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1.
J Infect Dis ; 210(3): 392-9, 2014 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-24550442

RESUMO

BACKGROUND: Epstein-Barr Virus (EBV) is involved in a wide range of malignancies, particularly in immunocompromised subjects. In Africa, EBV primary infection occurs during early childhood, but little is known about the EBV load in Human Immunodeficiency Virus type 1 (HIV-1)-infected children. METHODS: Blood samples from 213 HIV-1-infected children, 140 of whom were receiving antiretroviral therapy (ART), were collected at the Nsambya Hospital in Kampala, Uganda, and obtained for dried blood spot analysis. Nucleic acids were extracted and analyzed for quantification of EBV types 1 and 2; 16S ribosomal DNA (rDNA), a marker of microbial translocation; and HIV-1 RNA. RESULTS: Ninety-two of 140 children (66%) receiving ART and 57 of 73 ART-naive children (78%) had detectable EBV DNA levels. Coinfection with both EBV types was less frequent in ART-treated children than in ART-naive children (odds ratio, 0.54 [95% confidence interval {CI}, .30-.98]; P = .042). Mean EBV DNA levels (±standard deviation) were lower in the former (3.99 ± 0.59 vs 4.22 ± 0.54 log10 copies/mL; P = .006) and tended to be inversely associated with ART duration. EBV DNA levels were higher in children with an HIV-1 RNA load of > 3 log10 copies/mL of blood (regression coefficient, 0.32 [95% CI, .05-.59]; P = .020) and correlated with circulating 16S rDNA levels (rs = 0.25 [95% CI, .02-.46]; P = .031). CONCLUSIONS: These findings suggest that ART, by limiting HIV-1 replication, microbial translocation, and related immune activation, prevents superinfection with both EBV types and keeps EBV viremia down, thus potentially reducing the risk of EBV-associated lymphomas.


Assuntos
Infecções por Vírus Epstein-Barr/virologia , Infecções por HIV/complicações , HIV-1/isolamento & purificação , Herpesvirus Humano 4/isolamento & purificação , Carga Viral , Adolescente , Fármacos Anti-HIV/uso terapêutico , Criança , Pré-Escolar , DNA Viral/isolamento & purificação , Feminino , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Humanos , Lactente , Masculino
2.
New Microbiol ; 35(3): 249-57, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22842595

RESUMO

Variability in the susceptibility to HIV-1 infection and disease progression depends on both virus and host determinants. Some exposed individuals remain HIV-1-uninfected and HIV-1-infected subjects develop disease at varying intervals with a small percentage remaining long-term non-progressors. As innate immunity is the earliest response to microbial entry and injury, host factors that impact innate immunity may play a role in viral infectivity and pathogenesis. In the pediatric population the interactions between the virus and the host may be of particular relevance due to the still developing adaptive immune system. Data indicate that genetic variants of defensins and Toll-Like Receptors (TLRs), key elements of innate immunity, play a role in mother-to-child transmission (MTCT) of HIV-1, and in the outcome of pediatric HIV-1 disease. Although the mechanisms by which these genetic variants influence HIV-1 interactions with the host are still largely unknown, defensins and TLRs, along with their link with regulatory T cells (Tregs), may play a critical role in the onset and persistence of immune activation, a hallmark of HIV-1 disease.


Assuntos
Progressão da Doença , Infecções por HIV/imunologia , HIV-1/imunologia , Interações Hospedeiro-Patógeno , Imunidade Inata , Criança , Suscetibilidade a Doenças/imunologia , Infecções por HIV/transmissão , Infecções por HIV/virologia , HIV-1/patogenicidade , Humanos , Polimorfismo de Nucleotídeo Único , Linfócitos T Reguladores/imunologia , Receptor Toll-Like 9/genética , Receptor Toll-Like 9/imunologia , beta-Defensinas/genética , beta-Defensinas/imunologia
3.
Cancers (Basel) ; 14(17)2022 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-36077711

