RESUMEN
Speech disorder is a significant problem for people affected with Parkinson's disease (PD) leading to a substantial disability to communicate with others. PD affects the voice, including changes in pitch, intensity, articulation, and syllable rate.We aimed to study the current status of artificial intelligence (AI) using machine learning algorithms (MLAs) in the assessment of speech abnormalities in PD along with the generation of intelligible synthetic speech for voice rehabilitation. We searched the literature for studies focusing on speech/voice disorder in PD and rehabilitation techniques till June 18, 2022. We searched PubMed and Engineering Village (Compendex and Inspec combined) databases. After careful screening of the title and evaluation of abstracts, we used select articles describing the use of AI or its various forms in the management of speech abnormalities in PD to synthesize this review. MLAs classify PD and non-PD patients with an accuracy of more than 90% using only voice features. Non-acoustic sensors can rehabilitate PD patient by converting dysarthric speech to highly intelligible speech using MLAs. MLAs can automatically assess several speech features and quantify the progression of speech abnormalities in PD. PD speech rehabilitation using MLAs may prove superior to other available therapies.
RESUMEN
It has been shown that caspase-1, but not its upstream activator, ASC, contributes to oviduct pathology during mouse genital Chlamydia muridarum infection. We hypothesized that this dichotomy is due to the inadvertent absence of caspase-11 in previously used caspase-1-deficient mice. To address this, we studied the independent contributions of caspase-1 and -11 during genital Chlamydia infection. Our results show that caspase-11 deficiency was sufficient to recapitulate the effect of the combined absence of both caspase-1 and caspase-11 on oviduct pathology. Further, mice that were deficient for both caspase-1 and -11 but that expressed caspase-11 as a transgene (essentially, caspase-1-deficient mice) had no significant difference in oviduct pathology from control mice. Caspase-11-deficient mice showed reduced dilation in both the oviducts and uterus. To determine the mechanism by which caspase-11-deficient mice developed reduced pathology, the chlamydial burden and immune cell infiltration were determined in the oviducts. In the caspase-11-deficient mice, we observed increased chlamydial burdens in the upper genital tract, which correlated with increased CD4 T cell recruitment, suggesting a contribution of caspase-11 in infection control. Additionally, there were significantly fewer neutrophils in the oviducts of caspase-11-deficient mice, supporting the observed decrease in the incidence of oviduct pathology. Therefore, caspase-11 activation contributes to pathogen control and oviduct disease independently of caspase-1 activation.
Asunto(s)
Caspasas/fisiología , Infecciones por Chlamydia/patología , Oviductos/patología , Infecciones del Sistema Genital/patología , Animales , Caspasa 1/fisiología , Caspasas/genética , Caspasas Iniciadoras , Femenino , Ratones , Ratones Endogámicos C57BL , Infiltración NeutrófilaRESUMEN
Increasing evidence indicates that human cytomegalovirus (HCMV) populations under the influence of host environment, can either be stable or rapidly differentiating, leading to tissue compartment colonization. We isolated previously from a 30-years old pregnant woman, a clinical isolate of HCMV, that we refered to as the HCMV-DB strain (accession number KT959235). The HCMV-DB clinical isolate demonstrated its ability to infect primary macrophages and to upregulate the proto-oncogene Bcl-3. We observed in this study that the genome of HCMV-DB strain is close to the genomes of other primary clinical isolates including the Toledo and the JP strains with the later having been isolated from a glandular tissue, the prostate. Using a phylogenetic analysis to compare the genes involved in virus entry, we observed that the HCMV-DB strain is close to the HCMV strain Merlin, the prototype HCMV strain. HCMV-DB infects human mammary epithelial cells (HMECs) which in turn display a ER-/PR-/HER2- phenotype, commonly refered to as triple negative. The transcriptome of HCMV-DB-infected HMECs presents the characteristics of a pro-oncogenic cellular environment with upregulated expression of numerous oncogenes, enhanced activation of pro-survival genes, and upregulated markers of cell proliferation, stemcellness and epithelial mesenchymal transition (EMT) that was confirmed by enhanced cellular proliferation and tumorsphere formation in vitro. Taken together our data indicate that some clinical isolates could be well adapted to the mammary tissue environment, as it is the case for the HCMV-DB strain. This could influence the viral fitness, ultimately leading to breast cancer development.
