RESUMO
In the era of highly active antiretroviral therapy (HAART), HIV-1-associated neurocognitive disorders (HAND) persist in infected individuals with adequate immunological and virological status. Risk factors for cognitive impairment include hepatitis C virus co-infection, host genetic factors predisposing to HAND, the early establishment of the virus in the CNS and its persistence under HAART; thus, the CNS is an important reservoir for HIV. Microglial cells are permissive to HIV-1, and NLRP3 inflammasome-associated genes were found expressed in brains of HIV-1-infected persons, contributing to brain disease. Inflammasomes can be triggered by alarmins or danger-associated molecular patterns (DAMPs), which directly stimulate the production of proinflammatory mediators by glial cells, contribute to blood-brain barrier injury through induction of release of various proteases and allow the passage of infected macrophages, and trigger IL-1ß release from primed cells. Amongst alarmins involved in HIV-1-induced neuropathogenesis, IL-33 and high-mobility group box 1 (HMGB1) are of particular interest. Neurocognitive alterations were recently associated with dysregulation of the IL-33/ST2 axis in the CNS, leading to the induction of neuronal apoptosis, decrease in synaptic function and neuroinflammation. Specific biomarkers, including HMGB1 and anti-HMGB1 antibodies, have been identified in cerebrospinal fluid from patients with HAND, correlated with immune activation and identifying a very early stage of neurocognitive impairment that precedes changes in metabolites detected by magnetic resonance spectroscopy. Moreover, HMGB1 plays a crucial role in HIV-1 persistence in dendritic cells and in the constitution of viral reservoirs. In this review, the mechanisms whereby alarmins contribute to HIV-1-induced CNS inflammation and neuropathogenesis will be discussed.
Assuntos
Alarminas/fisiologia , Doenças do Sistema Nervoso Central/virologia , Infecções por HIV/etiologia , HIV-1 , Neurite (Inflamação)/virologia , Fármacos Anti-HIV/uso terapêutico , Biomarcadores/metabolismo , Doenças do Sistema Nervoso Central/imunologia , Doença Crônica , Reservatórios de Doenças , Proteína gp120 do Envelope de HIV/fisiologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Proteína HMGB1/fisiologia , Humanos , Imunidade Inata/imunologia , Inflamassomos/fisiologia , Interleucina-33/fisiologia , Neurite (Inflamação)/imunologia , Doenças Neurodegenerativas/imunologia , Doenças Neurodegenerativas/virologia , Produtos do Gene tat do Vírus da Imunodeficiência Humana/fisiologiaRESUMO
BACKGROUND: It has been suggested that patients who initiate highly active antiretroviral therapy (HAART) late in their course of infection may have suboptimal CD4 T-cell gains, persistent alterations in T-cell subsets and residual inflammation. To address this issue, we carried out a comprehensive 48-week immunological study in HIV-infected patients who had experienced failures of prior therapies, had low CD4 cell counts, and were receiving enfuvirtide-based salvage therapy. METHODS: Immunological monitoring of peripheral lymphocytes from enfuvirtide-responder patients was performed over a 48-week period. A detailed assessment of immune cell subsets, their activation state [CD38 and human leucocyte antigen (HLA)-DR expression] and homeostasis [activation-induced cell death (AICD) and Ki67 expression], and the expression of co-receptors was performed by flow cytometry. Cytokine and chemokine signatures were assessed using multianalyte profiling technology. RESULTS: Enfuvirtide-based salvage therapy induced a progressive restoration of naïve and central memory CD4 T cells, associated with a decrease in their activation state, suppression of premature priming for AICD and increased expression of Ki67. In addition, a significant decrease in C-C chemokine receptor 5 (CCR5) expression was detected on CD4 T cells, which was strongly correlated with the suppression of immune activation. Changes in circulating proinflammatory molecules occurred; i.e. there were decreases in the concentrations of interleukin (IL)-12, macrophage inflammatory protein MIP-1α, MIP-1ß, monokine induced by IFNγ (MIG) and interferon-γ-inducible protein-10 (IP-10). The decline in circulating IL-12 and IP-10 was correlated with both the reduction in the viral load and CD4 T-cell restoration. CONCLUSIONS: This study shows that suppression of HIV-1 replication with enfuvirtide-based salvage therapy in patients with low CD4 cell counts may result in an immunological benefit, characterized by the restoration of CD4 T-cell subsets associated with decreased immune activation and suppression of inflammation.