RESUMO

Multiple myeloma (MM) is a malignant plasma cell (PC) neoplasm, which also displays pathological bone involvement. Clonal expansion of MM cells in the bone marrow causes a perturbation of bone homeostasis that culminates in MM-associated bone disease (MMABD). We previously demonstrated that the S/T kinase CK1α sustains MM cell survival through the activation of AKT and ß-catenin signaling. CK1α is a negative regulator of the Wnt/ß-catenin cascade, the activation of which promotes osteogenesis by directly stimulating the expression of RUNX2, the master gene regulator of osteoblastogenesis. In this study, we investigated the role of CK1α in the osteoblastogenic potential of mesenchymal stromal cells (MSCs) and its involvement in MM-MSC cross-talk. We found that CK1α silencing in in vitro co-cultures of MMs and MSCs modulated RUNX2 expression differently in PCs and in MSCs, mainly through the regulation of Wnt/ß-catenin signaling. Our findings suggest that the CK1α/RUNX2 axis could be a potential therapeutic target for constraining malignant PC expansion and supporting the osteoblastic transcriptional program of MSCs, with potential for ameliorating MMABD. Moreover, considering that Lenalidomide treatment leads to MM cell death through Ikaros, Aiolos and CK1α proteasomal degradation, we examined its effects on the osteoblastogenic potential of MSC compartments.

4.
Oncotarget ; 8(9): 14604-14619, 2017 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-28099937

RESUMO

Recent evidence indicates that protein kinase CK1α may support the growth of multiple myeloma (MM) plasma cells. Here, by analyzing a large cohort of MM cases, we found that high CK1α mRNA levels are virtually associated with all MM patients. Moreover, we provided functional evidence that CK1α activity is essential for malignant plasma cell survival even in the protective niche generated by co-cultures with bone marrow stromal cells. We demonstrated that CK1α inactivation, while toxic for myeloma cells, is dispensable for the survival of healthy B lymphocytes and stromal cells. Disruption of CK1α function in myeloma cells resulted in decreased Mdm2, increased p53 and p21 and reduced expression of ß-catenin and AKT. These effects were mediated partially by p53 and caspase activity. Finally, we discovered that CK1α inactivation enhanced the cytotoxic effect of both bortezomib and lenalidomide. Overall, our study supports a role for CK1α as a potential therapeutic target in MM in combination with proteasome inhibitors and/or immunomodulatory drugs.


Assuntos
Caseína Quinase I/genética , Mieloma Múltiplo/genética , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/genética , beta Catenina/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Bortezomib/farmacologia , Caseína Quinase I/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Células Cultivadas , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Lenalidomida , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacos , Talidomida/análogos & derivados , Talidomida/farmacologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , beta Catenina/metabolismo
5.
AIDS ; 30(9): 1363-73, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-26990630

RESUMO

OBJECTIVE: Several pieces of evidence indicate that HIV-infected adults undergo premature aging. The effect of HIV and antiretroviral therapy (ART) exposure on the aging process of HIV-infected children may be more deleterious since their immune system coevolves from birth with HIV. DESIGN: Seventy-one HIV-infected (HIV+), 65 HIV-exposed-uninfected (HEU), and 56 HIV-unexposed-uninfected (HUU) children, all aged 0-5 years, were studied for biological aging and immune senescence. METHODS: Telomere length and T-cell receptor rearrangement excision circle levels were quantified in peripheral blood cells by real-time PCR. CD4 and CD8 cells were analysed for differentiation, senescence, and activation/exhaustion markers by flow cytometry. RESULTS: Telomere lengths were significantly shorter in HIV+ than in HEU and HUU children (overall, P < 0.001 adjusted for age); HIV+ ART-naive (42%) children had shorter telomere length compared with children on ART (P = 0.003 adjusted for age). T-cell receptor rearrangement excision circle levels and CD8 recent thymic emigrant cells (CD45RACD31) were significantly lower in the HIV+ than in control groups (overall, P = 0.025 and P = 0.005, respectively). Percentages of senescent (CD28CD57), activated (CD38HLA-DR), and exhausted (PD1) CD8 cells were significantly higher in HIV+ than in HEU and HUU children (P = 0.004, P < 0.001, and P < 0.001, respectively). Within the CD4 cell subset, the percentage of senescent cells did not differ between HIV+ and controls, but programmed cell death receptor-1 expression was upregulated in the former. CONCLUSIONS: HIV-infected children exhibit premature biological aging with accelerated immune senescence, which particularly affects the CD8 cell subset. HIV infection per se seems to influence the aging process, rather than exposure to ART for prophylaxis or treatment.