Asunto(s)
Mama/citología , Carcinogénesis , Citomegalovirus/fisiología , Células Epiteliales/metabolismo , Células Epiteliales/virología , Perfilación de la Expresión Génica , Proliferación Celular , Citomegalovirus/genética , Metilación de ADN , Células Epiteliales/citología , Genes Virales/genética , Humanos , Células MCF-7 , Filogenia , Proteolisis , Proto-Oncogenes Mas , Transducción de Señal , Internalización del VirusRESUMEN
BACKGROUND: Human cytomegalovirus (HCMV) establishes a persistent life-long infection and increasing evidence indicates HCMV infection can modulate signaling pathways associated with oncogenesis. Breast milk is an important route of HCMV transmission in humans and we hypothesized that mammary epithelial cells could be one of the main cellular targets of HCMV infection. METHODS: The infectivity of primary human mammary epithelial cells (HMECs) was assessed following infection with the HCMV-DB strain, a clinical isolate with a marked macrophage-tropism. The impact of HCMV-DB infection on expression of p53 and retinoblastoma proteins, telomerase activity and oncogenic pathways (c-Myc, Akt, Ras, STAT3) was studied. Finally the transformation of HCMV-DB infected HMECs was evaluated using soft agar assay. CTH cells (CMV Transformed HMECs) were detected in prolonged cultures of infected HMECs. Tumor formation was observed in NOD/SCID Gamma (NSG) mice injected with CTH cells. Detection of long non coding RNA4.9 (lncRNA4.9) gene was assessed in CTH cells, tumors isolated from xenografted NSG mice and biopsies of patients with breast cancer using qualitative and quantitative PCR. RESULTS: We found that HCMV, especially a clinical strain named HCMV-DB, infects HMECs in vitro. The clinical strain HCMV-DB replicates productively in HMECs as evidenced by detection of early and late viral transcripts and proteins. Following infection of HMECs with HCMV-DB, we observed the inactivation of retinoblastoma and p53 proteins, the activation of telomerase activity, the activation of the proto-oncogenes c-Myc and Ras, the activation of Akt and STAT3, and the upregulation of cyclin D1 and Ki67 antigen. Colony formation was observed in soft agar seeded with HCMV-DB-infected HMECs. Prolonged culture of infected HMECs resulted in the development of clusters of spheroid cells that we called CTH cells (CMV Transformed HMECs). CTH cells when injected in NOD/SCID Gamma (NSG) mice resulted in the development of tumors. We detected in CTH cells the presence of a HCMV signature corresponding to a sequence of the long noncoding RNA4.9 (lncRNA4.9) gene. We also found the presence of the HCMV lncRNA4.9 sequence in tumors isolated from xenografted NSG mice injected with CTH cells and in biopsies of patients with breast cancer using qualitative and quantitative PCR. CONCLUSIONS: Our data indicate that key molecular pathways involved in oncogenesis are activated in HCMV-DB-infected HMECs that ultimately results in the transformation of HMECs in vitro with the appearance of CMV-transformed HMECs (CTH cells) in culture. CTH cells display a HCMV signature corresponding to a lncRNA4.9 genomic sequence and give rise to fast growing triple-negative tumors in NSG mice. A similar lncRNA4.9 genomic sequence was detected in tumor biopsies of patients with breast cancer.