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Quimiocina CXCL10/sangue , Proteína gp41 do Envelope de HIV/uso terapêutico , Inibidores da Fusão de HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Interleucina-12/sangue , Fragmentos de Peptídeos/uso terapêutico , Receptores CCR5/metabolismo , Adolescente , Adulto , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Linfócitos T CD4-Positivos/efeitos dos fármacos , Enfuvirtida , HIV-1/efeitos dos fármacos , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Terapia de Salvação , Carga Viral , Replicação Viral/efeitos dos fármacos , Adulto JovemRESUMO
We have analyzed the V beta usage by CD4+ and CD8+ T cells from human immunodeficiency virus (HIV)-infected individuals in response to an in vitro stimulation with the superantigenic erythrogenic toxin A (ETA) of Streptococcus pyogenes. ETA amplifies specifically CD4+ and CD8+ T cells from control donors expressing the V beta 8 and the V beta 12 elements. When peripheral T cells from asymptomatic HIV-infected individuals were stimulated with ETA, there was a complete lack of activation of the V beta 8+ T cell subset, whereas the V beta 12+ T cell subset responded normally to the superantigen. This V beta-specific anergy, which was also observed in response to staphylococcal enterotoxin E (SEE), affected both CD4+ and CD8+ T cells and represented an intrinsic functional defect rather than a specific lack of response to bacterial superantigens since it was also observed after a stimulation with V beta 8 monoclonal antibodies. The V beta 8 anergic T cells did not express interleukin 2 receptors (IL-2Rs) and failed to proliferate in response to exogenous IL-2 or IL-4, suggesting that this anergy was not a reversible process, at least by the use of these cytokines. The unresponsiveness of the V beta 8 T cell subset is frequent since it was found in 56% of the patients studied, and comparison of the clinical status of responder vs. anergic patients indicated that the only known common factor between them was HIV infection. In addition, it is noteworthy that the anergy of the V beta 8 subset may be a very early phenomenon since it was found in a patient at Centers for Disease Control stage I of the disease. These data provide evidence that a dominant superantigen may be involved in the course of HIV infection and that the contribution of HIV has to be considered.
Assuntos
Proteínas de Bactérias , Linfócitos T CD4-Positivos/imunologia , Anergia Clonal , Infecções por HIV/imunologia , Proteínas de Membrana , Linfócitos T Reguladores/imunologia , Adulto , Anticorpos Monoclonais/imunologia , Antígenos de Bactérias/imunologia , Antígenos CD4 , Antígenos CD8 , Exotoxinas/imunologia , Feminino , Humanos , Masculino , Receptores de Interleucina-2/biossíntese , Streptococcus pyogenes/imunologia , Superantígenos/imunologiaRESUMO
CD4(+) T cell lymphocytes are a major target for human immunodeficiency virus type-1 (HIV-1) infection. During this chronic infection, CD4(+) T cell loss (induced through direct viral replication), generalized immune activation and increased susceptibility to apoptosis result in impaired T cell homeostasis with subsequent development of opportunistic infections and cancers. Highly active antiretroviral therapy (HAART) has a well-defined, beneficial effect on HIV-1-related clinical outcome; however, it does not lead to normalization of immune dysregulation. In order to boost both CD4(+) T cell restoration and HIV-1 specific immunity, immunotherapy with gamma-chain cytokines has been used in HIV-1-infected patients during concomitant HAART. In this review, we summarize the role of gamma-chain cytokines, especially interleukin (IL)-2 and IL-7, in influencing T cell homeostasis and proliferation, and discuss how immunotherapy with these cytokines may be beneficial to reconstitute the T cell compartment in the context of HIV-1 infection. The intriguing results of two large trials evaluating the efficacy of IL-2 in restoring immune function during HIV-1 infection are also discussed. In addition, we consider the promises and caveats of the first phase I/II clinical trials with IL-7 in HIV-1-infected patients and the knowledge that is still lacking in the field of T cell reconstitution through gamma-chain cytokines.
