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1.
Infectio ; 23(supl.1): 97-106, dic. 2019. tab, graf
Artigo em Espanhol | LILACS-Express | ID: biblio-984513

RESUMO

Resumen Objetivo: Estimar las frecuencias de mutaciones y de polimorfismos adicionales asociados con resistencia a los fármacos inhibidores de la integrasa del virus de inmunodeficiencia humana tipo 1 (VIH-1). Metodología: Estudio descriptivo, de corte transversal, en individuos VIH-1 positivos de la ciudad de Medellín, quienes no habían recibido tratamiento antirretroviral. En ellos se determinó, a través del método de 2-dideoxinucleótidos y el sistema ABI3730XL, la secuencia del gen de la integrasa del VIH-1 a partir del ARN viral circulante, la cual fue analizada en la base de datos de resistencia a medicamentos antirretrovirales de la Universidad de Stanford y según reportes de literatura científica. Resultados: Se encontraron las siguientes mutaciones (con sus respectivas frecuencias): una mutación mayor, E138K (1/46), tres mutaciones accesorias G163E (3/46), L74I (3/50) y E157Q (2/48), una mutación no polimórfica A128T (1/49) y otras dos mutaciones potencialmente asociadas con resistencia a inhibidores de integrasa S230N (9/39) y S119P/R/T (4/47, 2/47 y 14/47, respectivamente). Conclusiones: En las secuencias analizadas, llama la atención la presencia de al menos una mutación asociada a resistencia a inhibidores de integrasa en el 14% de los individuos estudiados, sugiriendo una pobre presión selectiva de este tipo de fármacos en la población viral circulante en la zona.


Abstract Aim: To estimate the frequencies of major and accessory mutations, as well as additional polymorphisms associated with resistance to human immunodeficiency virus type 1 (VIH-1) integrase strand transfer inhibitors. Materials and methods: Descriptive cross-sectional study, focused on HIV-1 positive individuals from Medellín, recruited between 2013 and 2015, and that had not received antiretroviral therapy. In these patients, the sequence from HIV-1 integrase was determined from circulating viral RNA through Sanger chain termination method with the ABI3730XL system, and the sequences were analyzed using the HIV Drug Resistance Database from the University of Stanford, together with previous literature reports. Results: The following mutations associated with resistance to integrase strand transfer inhibitors, along with its respective frequencies, were found: one major mutation, E138K (1/46), three accessory mutations, G163E (3/46), L74I (3/50) and E157Q (2/48); one non-polymorphic mutation, A128T (1/49); and two mutations potentially associated with resistance to integrase strand transfer inhibitors, S230N (9/39) and S119P/R/T (4/47, 2/47 and 14/47, respectively). Conclusions: In the sequences analyzed, it is noteworthy the presence of at least one mutation related with resistance to integrase inhibitors in 14% of the studied patients, suggesting a poor selective pressure of this kind of drugs in the circulating viral population in our region.

2.
J Clin Virol ; 119: 17-23, 2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31445411

RESUMO

Classically, CD4+ T-cells have been referred as cytokine-producing cells and important players in immune responses by providing soluble factors that potentiate several effector immune functions. However, it is now evident that CD4+ T-cells can also elaborate cytotoxic responses, inducing apoptosis of target cells. Cytotoxic CD4+ T cells (CD4+ CTLs), exhibit cytolytic functions that resemble those of CD8+ T-cells; in fact, there is evidence suggesting that they may have a role in the control of viral infections. In this article, we discuss the role of CD4+ CTLs during HIV infection, where CD4+ CTLs have been associated with viral control and slow disease progression. In addition, we address the implication of CD4+ CTLs in the context of antiretroviral therapy and the partial reconstitution of CD8+ T-cells effector function.