Asunto(s)
Mama/patología , Carcinogénesis/patología , Citomegalovirus/metabolismo , Células Epiteliales/patología , Células Epiteliales/virología , Animales , Carcinogénesis/genética , Agregación Celular , Proliferación Celular , Transformación Celular Neoplásica/patología , Células Cultivadas , Ensayo de Unidades Formadoras de Colonias , Ciclina D1/genética , Ciclina D1/metabolismo , Citomegalovirus/genética , Infecciones por Citomegalovirus/patología , Infecciones por Citomegalovirus/virología , Células Epiteliales/metabolismo , Femenino , Humanos , Ratones Endogámicos NOD , Ratones SCID , Fosforilación , Filogenia , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Esferoides Celulares/patología , Telomerasa/genética , Telomerasa/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Regulación hacia Arriba , Proteínas Virales/genética , Proteínas Virales/metabolismo , Replicación ViralRESUMEN
Sexually transmitted infections with Chlamydia trachomatis and/or Neisseria gonorrhoeae and rates of pelvic inflammatory disease (PID) in women continue to rise, with reinfection being common because of poor adaptive immunity. Diagnosis remains imprecise, and pathogenesis data are derived primarily from monoinfection of mice with C. trachomatis or N. gonorrhoeae By comparing blood mRNA responses of women with C. trachomatis- and/or N. gonorrhoeae-induced PID and histologic endometritis with those from women with C. trachomatis and/or N. gonorrhoeae infection limited to their cervix and asymptomatic uninfected women determined via microarray, we discovered important pathogenic mechanisms in PID and response differences that provide a pathway to biomarker discovery. Women with N. gonorrhoeae- and/or C. trachomatis-induced PID exhibit overexpression of myeloid cell genes and suppression of protein synthesis, mitochondrial oxidative phosphorylation, and T cell-specific genes. Coinfected women exhibited the greatest activation of cell death pathways and suppression of responses essential for adaptive immunity. Women solely infected with C. trachomatis expressed elevated levels of type I and type II IFN genes, and enhanced type I IFN-induced chemokines in cervical secretions were associated with ascension of C. trachomatis to the endometrium. Blood microarrays reveal discrete pathobiological endotypes in women with PID that are driven by pathogen invasion of the upper genital tract.
Asunto(s)
Infecciones por Chlamydia/inmunología , Gonorrea/inmunología , Enfermedad Inflamatoria Pélvica/sangre , Enfermedad Inflamatoria Pélvica/etiología , Enfermedad Inflamatoria Pélvica/inmunología , Inmunidad Adaptativa/inmunología , Adolescente , Adulto , Infecciones por Chlamydia/complicaciones , Chlamydia trachomatis/inmunología , Coinfección , Femenino , Gonorrea/complicaciones , Humanos , Neisseria gonorrhoeae/inmunología , Adulto JovenRESUMEN
Chlamydia muridarum and Chlamydia caviae have equivalent growth rates in mouse epithelial cells but only C. muridarum replicates inside mouse macrophages, while C. caviae does not. Macrophages infected with C. muridarum or C. caviae were used to address the hypothesis that the early signaling pathways initiated during infection depend on the fate of chlamydiae in the host cell. Transmission electron microscopy of C. muridarum-infected macrophages showed intact chlamydial elementary bodies and reticulate bodies 2 h postinfection in compact vacuoles. Conversely, in macrophages infected with C. caviae, chlamydiae were observed in large phagocytic vacuoles. Furthermore, C. caviae infections failed to develop into inclusions or produce viable bacteria. Expression of proinflammatory cytokines TNFα, IL-1ß and MMP13 was similar in C. caviae- or C. muridarum-infected macrophages at 3 h postinfection, indicating that chlamydial survival is not required for initiation of these responses. IL-1ß secretion, dependent on inflammasome activation, occurred in C. caviae-infected macrophages despite no chlamydial growth. Conversely, IFNß mRNA was observed only in C. muridarum- but not in C. caviae-infected macrophages. These data demonstrate that differential signaling events are initiated during a productive versus nonproductive chlamydial infection in a macrophage.