Assuntos
Antirretrovirais/farmacologia , Linfócitos T CD4-Positivos , Infecções por HIV , HIV-1 , Interleucina-2/farmacologia , Interleucina-7/farmacologia , Apoptose/efeitos dos fármacos , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Proliferação de Células/efeitos dos fármacos , Doença Crônica , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Homeostase/efeitos dos fármacos , Humanos , Receptores de Citocinas/metabolismoRESUMO
BACKGROUND: In Europe, sensitization to ash pollen induces pollinosis with cross-reactivities with other pollen sources. The aim of the study was to identify the repertoire of ash pollen allergens and evaluate the extent of the diversity of the IgE response in ash allergic patients. METHODS: The IgE reactivities of 114 ash pollen- and eight grass pollen-sensitized patients were screened by 1D immunoblot (SDS-PAGE) against ash pollen extract. The IgE reactivities of 13 ash pollen- and two grass pollen-sensitized patients were then evaluated in 2D immunoblots. Some IgE- and non-IgE-reactive proteins were identified by mass spectrometry. RESULTS: In 1D analysis, 86% of sera showed binding to Fra e 1 (18-20 kDa), 23% to Fra e 2 (14 kDa), 3% to Fra e 3 (10 kDa) and 57% to High Molecular Weight allergens (HMW, >30 kDa). Individual analysis of 2D immunoblots showed several IgE-binding protein areas among which three were more often recognized: (i) Fra e 1 comprising, at least, 15 isoforms, (ii) a series of acidic spots (45 kDa), and (iii) Fra e 2, the ash profilin. HMW allergens could be resolved in four areas; two unidentified, one homologous to beta-galactosidase and the other to sugar transport proteins. A malate deshydrogenase and calmodulin were shown to be IgE-binding proteins and 10 non-IgE reactive proteins were identified. CONCLUSIONS: No direct correlation was evidenced between IgE profile and the degree of sensitization even though 2 spectrotypes could be distinguished. Our data contribute to a better delineation of ash pollen allergens and patterns of sensitization.
Assuntos
Fraxinus/imunologia , Imunoglobulina E/sangue , Rinite Alérgica Sazonal/sangue , Rinite Alérgica Sazonal/imunologia , Western Blotting , Reações Cruzadas/imunologia , Eletroforese em Gel de Poliacrilamida , Humanos , Imunoglobulina E/imunologia , Proteômica , Rinite Alérgica Sazonal/epidemiologia , Testes Cutâneos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por MatrizRESUMO
Viruses manipulate host cells to ensure their own survival and, at late stages of the viral life cycle, they kill the infected target cell to ensure their propagation. In addition, some viruses induce a bystander killing, a viral strategy to escape from the host's innate and cognate defense systems. In HIV-infection, the disabling of the immune system is initially due to the preferential depletion by apoptosis of virus-specific CD4(+) T cells in lymphoid tissues, followed by the destruction of non-infected bystander cells. Both the extrinsic and the intrinsic pathways are activated, and this is the consequence of systemic immune activation. This review presents recent developments showing that the gastrointestinal tract is the major reservoir of infected cells and the site of rapid and profound loss of CD4 T cells, and that microbial translocation from the gastrointestinal tract is the cause of immune activation. Furthermore, apoptosis mechanisms involved in HIV-induced neuropathological disorders are discussed, including the role of syncytia that involve the sequential activation of ATM, p38MAPK and p53. Finally, HIV-associated dementia (HAD) was recently found in monkey models to be linked to inhibition of autophagy in neurons, suggesting that homeostasis of autophagy is a reliable security factor for neurons, and challenging the development of new therapeutics aimed at boosting neuronal autophagy to prevent HAD.