3.
Infect Genet Evol ; 69: 267-278, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30808498

RESUMO

The introduction of highly active antiretroviral therapy (HAART) has significantly improved life expectancy of HIV-infected patients; nevertheless, it does not eliminate the virus from hosts, so a cure for this infection is crucial. Some strategies have employed the induction of anti-HIV CD8+ T cells. However, the high genetic variability of HIV-1 represents the biggest obstacle for these strategies, since immune escape mutations within epitopes restricted by Human Leukocyte Antigen class I molecules (HLA-I) abrogate the antiviral activity of these cells. We used a bioinformatics pipeline for the determination of such mutations, based on selection pressure and docking/refinement analyses. Fifty HIV-1 infected patients were recruited; HLA-A and HLA-B alleles were typified using sequence-specific oligonucleotide approach, and viral RNA was extracted for the amplification of HIV-1 gag, which was bulk sequenced and aligned to perform selection pressure analysis, using Single Likelihood Ancestor Counting (SLAC) and Fast Unconstrained Bayesian Approximation (FUBAR) algorithms. Positively selected sites were mapped into HLA-I-specific epitopes, and both mutated and wild type epitopes were modelled using PEP-FOLD. Molecular docking and refinement assays were carried out using AutoDock Vina 4 and FlexPepDock. Five positively selected sites were found: S54 at HLA-A*02 GC9, T84 at HLA-A*02 SL9, S125 at HLA-B*35 HY9, S173 at HLA-A*02/B*57 KS12 and I223 at HLA-B*35 HA9. Although some mutations have been previously described as immune escape mutations, the majority of them have not been reported. Molecular docking/refinement analysis showed that one combination of mutations at GC9, one at SL9, and eight at HY9 epitopes could act as immune escape mutations. Moreover, HLA-A*02-positive patients harbouring mutations at KS12, and HLA-B*35-positive patients with mutations at HY9 have significantly higher plasma viral loads than patients lacking such mutations. Thus, HLA-A and -B alleles could be shaping the genetic diversity of HIV-1 through the selection of potential immune escape mutations.

4.
PLoS One ; 14(1): e0210540, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30625227

RESUMO

Despite the suppression of viral replication induced by the highly active anti-retroviral therapy (HAART), an increased immune activation and inflammatory state persists in HIV-infected patients, contributing to lower treatment response and immune reconstitution, and development of non-AIDS conditions. The chronic activation and inflammation affect the functionality and differentiation of CD8+ T-cells, particularly reducing their cytotoxic capacity, which is critical in the control of HIV replication. Although previous studies have shown that HAART induce a partial immune reconstitution, its effect on CD8+ T-cells cytotoxic function, as well as its relationship with the inflammatory state, is yet to be defined. Here, we characterized the functional profile of polyclonal and HIV-specific CD8+ T cells, based on the expression of cell activation and differentiation markers, in individuals chronically infected with HIV, under HAART. Compared with seronegative controls, CD8+ T-cells from patients on HAART exhibited a low degranulation capacity (surface expression of CD107a), with consequent low secreted levels and high intracellular expression of granzyme B and perforin. This degranulation defect was particularly observed in those cells expressing the activation marker HLA-DR, which were further characterized as effector memory cells with high expression of CD57. The expression of CD107a, but not of granzyme B and perforin, in CD8+ T-cells from HIV-infected patients on HAART reached levels similar to those in seronegative controls when the treatment duration was higher than 25 months. In addition, the expression of CD107a was negatively correlated with the expression of exhaustion markers on CD8+ T-cells and the plasma inflammatory molecule sCD14. Thus, despite HAART-induced viral suppression, CD8+ T-cells from HIV-infected patients have an alteration in their cytotoxic program. This defect is associated with the cellular activation, differentiation and exhaustion state, as well as with the inflammation levels, and can be partially recovered with a long and continuous treatment.