Asunto(s)
Infecciones por Chlamydia/metabolismo , Infecciones por Chlamydia/microbiología , Chlamydia/fisiología , Espacio Intracelular/microbiología , Macrófagos/metabolismo , Macrófagos/microbiología , Transducción de Señal , Animales , Línea Celular , Chlamydia/crecimiento & desarrollo , Chlamydia/ultraestructura , Infecciones por Chlamydia/genética , Infecciones por Chlamydia/patología , Endosomas/metabolismo , Endosomas/ultraestructura , Regulación de la Expresión Génica , Inflamación/genética , Interleucina-1beta , Macrófagos/patología , Macrófagos/ultraestructura , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
Proton transfer processes from mineral acids to bases (HX, where X = F, Cl, Br and I to ammonia) are normally feasible in solution and they cannot spontaneously occur in the gas phase. We demonstrate that this process can be feasible under nanoconfinement without using any solvent molecules. More interestingly, in contrast to the general observation, halide ions except fluoride behave like protons under high confinement, leading to the formation of NH3X instead of NH4 ions. The triggering transformation of hydrogen bonded to the proton transferred complex under nanoconfinement is explained based on the thermodynamic quantity, static pressure.
RESUMEN
UNLABELLED: Histone methyltransferase inhibitors (HMTis) and histone deacetylase inhibitors (HDACis) are reported to synergistically induce the expression of latent human immunodeficiency virus type 1 (HIV-1), but studies have largely been performed with cell lines. As specific and potent HMTis directed at EZH1 (enhancer of zeste 2 Polycomb repressive complex 2 subunit 1)/EZH2 are now in human testing, we wished to rigorously test such an inhibitor in a primary resting T-cell model of HIV latency. We found that GSK343, a potent and selective EZH2/EZH1 inhibitor, reduced trimethylation of histone 3 at lysine 27 (H3K27) of the HIV provirus in resting cells. Remarkably, this epigenetic change was not associated with increased proviral expression in latently infected resting cells. However, following the reduction in H3K27 at the HIV long terminal repeat (LTR), subsequent exposure to the HDACi suberoylanilide hydroxamic acid or vorinostat (VOR) resulted in increases in HIV gag RNA and HIV p24 antigen production that were up to 2.5-fold greater than those induced by VOR alone. Therefore, in primary resting CD4(+) T cells, true mechanistic synergy in the reversal of HIV latency may be achieved by the combination of HMTis and HDACis. Although other cellular effects of EZH2 inhibition may contribute to the sensitization of the HIV LTR to subsequent exposure to VOR, and to increase viral antigen production, this synergistic effect is directly associated with H3K27 demethylation at nucleosome 1 (Nuc-1). Based upon our findings, the combination of HMTis and HDACis should be considered for testing in animal models or clinical trials. IMPORTANCE: Demethylation of H3K27 mediated by the histone methyltransferase inhibitor GSK343 in primary resting T cells is slow, occurring over 96 h, but by itself does not result in a significant upregulation of cell-associated HIV RNA expression or viral antigen production. However, following H3K27 demethylation, latent viral expression within infected primary resting CD4(+) T cells is synergistically increased upon exposure to the histone deacetylase inhibitor vorinostat. Demethylation at H3K27 sensitizes the HIV promoter to the effects of an HDACi and provides a proof-of-concept for the testing of combination epigenetic approaches to disrupt latent HIV infection, a necessary step toward the eradication of HIV infection.