Assuntos
Síndrome da Imunodeficiência Adquirida/etiologia , Apoptose/fisiologia , Autofagia/fisiologia , Infecções por HIV/patologia , HIV-1/fisiologia , Complexo AIDS Demência/patologia , Animais , Proteínas Mutadas de Ataxia Telangiectasia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/fisiologia , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ligação a DNA/metabolismo , Ativação Enzimática , Células Gigantes/metabolismo , Células Gigantes/patologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/metabolismo , Haplorrinos , Humanos , Proteínas Serina-Treonina Quinases/metabolismo , Linfócitos T/patologia , Proteína Supressora de Tumor p53/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
In this paper we used a multiparametric approach to analyze extensively the events occurring during apoptotic cell death of thymocytes, and furthermore, we asked whether alterations in mitochondrial structure and function are occurring in early stages of apoptosis. A multiparametric quantitative analysis was performed on normal or apoptotic thymocytes emerging from a few-hour culture performed in culture medium or in the presence of dexamethasone. Simultaneous detection of light scattering properties, integrity of plasma membrane (trypan blue exclusion), chromatin condensation (AO/EB staining of entire cells or PI staining of nuclei), and DNA fragmentation (in situ nick-translation in apoptotic cells) allowed a precise analysis of the preapoptotic and apoptotic stages. Moreover a thorough study of mitochondrial transmembrane potential (delta psi m) assessed following in a time course study the uptake by apoptotic cells of the cationic lipophilic dye DiOC6(3) or the J-aggregate-forming cation JC-1, indicates that a drop in delta psi m occurs very early in thymocyte apoptosis, before DNA fragmentation. This is associated with alteration in mitochondrial structure assessed by cytofluorimetric study of NAO uptake in apoptotic cells. Finally these dramatic alterations in mitochondrial structure and function occurring in early stages of apoptosis were confirmed by confocal and electron microscopy analysis.
Assuntos
Apoptose/efeitos dos fármacos , Dexametasona/farmacologia , Mitocôndrias/efeitos dos fármacos , Timo/efeitos dos fármacos , Animais , Dano ao DNA , Citometria de Fluxo , Membranas Intracelulares/ultraestrutura , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Eletrônica , Mitocôndrias/ultraestrutura , ATPases Translocadoras de Prótons/metabolismo , Timo/citologia , Fatores de TempoRESUMO
By pumping calcium from the cytosol to the ER, sarco/endoplasmic reticulum calcium ATPases (SERCAs) play a major role in the control of calcium signaling. We describe two SERCA1 splice variants (S1Ts) characterized by exon 4 and/or exon 11 splicing, encoding COOH terminally truncated proteins, having only one of the seven calcium-binding residues, and thus unable to pump calcium. As shown by semiquantitative RT-PCR, S1T transcripts are differentially expressed in several adult and fetal human tissues, but not in skeletal muscle and heart. S1T proteins expression was detected by Western blot in nontransfected cell lines. In transiently transfected cells, S1T homodimers were revealed by Western blot using mildly denaturing conditions. S1T proteins were shown, by confocal scanning microscopy, to colocalize with endogenous SERCA2b into the ER membrane. Using ER-targeted aequorin (erAEQ), we have found that S1T proteins reduce ER calcium and reverse elevation of ER calcium loading induced by SERCA1 and SERCA2b. Our results also show that SERCA1 variants increase ER calcium leakage and are consistent with the hypothesis of a cation channel formed by S1T homodimers. Finally, when overexpressed in liver-derived cells, S1T proteins significantly induce apoptosis. These data reveal a further mechanism modulating Ca(2+) accumulation into the ER of nonmuscle cells and highlight the relevance of S1T proteins to the control of apoptosis.
Assuntos
Apoptose , ATPases Transportadoras de Cálcio/metabolismo , Cálcio/metabolismo , Retículo Endoplasmático/metabolismo , Splicing de RNA , Adulto , Sequência de Aminoácidos , ATPases Transportadoras de Cálcio/química , ATPases Transportadoras de Cálcio/genética , Clonagem Molecular , Dimerização , Expressão Gênica , Células HeLa , Humanos , Membranas Intracelulares/metabolismo , Dados de Sequência Molecular , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Estrutura Secundária de Proteína , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático , Distribuição Tecidual , Células Tumorais CultivadasRESUMO
We investigated whether glatiramer acetate (GA) treatment may affect Th1 differentiation at various T-cell maturation stages. Specifically, we analyzed the effect of in vivo GA treatment on intracellular synthesis of IL-2 and TNF-alpha by naive, memory and effector CD4(+) and CD8(+) T cells by five-colour flow cytometry. Our data indicate that GA treatment downregulates/normalizes an accelerated Th1 differentiation of CD4(+) T cells in RRMS patients at all stages of T-cell maturation. Most notably, we conclude that, by altering naive, unprimed CD4(+) T cells, GA treatment appears to affect T-cell differentiation, at least in part, in an antigen-independent manner.