5.
Immunology ; 2018 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-30315653

RESUMO

Although dengue can progress to severe stages, the exact causes of this phenomenon are unknown; however, the possibility of monocyte participation is acknowledged. It has been suggested that monocyte subsets (classical, intermediate and non-classical) play differential roles in dengue immunopathology. Therefore, we determined the count of monocyte subsets and obtained the clinical information of patients with dengue. We noted a significant decrease in the count of non-classical monocytes in patients compared with controls. With this finding, we focused on studying the phenotype of non-classical monocytes in the present study. An increase in activation and differentiation markers, such as CD64, CD86, the percentage of tumor necrosis factor-α+ cells and exposure of phosphatidylserine, were recorded in the non-classical monocytes of patients compared with controls. Moreover, a significant decrease in the expression of CX3CR1 with a corresponding increase in the expressions of CCR2, CCR5, CD11b and CD54 was detected in the non-classical monocytes of patients in comparison with that of the controls. Significant increases in the frequency of microparticles from endothelium and in the concentrations of interleukin-6 (IL-6), IL-8 and IL-10 were noted in the plasma of patients. These findings demonstrate that in patients with dengue, non-classical monocytes are activated, exhibiting a phenotype associated with more differentiation, produces tumor necrosis factor-α and has a profile of less endothelial surveillance closer to the cellular migration. These changes were associated with hepatic compromise, endothelial alteration and high concentration of circulating cytokines. Hence, alterations of non-classical monocytes seem to be associated with the immunopathology of dengue infection.

6.
Viral Immunol ; 30(1): 3-12, 2017 Jan/Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27805477

RESUMO

Human immunodeficiency virus type-1 (HIV-1) infection represents one of the biggest public health problems worldwide. The immune response, mainly the effector mechanisms mediated by CD8+ T cells, induces the selection of mutations that allows the virus to escape the immune control. These mutations are generally selected within CD8+ T cell epitopes restricted to human leukocyte antigen class I (HLA-I), leading to a decrease in the presentation and recognition of the epitope, decreasing the activation of CD8+ T cells. However, these mutations may also affect cellular processing of the peptide or recognition by the T cell receptor. Escape mutations often carry a negative impact in viral fitness that is partially or totally compensated by the selection of compensatory mutations. The selection of either escape mutations or compensatory mutations may negatively affect the course of the infection. In addition, these mutations are a major barrier for the development of new therapeutic strategies focused on the induction of specific CD8+ T cell responses.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , Interações Hospedeiro-Patógeno , Evasão da Resposta Imune , Mutação , Seleção Genética , Epitopos de Linfócito T/genética , Epitopos de Linfócito T/imunologia , Aptidão Genética , Infecções por HIV/genética , Humanos
7.
Immunol Res ; 64(5-6): 1168-1178, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27592234

RESUMO

The aim of this study was to explore the association between some SNPs of the TNF, LTA, IL1B and IL10 genes with cytokine concentrations and clinical course in Colombian septic patients. We conducted a cross-sectional study to genotype 415 septic patients and 205 patients without sepsis for the SNPs -308(G/A) rs1800629 of TNF; +252 (G/A) rs909253 of LTA; -511(A/G) rs16944 and +3953(C/T) rs1143634 of IL1B; and -1082(A/G) rs1800896, -819(C/T) rs1800871 and -592(C/A) rs1800872 of IL10. The association of theses SNPs with the following parameters was evaluated: (1) the presence of sepsis; (2) severity and clinical outcomes; (3) APACHE II and SOFA scores; and (4) procalcitonin, C-reactive protein, tumor necrosis factor, lymphotoxin alpha, interleukin 1 beta and interleukin 10 plasma concentrations. We found an association between the SNP LTA +252 with the development of sepsis [OR 1.29 (1.00-1.68)]; the SNP IL10 -1082 with sepsis severity [OR 0.53 (0.29-0.97)]; the TNF -308 with mortality [OR 0.33 (0.12-0.95)]; and the IL10 -592 and IL10 -1082 with admission to the intensive care unit (ICU) [OR 3.36 (1.57-7.18)] and [OR 0.18 (0.04-0.86)], respectively. None of the SNPs were associated with cytokine levels, procalcitonin and C-reactive protein serum concentrations, nor with APACHE II and SOFA scores. Our results suggest that these genetic variants play an important role in the development of sepsis and its clinical course.


