantly decreased with MGBG treatment. Numbers of macrophage and the degree of fibrosis in treated animals were similar to uninfected animals. A positive correlation between decreased macrophage in the carotid artery and cIMT, and cardiac macrophages and fibrosis was found. CONCLUSIONS: These data demonstrate that directly targeting macrophages with MGBG can reduce cardiovascular inflammation, cIMT, and fibrosis. They suggest that therapies targeting macrophages with HIV could be used in conjunction with combination antiretroviral therapy.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Fatores Imunológicos/administração & dosagem , Inflamação/patologia , Macrófagos/efeitos dos fármacos , Mitoguazona/administração & dosagem , Síndrome de Imunodeficiência Adquirida dos Símios/complicações , Animais , Artérias Carótidas/patologia , Fibrose/patologia , Fatores Imunológicos/farmacologia , Macaca mulatta , Macrófagos/imunologia , Mitoguazona/farmacologia , Placebos/administração & dosagem , Resultado do Tratamento , Túnica Íntima/patologia
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