Assuntos
Linfócitos T CD4-Positivos/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Imunossupressores/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Peptídeos/uso terapêutico , Adulto , Linfócitos T CD4-Positivos/citologia , Diferenciação Celular/imunologia , Feminino , Citometria de Fluxo , Acetato de Glatiramer , Humanos , Interleucina-2/biossíntese , Masculino , Esclerose Múltipla/imunologia , Células Th1 , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/efeitos dos fármacosRESUMO
The hepatitis B virus protein HBx is a promiscuous transactivator implicated in both cell growth and death and in the development of hepatocellular carcinoma. We recently reported that HBx can potentiate c-myc-induced liver oncogenesis in a transgenic model where low level expression of HBx induces no pathology. To assess if HBx could affect the hepatocyte turnover, we investigated the HBx-elicited apoptotic responses in transgenic livers and in primary hepatocyte cultures. Here we show that transgenic expression of HBx is associated with a twofold increase of spontaneous cell death in the mouse liver. The finding that apoptosis was enhanced to similar extents in HBx mice carrying homozygous p53 null mutations implied that functionally intact p53 was not required to transduce the death signal. A direct, dose-dependent apoptotic function of HBx was demonstrated in transient transfections of liver-derived cell lines. We further show that stable expression of HBx at low, presumably physiological levels in primary hepatocytes, induced cellular susceptibility to diverse apoptotic insults, including growth factor deprivation, treatment with anti-Fas antibodies or doxorubicine and oxidative stress. HBx expression, but not p53 status profoundly affected the commitment of cells to die upon apoptotic stimuli. These data strengthen the notion that HBX may contribute to HBV pathogenesis by enhancing apoptotic death in the chronically infected liver.
Assuntos
Apoptose , Vírus da Hepatite B/fisiologia , Transativadores/fisiologia , Proteína Supressora de Tumor p53/fisiologia , Animais , Células Cultivadas , Feminino , Expressão Gênica , Antígenos da Hepatite B/genética , Antígenos da Hepatite B/fisiologia , Fígado/patologia , Fígado/virologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transativadores/genética , Proteínas Virais Reguladoras e AcessóriasRESUMO
We have used the Hepatitis B Virus DNA genome as a probe to identify genes clonally mutated in vivo, in human liver cancers. In a tumor, HBV-DNA was found to be integrated into the gene encoding Sarco/Endoplasmic Reticulum Calcium ATPase (SERCA), which pumps calcium, an important intracellular messenger for cell viability and growth, from the cytosol to the endoplasmic reticulum. The HBV X gene promoter cis-activates chimeric HBV X/SERCA1 transcripts, with splicing of SERCA1 exon 11, encoding C-terminally truncated SERCA1 proteins. Two chimeric HBV X/SERCA1 proteins accumulate in the tumor and form dimers. In vitro analyses have demonstrated that these proteins localize to the ER, determine its calcium depletion and induce cell death. We have also shown that these biological effects are related to expression of the SERCA, rather than of the viral moiety. This report involves for the first time the expression of mutated SERCA proteins in vivo in a tumor cell proliferation and in vitro in the control of cell viability. Oncogene (2000).
Assuntos
Apoptose/genética , ATPases Transportadoras de Cálcio/genética , Vírus da Hepatite B/fisiologia , Mutagênese Insercional/genética , Idoso , ATPases Transportadoras de Cálcio/metabolismo , Dimerização , Humanos , RNA Mensageiro/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Retículo Sarcoplasmático/enzimologia , Células Tumorais Cultivadas , Integração ViralRESUMO
HIV infection is associated with immune activation, which in turn stimulates HIV replication. Certain other co-infections cause immune activation and may contribute to an increased viral load. The impact of co-infections by microorganisms such as Mycobacterium tuberculosis can be important for patient survival, particularly those at high risk of exposure to infection and with poor access to medical care.