Assuntos
Interleucina-10/genética , Interleucina-1beta/genética , Linfotoxina-alfa/genética , Sepse/imunologia , Fator de Necrose Tumoral alfa/genética , Proteína C-Reativa/metabolismo , Calcitonina/sangue , Colômbia , Cuidados Críticos , Estudos Transversais , Progressão da Doença , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Interleucina-10/sangue , Interleucina-1beta/sangue , Linfotoxina-alfa/sangue , Polimorfismo de Nucleotídeo Único , Sepse/genética , Sepse/mortalidade , Análise de Sobrevida , Fator de Necrose Tumoral alfa/sangue
10.
J Immunol Res ; 2015: 762506, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25759848

RESUMO

Statins have been shown to modulate the number and the suppressive function of CD4(+)FOXP3(+) T cells (Treg) in inflammatory conditions. However, it is not well established whether statin could also affect Treg in absence of inflammation. To address this question, eighteen normocholesterolemic male subjects were treated with lovastatin or atorvastatin daily for 45 days. The frequency and phenotype of circulating Treg were evaluated at days 0, 7, 30, and 45. mRNA levels of FOXP3, IDO, TGF-ß, and IL-10 were measured in CD4(+) T cells. We found that both statins significantly increased Treg frequency and FOXP3 mRNA levels at day 30. At day 45, Treg numbers returned to baseline values; however, TGF-ß and FOXP3 mRNA levels remained high, accompanied by increased percentages of CTLA-4- and GITR-expressing Treg. Treg Ki-67 expression was decreased upon statin treatment. Treg frequency positively correlated with plasma levels of high-density lipoprotein cholesterol (HDL-c), suggesting a role for HDL-c in Treg homeostasis. Therefore, statins appear to have inflammation-independent immune-modulatory effects. Thus, the increase in Treg cells frequency likely contributes to immunomodulatory effect of statins, even in healthy individuals.


Assuntos
Contagem de Linfócito CD4 , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Adulto , HDL-Colesterol/sangue , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Expressão Gênica , Voluntários Saudáveis , Humanos , Imunofenotipagem , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/sangue , Masculino , Fenótipo , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Adulto Jovem
11.
Crit Care Med ; 42(4): 771-80, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24365860

RESUMO

OBJECTIVES: To perform a complete immunological characterization of compensatory anti-inflammatory response syndrome in patients with sepsis and to explore the relationship between these changes and clinical outcomes of 28-day mortality and secondary infections. DESIGN: Prospective single-center study conducted between April 2011 and December 2012. SETTING: ICUs from Hospital Universitario San Vicente Fundación at Medellin, Colombia. PATIENTS: One hundred forty-eight patients with severe sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: At days 0, 1, 3, 5, 10, and 28, we determined the expression of HLA-DR in monocytes and the apoptosis and the proliferation index in T lymphocytes, as well as the levels of tumor necrosis factor-α, interleukin-6, interleukin-1ß, interleukin-10, and transforming growth factor-ß in both plasma and cell culture supernatants of peripheral blood mononuclear cells. The mean percentage of HLA-DR was 60.7 at enrollment and increased by 0.9% (95% CI, 0.7-1.2%) per day. The mean percentage of CD4 T cells and CD8 T cells AV+/7-AAD- at enrollment was 37.2% and 20.4%, respectively, but it diminished at a rate of -0.5% (95% CI, -0.7% to -0.3%) and -0.3% (95% CI, -0.4% to -0.2%) per day, respectively. Plasma levels of interleukin-6 and interleukin-10 were 290 and 166 pg/mL and decreased at a rate of -7.8 pg/mL (95% CI, -9.5 to -6.1 pg/mL) and -4 pg/mL (95% CI, -5.1 to -2.8 pg/mL) per day, respectively. After controlling for confounders, only sustained plasma levels of interleukin-6 increase the risk of death (hazard ratio 1.003; 95% CI, 1.001-1.006). CONCLUSIONS: We found no evidence to support a two-phase model of sepsis pathophysiology. However, immunological variables did behave in a mixed and time-dependent manner. Further studies should evaluate changes over time of interleukin-6 plasma levels as a prognostic biomarker for critically ill patients.