Assuntos
Senilidade Prematura , Infecções por HIV/patologia , Fenômenos do Sistema Imunitário , Biomarcadores/análise , Linfócitos T CD4-Positivos/química , Linfócitos T CD4-Positivos/fisiologia , Linfócitos T CD8-Positivos/química , Linfócitos T CD8-Positivos/fisiologia , Diferenciação Celular , Senescência Celular , Pré-Escolar , Feminino , Rearranjo Gênico , Humanos , Lactente , Leucócitos Mononucleares/fisiologia , Masculino , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Antígenos de Linfócitos T/genética , Encurtamento do Telômero
6.
J Virus Erad ; 1(3): 140-7, 2015 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-27482405

RESUMO

A body of evidence indicates that a threshold level of the virus is required to establish systemic and persistent HIV infection in the host and that this level depends on virus-host interactions. Mother-to-child transmission (MTCT) of HIV is the main source of paediatric HIV infection and occurs when the host's immune system is still developing. Thus, innate resistance and immunity, rather than adaptive immune response, may be the main drivers in restricting the establishment of HIV reservoirs and the long-lived persistence of HIV infection in infants. Genetic variations in HIV co-receptors and their ligands, as well as in Toll-like receptors and defensins, key elements of innate immunity, have been demonstrated to influence the risk of perinatal HIV infection and disease progression in HIV-infected infants. Early treatments with combined antiretroviral therapy (cART) restrict paediatric infection by reducing the level of the transmitted/infecting virus to below the threshold required for the onset of immune response to the virus and also significantly reduce HIV reservoirs. However, despite long periods with no signs and symptoms of HIV infection, all early cART-treated children who later discontinued cART had a rebound of HIV, except for one case in whom a period of viral remission occurred. Which parameters predict viral remission or viral rebound after cART discontinuation? Could early cART prevent rather than just reduce the establishment of viral reservoirs? And, if so, how? Answers to these questions are also important in order to optimise the use of early cART in infants at high risk of HIV infection.

7.
Cancer Lett ; 347(1): 38-45, 2014 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-24513180

RESUMO

Highly active antiretroviral therapy (HAART) changed the natural history of pediatric HIV infection. This review focuses on trends of HIV-associated cancers in childhood in the HAART era and analyses potential pathogenetic mechanisms. HAART reduced AIDS-defined-malignancies (ADM), but incidence of several non-ADM is increasing. HIV-associated immune activation and inflammation, promoting tumorigenesis, can only partially be reduced by HAART. In addition, HIV-infected children may undergo accelerated immune senescence that favors cancer development. How HAART affects this condition is an open question. Lastly, there is no evidence that prenatal exposure to HAART increases the risk of cancer in childhood, but long-term studies are needed.


Assuntos
Terapia Antirretroviral de Alta Atividade , Infecções por HIV/tratamento farmacológico , Neoplasias/complicações , Criança , Infecções por HIV/complicações , Infecções por HIV/imunologia , Humanos , Neoplasias/imunologia
8.
Front Microbiol ; 4: 311, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24151490

RESUMO

Epstein-Barr virus (EBV) is a ubiquitous human γ-herpes virus which establishes a life-long asymptomatic infection in immunocompetent hosts. In human immunodeficiency virus type 1 (HIV-1) infected patients, the impaired immunosurveillance against EBV may favor the development of EBV-related diseases, ranging from lymphoproliferative disorders to B cell non-Hodgkin's lymphomas (NHL). Antiretroviral therapy (ART) has significantly modified the natural course of HIV-1 infection, resulting in decreased HIV-1 plasmaviremia, increased CD4 lymphocytes, and decreased opportunistic infections, indicating a restoration of immune functions. However, the impact of ART appears to be less favorable on EBV-related malignancies than on other AIDS-defining tumors, such as Kaposi's sarcoma, and NHL remains the most common cancer during the ART era. EBV-driven tumors are associated with selective expression of latent oncogenic proteins, but uncontrolled lytic cycle with virus replication and/or reactivation may favor cell transformation, at least in the early phases. Several host's factors may promote EBV reactivation and replication; besides immunodepression, inflammation/chronic immune stimulation may play an important role. Microbial pathogen-associated molecular patterns and endogenous damage-associated molecular patterns, through Toll-like receptors, activate the immune system and may promote EBV reactivation and/or polyclonal expansion of EBV-infected cells. A body of evidence suggests that chronic immune stimulation is a hallmark of HIV-1 pathogenesis and may persist even in ART-treated patients. This review focuses on lymphomagenesis driven by EBV both in the context of the natural history of HIV-1 infection and in ART-treated patients. Understanding the mechanisms involved in the expansion of EBV-infected cells is a premise for the identification of prognostic markers of EBV-associated malignancies.