Assuntos
Infecções Oportunistas Relacionadas com a AIDS/imunologia , Infecções por HIV/etiologia , Infecções Oportunistas Relacionadas com a AIDS/virologia , Animais , Fármacos Anti-HIV/farmacologia , Antígenos/administração & dosagem , HIV/imunologia , HIV/patogenicidade , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Sistema Imunitário/efeitos dos fármacos , Tuberculose/complicações , Tuberculose/imunologia , Tuberculose/virologia , Replicação ViralRESUMO
Despite an extensive knowledge of the molecular characteristics of the human immunodeficiency virus (HIV) identified more than ten years ago as the cause of AIDS (acquired immune deficiency syndrome) (Barre-Sinoussi et al. 1983) some critical questions have not been answered yet: Is the progressive disappearance of CD4+ helper T lymphocytes, the hallmark of AIDS, directly related to the killing of infected cells by the virus? If not, how do CD4+T cells die? Is HIV using its viral factory to kill uninfected bystander cells? What causes the immune system collapse in HIV infection? In the past three years some important studies have provided stimulating clues suggesting that AIDS is not only related to the killing of host cells by HIV but is also a consequence of mechanisms of misactivation of the immune system, leading to anergy or apoptosis of non-infected effector cells. We discuss some of the in vivo and in vitro models providing evidence that HIV is able to kill and cripple the immune system either by acting directly on its targets or indirectly in bystander T cells keeping in mind that HIV disease must be considered as a multifactorial process.
RESUMO
IL-15 shares many biological properties with IL-2, a cytokine whose administration to HIV-infected individuals has been effective in enhancing depleted CD4 T lymphocyte numbers. The present study examined whether exogenous IL-15 could protect lymphocytes of HIV-infected individuals from spontaneous apoptosis, associated with growth factor deprivation, and CD95-induced apoptosis, which is believed to play a major role in T lymphocyte loss and HIV pathogenesis. Although IL-15, like IL-2, failed to inhibit CD95-induced lymphocyte apoptosis in vitro, IL-15 was found to act as a potent survival factor in the prevention of spontaneous apoptosis. The greater enhancement of lymphocyte survival, promoted by IL-15 as compared with IL-2 when used at an equivalent concentration, was associated with higher up-regulation of bcl-2 expression. In addition, IL-15 was more potent than IL-2 in stimulating lymphocyte proliferation. Despite the strong ability of IL-15 to promote both lymphocyte survival and proliferation, the increases in representation and total numbers of viable cells induced by IL-15 were not higher than those induced by IL-2. This appears to be associated with the greater ability of IL-15 to activate lymphocytes and increase their apoptosis-susceptibility. Therefore, lymphocyte loss occurring by growth factor deprivation in HIV infection may be potentially prevented by IL-15, although its benefits for survival need to be closely assessed against its ability to augment lymphocyte activation.
Assuntos
Apoptose/efeitos dos fármacos , Apoptose/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Interleucina-15/imunologia , Interleucina-15/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Proteínas Proto-Oncogênicas c-bcl-2/efeitos dos fármacos , Receptor fas/imunologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD8-Positivos/citologia , Técnicas de Cultura de Células , Divisão Celular/efeitos dos fármacos , Divisão Celular/imunologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/imunologia , Citoproteção/efeitos dos fármacos , Citoproteção/imunologia , Etoposídeo/farmacologia , Humanos , Inibidores da Síntese de Ácido Nucleico/farmacologiaRESUMO
Many conditions that induce an oxidative stress are capable of evoking apoptosis. This has lead to the proposal of oxidative stress as a mediator of apoptosis. We show that, in murine thymocytes, oxidative stress and apoptosis occur in the same cell. We identified four distinct apoptotic subpopulations that appeared sequentially in time. Catalase protected from dex-amethasone-induced death in the initial stages of apoptosis, while iron chelators and Vitamin E did not. Further studies provided evidence supporting the early production of an intracellular oxidative intermediate as an obligatory step for the efficient induction of apoptosis. We propose that at least one of the molecules capable of filling this role is hydrogen peroxide.