Assuntos
Antígenos HLA-DR/biossíntese , Mediadores da Inflamação/imunologia , Leucócitos Mononucleares/imunologia , Sepse/imunologia , APACHE , Idoso , Apoptose , Proliferação de Células , Comorbidade , Grupos de Populações Continentais , Feminino , Humanos , Mediadores da Inflamação/sangue , Unidades de Terapia Intensiva , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Escores de Disfunção Orgânica , Estudos Prospectivos , Sepse/sangue
12.
PLoS One ; 8(8): e71062, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23967152

RESUMO

INTRODUCTION: To evaluate the effect of late initiation of HAART and poor immune reconstitution on the frequency of regulatory T-cells (Treg) in the peripheral blood and gut of HIV-infected patients, we studied Colombian HIV-infected patients who had been on suppressive HAART for at least one year. They had undetectable viremia but were either immunological responders (HIR); (CD4 counts >500 cells/µl) or non-immunological responders (NIR); (CD4 T-cell count <300 cells/µl). Untreated HIV-infected patients and uninfected controls from the same region were also evaluated. METHODS: Frequency and phenotype of regulatory T-cells (Treg) were analyzed in gut biopsies and blood samples. The functional effect of Treg depletion on CMV and HIV responses was determined. Markers of immune activation and circulating LPS levels were quantified. RESULTS: Untreated patients exhibited high Treg frequency in PBMC and gut, and their Treg express high levels of CTLA-4 and PD-1. Although HAART significantly decreased mucosal Treg frequency, it did not normalize it in any of the treated groups (HIR and NIR patients). Treg normalization was observed in the blood of HIR patients following HAART, but did not occur in NIR patients. Treg from HIV-infected patients (treated or not) suppressed HIV and hCMV-specific T-cells from gut and blood. Plasma LPS levels and percentage of HLA-DR+CD38+ T-cells were significantly elevated in all infected groups compared to controls. CONCLUSIONS: These findings suggest that control of viral replication is not sufficient to normalize gut Treg frequency in patients, independent of their response to HAART. Furthermore, persistence of functional Treg in the gut appears to be associated with the failure of HAART to repair mucosal damage.


Assuntos
Infecções por HIV/imunologia , HIV-1/imunologia , Mucosa Intestinal/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Terapia Antirretroviral de Alta Atividade , Contagem de Linfócito CD4 , Antígeno CTLA-4/metabolismo , Estudos de Casos e Controles , Citocinas/biossíntese , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Fenótipo , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T Reguladores/metabolismo , Resultado do Tratamento , Carga Viral
13.
AIDS Res Hum Retroviruses ; 28(1): 49-53, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21916808

RESUMO

Intracellular levels of cyclic adenosine 3',5'-monophosphate (cAMP) are important regulators of immune cells, partially determining the balance between activation and suppression. In this review, we discuss the mechanisms by which HIV infection increases cAMP levels in T cells, as well as the effect of cAMP on HIV-specific responses and its effect on HIV replication and infection. Results suggest that increased cAMP levels during HIV infection may have a dual and opposite roles. On the one hand, they could have a protective effect by limiting viral replication in infected cells and decreasing viral entry. On the other hand, they could have a detrimental role by reducing HIV-specific antiviral immune responses, thus reducing the clearance of the virus and contributing to T cell dysfunction. Future studies are thus needed to further define the beneficial versus detrimental roles of cAMP, as they could help establish new therapeutic targets to combat HIV replication and/or identify novel ways to boost antiviral immune responses.