9.
Exp Gerontol ; 48(12): 1436-42, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24120567

RESUMO

BACKGROUND: The challenge of immune senescence has never been addressed in elderly cancer patients. This study compares the thymic output and peripheral blood telomere length in ≥70year old cancer patients. PATIENTS AND METHODS: Fifty-two elderly cancer patients and 39 age-matched controls without personal history of cancer were enrolled. All patients underwent a Comprehensive Geriatric Assessment (CGA), from which a multidimensional prognostic index (MPI) score was calculated. Peripheral blood samples were studied for naïve and recent thymic emigrant (RTE) CD4(+) and CD8(+) cells by flow cytometry. T-cell receptor rearrangement excision circle (TREC) levels, telomere length and telomerase activity in peripheral blood cells were quantified by real-time PCR. RESULTS: The percentages of CD8(+) naïve and CD8(+) RTE cells and TREC levels were significantly lower in cancer patients than in controls (p=0.003, p=0.004, p=0.031, respectively). Telomere lengths in peripheral blood cells were significantly shorter in cancer patients than in controls (p=0.046) and did not correlate with age in patients, whereas it did in controls (r=-0.354, p=0.031). Short telomere (≤median)/low TREC (≤median) profile was associated with higher risk of cancer (OR=3.68 [95% CI 1.22-11.11]; p=0.021). Neither unfitness on CGA nor MPI score were significantly related to thymic output or telomere length in either group. CONCLUSIONS: Immune senescence is significantly worse in elderly cancer patients than in age-matched controls. The low thymic output and the shorter telomeres in peripheral blood cells of cancer patients may reflect a pre-existing condition which facilitates the onset of malignancies in elderly people.


Assuntos
Envelhecimento/imunologia , Neoplasias da Mama/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Neoplasias Colorretais/imunologia , Timo/imunologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/sangue , Envelhecimento/genética , Biomarcadores/sangue , Neoplasias da Mama/sangue , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Neoplasias Colorretais/sangue , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Feminino , Citometria de Fluxo , Rearranjo Gênico do Linfócito T , Avaliação Geriátrica , Humanos , Modelos Logísticos , Masculino , Razão de Chances , Reação em Cadeia da Polimerase , Estudos Prospectivos , Fatores de Risco , Telomerase/metabolismo , Encurtamento do Telômero , Timo/metabolismo
10.
AIDS ; 26(6): 765-8, 2012 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-22269973

RESUMO

Toll-like receptors (TLRs) and defensins (DEFs) play a crucial role in the host's innate immunity and may influence HIV-1 disease progression. We investigated the impact of TLR9 +1174G > A, 1635A > G and DEFß1 -44C > G, -52G > A single nucleotide polymorphisms on the clinical outcome of 95 HIV-1-infected children. The TLR9 1635AG genotype and TLR9 [G;G] haplotype were associated with rapid disease progression, whereas the DEFß1 -44CG genotype and DEFß1 [G;G] haplotype correlated with a better clinical outcome.


Assuntos
Infecções por HIV/genética , Imunidade Inata/genética , Polimorfismo de Nucleotídeo Único/genética , Receptor Toll-Like 9/genética , beta-Defensinas/genética , Criança , Pré-Escolar , Progressão da Doença , Predisposição Genética para Doença , Infecções por HIV/imunologia , HIV-1 , Humanos , Lactente , Recém-Nascido
11.
J Clin Virol ; 53(3): 195-200, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22209290