Asunto(s)
Linfocitos T CD4-Positivos/virología , VIH/efectos de los fármacos , Histonas/metabolismo , Ácidos Hidroxámicos/farmacología , Indazoles/farmacología , Piridonas/farmacología , Análisis de Varianza , Inmunoprecipitación de Cromatina , Proteína Potenciadora del Homólogo Zeste 2 , Ensayo de Inmunoadsorción Enzimática , VIH/fisiología , Humanos , Immunoblotting , Metilación/efectos de los fármacos , Complejo Represivo Polycomb 2/antagonistas & inhibidores , Regiones Promotoras Genéticas/genética , Provirus/genética , ARN Interferente Pequeño/genética , VorinostatRESUMEN
BACKGROUND: A single dose of the histone deacetylase inhibitor vorinostat (VOR) up-regulates HIV RNA expression within resting CD4(+) T cells of treated, aviremic human immunodeficiency virus (HIV)-positive participants. The ability of multiple exposures to VOR to repeatedly disrupt latency has not been directly measured, to our knowledge. METHODS: Five participants in whom resting CD4(+) T-cell-associated HIV RNA (rc-RNA) increased after a single dose of VOR agreed to receive daily VOR Monday through Wednesday for 8 weekly cycles. VOR serum levels, peripheral blood mononuclear cell histone acetylation, plasma HIV RNA single-copy assays, rc-RNA, total cellular HIV DNA, and quantitative viral outgrowth assays from resting CD4(+) T cells were assayed. RESULTS: VOR was well tolerated, with exposures within expected parameters. However, rc-RNA measured after dose 11 (second dose of cycle 4) or dose 22 (second dose of cycle 8) increased significantly in only 3 of the 5 participants, and the magnitude of the rc-RNA increase was much reduced compared with that after a single dose. Changes in histone acetylation were blunted. Results of quantitative viral outgrowth and other assays were unchanged. CONCLUSIONS: Although HIV latency is disrupted by an initial VOR dose, the effect of subsequent doses in this protocol was much reduced. We hypothesize that the global effect of VOR results in a refractory period of ≥ 24 hours. The optimal schedule for VOR administration is still to be defined.
Asunto(s)
Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/virología , VIH-1/crecimiento & desarrollo , Inhibidores de Histona Desacetilasas/administración & dosificación , Ácidos Hidroxámicos/administración & dosificación , Adulto , Sangre/virología , ADN Viral/análisis , ADN Viral/genética , Humanos , Leucocitos Mononucleares/virología , Masculino , Persona de Mediana Edad , ARN Viral/sangre , VorinostatRESUMEN
OBJECTIVES: There has been increased interest in the possible role of human cytomegalovirus (HCMV) in carcinogenesis during the last decade. HCMV seroprevalence was enhanced in patients with hepatocellular carcinoma (HCC) but a possible relationship between HCC and HCMV infection remained to be assessed. The aim of this work was to investigate the pro-tumor influence of HCMV on primary human hepatocytes (PHH) and HepG2 cells. METHODS: Following infection of PHH and HepG2 cells by two different strains of HCMV, we measured the production of IL-6 in culture supernatants by ELISA and the protein levels of STAT3, pSTAT3, JAK, cyclin D1, survivin, p53, p21, and Mdm2 by western Blotting in infected and uninfected cells. Cell proliferation and transformation were investigated using Ki67Ag expression measurement and soft-agar colony formation assay respectively. RESULTS: Infection of HepG2 cells and PHH by HCMV resulted in the production of IL-6 and the subsequent activation of the IL-6R-JAK-STAT3 pathway. HCMV increased the expression of cyclin D1 and survivin. Cell proliferation was enhanced in HepG2 and PHH infected with HCMV, despite a paradoxical overexpression of p53 and p21. More importantly, we observed the formation of colonies in soft agar seeded with PHH infected with HCMV and when we challenged the HepG2 cultures to form tumorspheres, we found that the HCMV-infected cultures formed 2.5-fold more tumorspheres than uninfected cultures. CONCLUSION: HCMV activated the IL-6-JAK-STAT3 pathway in PHH and HepG2 cells, favored cellular proliferation, induced PHH transformation and enhanced HepG2 tumorsphere formation. Our observations raise the possibility that HCMV infection might be involved in the genesis of hepatocellular carcinoma.
Asunto(s)
Citomegalovirus/fisiología , Hepatocitos/metabolismo , Hepatocitos/virología , Interleucina-6/metabolismo , Quinasas Janus/metabolismo , Factor de Transcripción STAT3/metabolismo , Animales , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/virología , Proliferación Celular , Ciclina D1/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Activación Enzimática , Células Hep G2 , Hepatocitos/patología , Humanos , Proteínas Inhibidoras de la Apoptosis/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/virología , Ratones , Survivin , Proteína p53 Supresora de Tumor/metabolismo , Regulación hacia ArribaRESUMEN
After entry into the target cell and reverse transcription, HIV-1 genes are integrated into the host genome. It is now well established that the viral promoter activity is directly governed by its chromatin environment. Nuc-1, a nucleosome located immediately downstream of the HIV-1 transcriptional initiation site directly impedes long-terminal repeat (LTR) activity. Epigenetic modifications and disruption of Nuc-1 are a prerequisite to the activation of LTR-driven transcription and viral expression. The compaction of chromatin and its permissiveness for transcription are directly dependent on the post-translational modifications of histones such as acetylation, methylation, phosphorylation and ubiquitination. Understanding the molecular mechanisms underlying HIV-1 transcriptional silencing and activation is thus a major challenge in the fight against AIDS and will certainly lead to new therapeutic tools.