RESUMO
Vgamma9Vdelta2-encoded T cell receptors (TCR) expressed by most human peripheral blood gammadelta T cells mediate the recognition of nonpeptidic phosphoantigens from various pathogens without any known requirement for HLA molecules. Functionally mature Vgamma9Vdelta2 T cells display a potent natural killer (NK)-like cytotoxic activity, share with NK cells the expression of inhibitory receptors for HLA class I molecules, and release a plethora of cytokines, most notably interferon-gamma and tumor necrosis factor alpha. Hence, through local activation, the early recruitment and stimulation of Vgamma9Vdelta2 T cells may promote efficient anti-infectious immunity. However, a chronic overactivation of this T cell subset may result in immunopathology. The meeting held in St. Vincent, Val d'Aosta, Italy (symposium on gammadelta T cells in natural immunity to infections: a rationale for vaccine development organized by the World Foundation for AIDS Research and Prevention, the UNESCO, and the Italian National Research Council, December 2-4, 1996) focused on the importance of gammadelta T cell activation and anergy for the pathogenesis of tuberculosis, malaria, and HIV infections.
Assuntos
Anergia Clonal , Doenças Transmissíveis/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Ativação Linfocitária , Subpopulações de Linfócitos/imunologia , Fosfatos/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/fisiologia , Antígenos de Bactérias/química , Antígenos de Protozoários/química , Humanos , LigantesRESUMO
There is growing interest in the use of innate immune reactions in the therapy and prophylaxis of various diseases. Natural T (NT) lymphocytes that recognize infected cells or microbial compounds without the classical genetic restriction by polymorphic MHC molecules are crucial components of innate immunity. NT cells bearing the Vgamma9Vdelta2 T-cell receptor (TCR) are broadly reactive against intracellular pathogens, can lyse human immunodeficiency virus (HIV) infected cells, and release cytokines capable of regulating HIV replication. The potent antiviral activities of Vgamma9Vdelta2 T cells may help to contain viral spread during acute HIV infection and/or to prevent the establishment of viral persistence. Substantial changes in the composition and function of circulating gammadelta T-cell pools occur in HIV-infected patients. These changes a) may contribute to the etiopathogenesis of opportunistic infections and neoplasms, and b) are partly reversed by highly active anti-retroviral therapy (HAART). In addition to direct antiviral activities, activated gammadelta T cells influence dendritic cell maturation and the adaptive alphabeta T-cell response. Vgamma9Vdelta2 T cells can be stimulated in vivo and in vitro by various nonpeptidic antigens (NpAgs) and recent animal experimental data suggest that activated Vgamma9Vdelta2 T cells may help to control SIV replication. Currently, NpAgs are being assessed as potential therapeutic agents in AIDS, tuberculosis and certain cancers susceptible to Vgamma9Vdelta2 T-cell effector mechanisms.
Assuntos
Infecções por HIV/imunologia , Infecções por HIV/virologia , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/fisiologia , Linfócitos T/imunologia , Linfócitos T/virologia , Síndrome da Imunodeficiência Adquirida/terapia , Animais , Terapia Antirretroviral de Alta Atividade , Antivirais/farmacologia , Linfócitos B/virologia , Diferenciação Celular , Citocinas/metabolismo , Humanos , Células Matadoras Naturais/virologia , Ligantes , Modelos Biológicos , Polimorfismo GenéticoRESUMO
Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as 'accidental cell death' (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. 'Regulated cell death' (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death.