Assuntos
AMP Cíclico/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Linfócitos T/imunologia , Replicação Viral/imunologia , AMP Cíclico/genética , Infecções por HIV/genética , HIV-1/fisiologia , Humanos , Ativação Linfocitária , Linfócitos T Reguladores/imunologia , Replicação Viral/efeitos dos fármacos
14.
Biomedica ; 31(2): 269-80, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22159545

RESUMO

The natural history of human immunodeficiency virus type-1 (HIV-1) infection is a complex and variable process that, similarly to other infections, has clearly demonstrated the existence of mechanisms of human natural resistance. The resistance either inhibits the establishment of infection or delays disease progression. When there is continuous exposure to infectious viral particles, several genetic and immunological mechanisms are essential to lead to resistance to HIV-1 infection/progression. The objective of this manuscript was to review the different mechanisms so far proposed to be responsible for HIV-1 resistance and to present the main results derived from 10 years of research in this area among Colombian subjects. In particular, this review focuses on determining the mechanisms involved in the protection of a group of individuals repeatedly exposed to the virus but who remained exempt of serological and clinical evidence of HIV-1 infection. Although the studies carried out in our research group corroborated the protective role of some of the previously proposed mechanisms of protection, ongoing research worldwide has made it clear that the phenomenon of human natural resistance depends on multiple factors with an important genetic influence, and only multicenter studies involving individuals with different genetic backgrounds may determine more universal mechanisms of resistance. Increasing our knowledge in this field will contribute to the development of novel preventive and therapeutic measures.


Assuntos
Infecções por HIV/imunologia , HIV-1/imunologia , Imunidade Inata/imunologia , Imunidade Adaptativa/imunologia , Colômbia , Soropositividade para HIV/imunologia , Humanos , Imunidade Inata/genética , Complexo Principal de Histocompatibilidade/genética , Complexo Principal de Histocompatibilidade/imunologia , Mutação , Polimorfismo Genético , Receptores CCR5/genética , Receptores CCR5/imunologia , Pesquisa
15.
J Reprod Immunol ; 92(1-2): 1-7, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22015004

RESUMO

Leukocytes are considered to be the main source of HIV-1 infection in semen. However, HIV-1 interaction with spermatozoa has also been demonstrated, suggesting that both spermatozoa and leukocytes might play a role during sexual transmission of HIV-1. The purpose of the present study was to evaluate if HIV-1 particles interact with sperm cells through the mannose receptor (MR), and then to determine the ability of "infected" sperm cells to transmit the virus to susceptible targets. The expression of classical HIV-1 receptor and co-receptors and the MR by sperm cells was determined by flow cytometry; the interaction in vitro between sperm and HIV-1 was evaluated by fluorescence microscopy. Additionally, the in vitro interaction of sperm cells and HIV-1 was determined detecting viral nucleic acids by PCR. D-Mannose was used to block HIV-1-sperm cell interaction. Sperm cells preincubated with HIV-1 particles and activated mononuclear cells were co-cultured to determine viral transmission. The presence of viral RNA was detected in 28% of the samples in which sperm cells were preincubated with HIV-1 particles. Mannose was able to block interaction in 75% of the cases. Finally, we demonstrated that "infected" sperm cells were able to transmit the HIV-1 infection to susceptible targets. In conclusion, these results indicate that the MR is involved in sperm cell-HIV-1 interaction. Our results also suggest that sperm cells could be an important source of infection.


Assuntos
Infecções por HIV/patologia , HIV-1/fisiologia , Lectinas Tipo C/metabolismo , Leucócitos Mononucleares/metabolismo , Lectinas de Ligação a Manose/metabolismo , Receptores de Superfície Celular/metabolismo , Espermatozoides/metabolismo , Comunicação Celular/efeitos dos fármacos , Células Cultivadas , Técnicas de Cocultura , Feminino , Infecções por HIV/imunologia , Infecções por HIV/transmissão , Infecções por HIV/virologia , HIV-1/patogenicidade , Humanos , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Lectinas Tipo C/imunologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/patologia , Masculino , Manose/farmacologia , Lectinas de Ligação a Manose/imunologia , Microscopia de Fluorescência , RNA Viral/análise , Receptores de Superfície Celular/imunologia , Espermatozoides/efeitos dos fármacos , Espermatozoides/imunologia , Espermatozoides/patologia , Espermatozoides/virologia , Vírion/patogenicidade , Virulência/efeitos dos fármacos
16.
Biomédica (Bogotá) ; 31(2): 269-280, jun. 2011. tab, graf
Artigo em Inglês | LILACS | ID: lil-617516