Asunto(s)
Metilación de ADN/fisiología , Epigénesis Genética/fisiología , Regulación Viral de la Expresión Génica/fisiología , Infecciones por VIH/metabolismo , VIH-1/fisiología , Histonas/metabolismo , Nucleosomas/metabolismo , Transcripción Genética/fisiología , Azepinas/farmacología , Epigénesis Genética/efectos de los fármacos , Regulación Viral de la Expresión Génica/efectos de los fármacos , Infecciones por VIH/tratamiento farmacológico , VIH-1/genética , Histona Acetiltransferasas/metabolismo , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/metabolismo , N-Metiltransferasa de Histona-Lisina/antagonistas & inhibidores , Humanos , Ésteres del Forbol/farmacología , Piperazinas/farmacología , Quinazolinas/farmacología , Integración Viral/fisiología , Productos del Gen tat del Virus de la Inmunodeficiencia Humana/metabolismoRESUMEN
BACKGROUND: Hepatocellular carcinoma (HCC) is the most common primary liver cancer, usually arising after years of chronic liver inflammation that could result from viral infections such as hepatitis B virus (HBV) and hepatitic C virus (HCV) infections. Human cytomegalovirus (HCMV) infects primary human hepatocytes and remains an important cause of morbidity in immunocompromised persons where it may manifest as symptomatic end-organ disease including hepatitis. The goal of the present study was to determine a potential correlation between HCMV infection and the appearance of HCC. METHODS: First, we analyzed the seroprevalence of HCMV in a cohort of 11,318 patients hospitalized between 2003 and 2009 in different departments of a French University Hospital. Second, we studied HCMV seroprevalence in a cohort of 190 subjects who were stratified on the basis of age, gender, HCC, cirrhosis (Cir), and the exposition to hepatotropic viruses (HCV, HBV). We further determined whether HCMV DNA was present specifically in tumour area in liver biopsies from HCC-positive patients by using nested PCR. RESULTS: We found that the HCMV seroprevalence was high in the Hepatology department. The HCMV seroprevalence was significantly higher in patients infected with HCV and/or HBV than in patients who were not infected by those later viruses (76.2% versus 56.5%, p < 0.001). The HCMV seroprevalence was significantly higher in patients with HCC (74%) and lower in patients without HCC (54% for HCC-/Cir+ patients, 57% for HCC-/Cir- subjects). We observed a positive correlation between serum IL-6 levels and HCMV seroprevalence in cirrhotic patients, but not in HCC patients. Serum IL-6 levels correlated positively with C-reactive protein (CRP) levels. Preliminary histological studies from liver biopsies from HCC-positive patients highlighted that HCMV DNA can be detected in tumour area of some of the patients studied. CONCLUSIONS: Our results indicate that HCMV seroprevalence in patients with HCC is significantly higher than in patients without HCC, is positively correlated with serum IL-6 levels in cirrhotic patients, and is positively associated with the presence of other hepatotropic viruses such as HCV and HBV.