RESUMO

BACKGROUND: Patients infected with HIV-1 are at high risk of developing Epstein-Barr Virus (EBV)-related diseases. Chronic immune activation is a hallmark of HIV-1 pathogenesis and may play a role in B-cell stimulation and expansion of EBV-infected cells. OBJECTIVES: The aim of the study was to define the relationship between parameters of immune activation and EBV load in HIV-1-infected subjects. STUDY DESIGN: A total of 156 HIV-1-infected patients were studied. EBV types 1 and 2 were quantified on peripheral blood mononuclear cells by multiplex real-time PCR. Plasma levels of cytokines and lipopolysaccharide (LPS) were determined by immunoenzymatic assays. B-cell activation was analyzed by flow cytometry. RESULTS: EBV-DNA was detected in 114 patients, and in all but 3 was EBV type 1. The median [interquartile] EBV-DNA load was 43[1-151] copies/10(5) PBMC. EBV-DNA load was higher in patients with detectable HIV-1 plasma viremia, despite good immunological status (CD4>500 cells/µl), than in patients with undetectable HIV-1 plasma viremia regardless of immunological status (46[5-136] copies/10(5) cells vs 17[1-56] copies/10(5) cells, p=0.008). Patients with high EBV-DNA load (>median value) had higher levels of LPS and proinflammatory cytokines (IL-6, IL-10 and TNF-α) than patients with low EBV load. Furthermore, percentages of activated B-cells correlated with EBV-DNA load (r(s)=0.754; p<0.001). CONCLUSIONS: Overall, these findings indicate a strong association between HIV-1 viremia, markers of immune activation and EBV load and suggest that persistence of HIV-1 viremia and immune activation, regardless of peripheral CD4 cell depletion/repopulation, may favor expansion of EBV-infected cells and onset of EBV-related malignancies.


Assuntos
Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/virologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , Herpesvirus Humano 4/isolamento & purificação , Adulto , Idoso , Terapia Antirretroviral de Alta Atividade , Linfócitos B/imunologia , Contagem de Linfócito CD4 , Células Cultivadas , Estudos de Coortes , Citocinas/sangue , DNA Viral/sangue , Infecções por Vírus Epstein-Barr/sangue , Feminino , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , HIV-1/isolamento & purificação , Herpesvirus Humano 4/genética , Interações Hospedeiro-Patógeno , Humanos , Leucócitos Mononucleares/imunologia , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , RNA Viral/sangue , Carga Viral
12.
PLoS One ; 7(9): e44460, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22962615

RESUMO

Stromal cell-Derived Factor 1 (SDF1) is the natural ligand of CXCR4, the coreceptor of HIV-1 X4 viruses. This study investigated the role of the single nucleotide polymorphism (SNP) rs1801157 (NM_000609.5:c.*519G>A) of the SDF1 gene in the natural history of mother-to-child transmission of HIV-1 and disease progression of HIV-1-infected children. The study was conducted in 428 children born to HIV-1-seropositive mothers, who had not undergone antiretroviral therapy (ART) during pregnancy, and in 120 HIV-1-infected children for whom the end-point was the onset of AIDS or the initiation of ART; 16 children developed early AIDS (<24 months of life), 13 from 24 to 84 months of age, and 14 had late AIDS (>84 months). The rs1801157 SNP was not associated with risk of perinatal infection in any genetic models tested. By contrast, this SNP influenced disease progression in a time-dependent manner. rs1801157 GA heterozygous children had a higher risk of late AIDS (HR = 6.3, 95%CI 1.9-20.7, p = 0.002) than children with the rs1801157 GG genotype. Children were studied for viral coreceptor usage at birth, after 84 months of age and/or at AIDS onset. While R5 viruses using CCR5 coreceptor were predominant at birth (94%) and at early AIDS (85%), viruses using CXCR4 coreceptor emerged during the course of infection and were detected in 49% of children older than 84 months and in 62% of late AIDS. The rs1801157 SNP did not influence the emergence of R5X4 viruses, but children with the rs1801157 GA genotype and R5X4 viruses were at significantly higher risk of late AIDS than children with rs1801157 GG genotype (OR = 8.0, 95% CI 1.2-52.2, p = 0.029). Our results indicate that the rs1801157 SNP does not influence perinatal infection, but impacts disease progression. This effect is time-dependent and linked to the coreceptor-usage of viral variants that undergo evolution during the course of HIV-1 infection.


Assuntos
Quimiocina CXCL12/genética , Infecções por HIV , HIV-1/fisiologia , Transmissão Vertical de Doenças Infecciosas , Receptores CXCR4/genética , Receptores Virais/genética , Idade de Início , Quimiocina CXCL12/metabolismo , Criança , Pré-Escolar , Progressão da Doença , Feminino , Genótipo , Infecções por HIV/epidemiologia , Infecções por HIV/genética , Infecções por HIV/transmissão , Infecções por HIV/virologia , Humanos , Itália/epidemiologia , Masculino , Polimorfismo de Nucleotídeo Único , Gravidez , Receptores CCR5/genética , Receptores CCR5/metabolismo , Receptores CXCR4/metabolismo , Receptores Virais/metabolismo
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