RESUMO

La historia natural de la infección por el virus de la inmunodeficiencia humana de tipo 1 (VIH-1) es un proceso variable y complejo que, en forma similar a otras infecciones, ha hecho evidente la existencia de mecanismos de resistencia natural que pueden inhibir el establecimiento de la infección o su progresión hacia estadios avanzados. Cuando hay una exposición continua a partículas virales infecciosas, varios mecanismos genéticos e inmunitarios son esenciales para que se establezca la resistencia. El objetivo de este manuscrito fue revisar todos los mecanismos de resistencia al VIH-1, hasta el momento propuestos en seres humanos, y presentar los resultados más importantes que se han obtenido en diferentes estudios realizados en los últimos 10 años de investigación en esta área, en individuos colombianos, particularmente enfocados en determinar los mecanismos involucrados en la protección de un grupo de personas que se han expuesto repetidamente al virus, pero que han permanecido sin evidencia clínica ni serológica de infección por el VIH-1. Aunque los estudios llevados a cabo por nuestro grupo de investigación han corroborado el papel protector de algunos de los mecanismos de protección previamente propuestos, la investigación actual en esta área, a nivel mundial, ha hecho evidente que el fenómeno de resistencia natural depende de múltiples factores con una gran influencia genética, y que sólo mediante estudios multicéntricos que involucren individuos con diferente componente genético, podrán establecerse los mecanismos universales de protección. Profundizar en el conocimiento en esta área permitirá el desarrollo de nuevas medidas preventivas y terapéuticas para la infección por el VIH-1.


The natural history of human immunodeficiency virus type-1 (HIV-1) infection is a complex and variable process that, similarly to other infections, has clearly demonstrated the existence of mechanisms of human natural resistance. The resistance either inhibits the establishment of infection or delays disease progression. When there is continuous exposure to infectious viral particles, several genetic and immunological mechanisms are essential to lead to resistance to HIV-1 infection/progression. The objective of this manuscript was to review the different mechanisms so far proposed to be responsible for HIV-1 resistance and to present the main results derived from 10 years of research in this area among Colombian subjects. In particular, this review focuses on determining the mechanisms involved in the protection of a group of individuals repeatedly exposed to the virus but who remained exempt of serological and clinical evidence of HIV-1 infection. Although the studies carried out in our research group corroborated the protective role of some of the previously proposed mechanisms of protection, ongoing research worldwide has made it clear that the phenomenon of human natural resistance depends on multiple factors with an important genetic influence, and only multicenter studies involving individuals with different genetic backgrounds may determine more universal mechanisms of resistance. Increasing our knowledge in this field will contribute to the development of novel preventive and therapeutic measures.


Assuntos
Síndrome de Imunodeficiência Adquirida , Defensinas , HIV , Antígenos HLA , Imunidade Inata , Células Matadoras Naturais , Apoptose , Controle de Infecções
17.
Iatreia ; 22(2): 159-168, jun. 2009. graf
Artigo em Espanhol | LILACS | ID: lil-554018

RESUMO

La infección por el VIH se asocia con una inmunodeficiencia secundaria grave que lleva a la aparición de infecciones oportunistas y procesos oncogénicos. En el curso de esta infección se observan comúnmente alteraciones de la inmunidad mediada por células T y células presentadoras de antígeno; en la actualidad se considera que ciertas poblaciones celulares con propiedades inmunorreguladoras son en parte responsables de estas alteraciones. De hecho, en los principales sitios de replicación viral, como los órganos linfoides y el tejido linfoide asociado a la mucosa gastrointestinal, se han observado alteraciones funcionales y cuantitativas en la subpoblación de células T reguladoras (Treg). Aunque se desconoce el papel de estas células en la patogénesis de la infección por el VIH, los estudios sugieren que podría ser dual: 1) proteger del daño tisular y de la eliminación de células T CD4+ causados por la hiperactivación inmunológica; 2) contribuir a la patogénesis de esta infección viral. La acumulación de células Treg funcionales afecta el desarrollo de respuestas inmunes específicas que permiten la eliminación del patógeno, facilitando de esta manera su permanencia en los tejidos. En esta revisión se presenta la evidencia científica disponible sobre el efecto de las células Treg en la patogénesis de la infección por el VIH.