Assuntos
Apoptose , Transdução de Sinais , Animais , Humanos , Terminologia como AssuntoRESUMO
BACKGROUND: A key factor leading to impaired immunity in HIV infection is an alteration of the pattern of cytokine response, although its precise nature remains controversial, particularly the in vivo influence of HIV on interleukin (IL)-12 synthesis. DESIGN: A cross-sectional study in 73 HIV-infected persons (28 of them receiving highly active antiretroviral therapy) and 18 HIV-seronegative healthy donors. METHODS: The frequency of monocytes/macrophages (M/M) synthesizing IL-12, IL-10 and tumour necrosis factor alpha (TNF-alpha) was determined in peripheral blood mononuclear cells. The cells were cultured in medium or were stimulated with lipopolysaccharide; proportions of CD64 M/M producing IL-12, TNF-alpha or IL-10 was determined by cytofluorometric analysis. The influence of exogenous interferon gamma (IFN-gamma), IL-10 or IL-15 on IL-12 synthesis was tested. RESULTS: Chronic HIV disease is associated with increased priming of M/M for IL-12 (involving both p40 and p70 molecules) and TNF-alpha synthesis; this was associated with cosynthesis of both cytokines by a fraction of M/M. Priming for IL-12 was physiologically enhanced by IFN-gamma and decreased by IL-10; IL-15 had no effect. The proportion of IL-10-producing CD64 M/M was not altered in patients compared with controls but there was an inverse correlation between IL-10-producing M/M and viral load. IL-12 production was not correlated with viral load but was increased following antiretroviral therapy. Following LPS stimulation, IL-12 and TNF-alpha responses were not altered in HIV-positive patients; however, the IL-10 response was decreased but restored by antiretroviral therapy. CONCLUSION: These observations argue for a preserved intrinsic CD64 M/M of IL-12 production in HIV pathogenesis.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/metabolismo , Interleucina-12/farmacologia , Monócitos/imunologia , Receptores de IgG/imunologia , Fator de Necrose Tumoral alfa/farmacologia , Terapia Antirretroviral de Alta Atividade , Citometria de Fluxo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Humanos , Interleucina-12/biossíntese , Lipopolissacarídeos/farmacologia , Monócitos/efeitos dos fármacos , Fator de Necrose Tumoral alfa/biossíntese , Carga ViralRESUMO
BACKGROUND: A syndrome of lipodystrophy, associated with hypertriglyceridaemia, hypercholesterolaemia, hyperinsulinaemia and peripheral insulin resistance has been reported in protease inhibitor (PI)-treated HIV-infected patients. Because lipid metabolism, fat mass distribution and insulin resistance are partly regulated by steroid hormones, we questioned whether lipodystrophy is related to hormonal perturbations. OBJECTIVE: To evaluate serum lipid and steroid hormone concentrations in HIV-positive men on highly active antiretroviral therapy (HAART) in order to determine whether dyslipidaemia, peripheral loss of fatty tissue and central fat accumulation are related to steroid hormone modifications. DESIGN: A cross-sectional study. METHODS: Thirty-seven HIV-1-positive men on HAART, 23 of whom had symptoms of lipodystrophy, according to a subjective clinical score of lipodystrophy (SCSL), were tested. Serum concentrations of cholesterol, triglycerides and their subclasses, apolipoproteins and steroid hormones, including cortisol, dehydroepiandrosterone (DHEA), DHEA sulphate, androstenedione, testosterone and dihydrotestosterone were measured. RESULTS: Serum cholesterol, very low density lipoprotein (VLDL) cholesterol, triglycerides, VLDL triglycerides, high density lipoprotein (HDL) and low density lipoprotein (LDL) triglycerides, apolipoprotein B (ApoB) and atherogenic ratios of cholesterol:HDL cholesterol, LDL cholesterol:HDL cholesterol and ApoB:apolipoprotein A1 (ApoA1) were significantly increased in lipodystrophy-positive compared with lipodystrophy-negative men. The serum cortisol level was similar in lipodystrophy-positive versus lipodystrophy-negative men, but was elevated compared with controls. Serum DHEA was significantly lower in lipodystrophy-positive versus lipodystrophy-negative men and, consequently, the cortisol:DHEA ratio was increased in lipodystrophy-positive patients. A positive correlation was found between the cortisol:DHEA ratio and increased levels of atherogenic lipids. In addition, the SCSL was positively correlated with dyslipidaemia and the cortisol:DHEA ratio. CONCLUSION: This study demonstrates an association between the cortisol:DHEA ratio, lipid alterations and lipodystrophy. This syndrome might result from an imbalance between peripheral lipolysis and lipogenesis, both regulated by cortisol and DHEA.