Asunto(s)
Carcinoma Hepatocelular/complicaciones , Carcinoma Hepatocelular/epidemiología , Infecciones por Citomegalovirus/complicaciones , Infecciones por Citomegalovirus/epidemiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Carcinoma Hepatocelular/virología , Niño , Preescolar , Coinfección , Comorbilidad , Citomegalovirus/aislamiento & purificación , Femenino , Francia/epidemiología , Hepacivirus/aislamiento & purificación , Virus de la Hepatitis B/aislamiento & purificación , Hospitales Universitarios , Humanos , Interleucina-6/sangre , Hígado/patología , Hígado/virología , Masculino , Persona de Mediana Edad , Estudios SeroepidemiológicosRESUMEN
One of the hallmarks of Human Immunodeficiency Virus-1 (HIV-1) infection is progressive depletion of the infected and bystander CD4+ T-cells by apoptosis. Different mitochondrial proteins have been implicated in this apoptotic process; however, the role of different subunits of mitochondrial oxidative phosphorylation (OXPHOS) complexes in apoptosis is not clearly understood. Some of the OXPHOS complex subunits seem to perform other functions in addition to their primary role in energy generating process. GRIM-19 (gene associated with retinoid-interferon-induced-mortality-19), a subunit of mitochondrial complex-I was previously implicated in Interferon-ß and retionoic acid induced apoptosis in many tumor cells. In this study we report, using differential gene expression analysis, that GRIM-19 is up-regulated in HIV-1 infected apoptotic T-cells. A temporal up regulation of this subunit was observed in different HIV-1 infected T-cell lines and human PBMC and the extent of increase correlated to increasing apoptosis and virus production. Moreover, silencing GRIM-19 in HIV-1 infected cells reduced apoptosis, indicating its involvement in HIV-1 induced T-cell death.
Asunto(s)
Proteínas Reguladoras de la Apoptosis , Apoptosis , Complejo I de Transporte de Electrón/metabolismo , Regulación Enzimológica de la Expresión Génica/genética , Infecciones por VIH/enzimología , Infecciones por VIH/inmunología , Mitocondrias/enzimología , Mitocondrias/virología , NADH NADPH Oxidorreductasas , Linfocitos T/enzimología , Linfocitos T/virología , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/inmunología , Proteínas Reguladoras de la Apoptosis/metabolismo , Línea Celular Tumoral , Clonación Molecular , Complejo I de Transporte de Electrón/genética , Regulación Enzimológica de la Expresión Génica/inmunología , Silenciador del Gen , Infecciones por VIH/fisiopatología , Infecciones por VIH/virología , VIH-1/inmunología , VIH-1/fisiología , Humanos , Mitocondrias/genética , Mitocondrias/inmunología , NADH NADPH Oxidorreductasas/genética , NADH NADPH Oxidorreductasas/inmunología , NADH NADPH Oxidorreductasas/metabolismo , Fosforilación Oxidativa , Estaurosporina/farmacología , Linfocitos T/citología , Linfocitos T/inmunología , Factor de Necrosis Tumoral alfa/farmacología , Regulación hacia ArribaRESUMEN
Human Immunodeficiency Virus-1 (HIV-1) infection leads to CD4+ T cell depletion primarily by apoptosis employing both intrinsic and extrinsic pathways. Although extensive literature exists about the role of mitochondrial proteins in HIV induced T cell apoptosis, there is little understanding about the role of different components of mitochondrial oxidative phosphorylation (OXPHOS) system in apoptosis. The OXPHOS system comprises of five enzyme complexes (Complex I, II, III, IV, V), subunits of which have been implicated in various functions in addition to their primary role in energy generating process. Here using differential gene expression analysis, we report that Cytochrome Oxidase-II (COX-II), a subunit of Complex-IV is induced in HIV infected apoptotic T-cells. We also observe a temporal up regulation of this subunit across different T-cell lines and in human PBMCs. Further analysis indicates increase in expression of majority of Complex-IV subunits with concomitant increase in Complex-IV activity in HIV infected T cells. Silencing of COX-II expression leads to reduced apoptosis in infected T-cells, indicating its importance in apoptosis. Furthermore, our results also show that the activities of enzyme complexes I, II and III are decreased while those of Complex IV and V are increased at the time of acute infection and apoptosis. This differential regulation in activities of OXPHOS system complexes indicate a complex modulation of host cell energy generating system during HIV infection that ultimately leads to T cell apoptosis.