HIV infection is associated with a severe secondary immunodeficiency leading to opportunistic infections and malignancies. Alterations of the cellular immunity mediated by T cells and antigen presenting cells are common characteristics of this infection. Recently, it has been proposed that the immunoregulatory properties of several cell populations are partially responsible for these alterations. In fact, functional and quantitative alterations of the regulatory T cell (Treg) subpopulation have been described in sites of active viral replication such as lymphoid organs and the lymphoid tissue associated with the gastrointestinal mucosa. Although the role of Treg in HIV pathogenesis is unknown, different studies suggest that it could be dual: (1) to protect from tissue damage and from CD4+ T cell elimination caused by the immune hyperactivation; (2) to contribute to HIV pathogenesis. The accumulation of functional Tregs affects the development of the specific immune responses that would allow elimination of the pathogen, thus favouring its permanence in different tissues. This review presents the scientific evidence available on the effect of Treg cells during the pathogenesis of HIV infection.


Assuntos
HIV , Mucosa Intestinal , Tecido Linfoide , Linfócitos T Reguladores
18.
J Immunol ; 181(3): 1835-48, 2008 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-18641321

RESUMO

Declines in immune function are well described in the elderly and are considered to contribute significantly to the disease burden in this population. Regulatory T cells (T(regs)), a CD4(+) T cell subset usually characterized by high CD25 expression, control the intensity of immune responses both in rodents and humans. However, because CD25 expression does not define all T(regs), especially in aged hosts, we characterized T(regs) by the expression of FOXP3, a transcription factor crucial for T(reg) differentiation and function. The proportion of FOXP3(+)CD4(+) T(regs) increased in the blood of the elderly and the lymphoid tissues of aged mice. The expression of functional markers, such as CTLA-4 and GITR, was either preserved or increased on FOXP3(+) T(regs) from aged hosts, depending on the tissue analyzed. In vitro depletion of peripheral T(regs) from elderly humans improves effector T cell responses in most subjects. Importantly, T(regs) from old FoxP3-GFP knock-in mice were suppressive, exhibiting a higher level of suppression per cell than young T(regs). The increased proportion of T(regs) in aged mice was associated with the spontaneous reactivation of chronic Leishmania major infection in old mice, likely because old T(regs) efficiently suppressed the production of IFN-gamma by effector T cells. Finally, in vivo depletion of T(regs) in old mice attenuated disease severity. Accumulation of functional T(regs) in aged hosts could therefore play an important role in the frequent reactivation of chronic infections that occurs in aging. Manipulation of T(reg) numbers and/or activity may be envisioned to enhance the control of infectious diseases in this fragile population.


Assuntos
Envelhecimento/imunologia , Leishmaniose Cutânea/imunologia , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Animais , Anticorpos/imunologia , Biomarcadores , Complexo CD3/imunologia , Movimento Celular/imunologia , Proliferação de Células , Doença Crônica , Citocinas/biossíntese , Citocinas/imunologia , Saúde , Humanos , Leishmania major/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Fenótipo
19.
Clin Immunol ; 126(3): 243-50, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18201932

RESUMO

Immaturity of the neonatal immune system is considered an underlying factor for enhanced severity of infections in newborns. Functional defects of neonatal antigen-presenting cells lead to defective T-cell responses. T cells from uninfected neonates exposed in utero to HIV-1 (EU) exhibit phenotypic and functional alterations; however, the function of their circulating dendritic cells (DCs) has not been characterized. We hypothesized that an HIV-1-infected maternal environment may influence the infants' DC number, phenotype and function. EU exhibited a higher percentage of myeloid DCs (mDCs) than unexposed neonates, although this frequency remained lower than that observed in adults. Plasmacytoid DC (pDC) frequencies were similar in all groups, although both groups of infants tended to have lower frequencies than adults. After LPS stimulation, mDCs from EU up-regulated CD80, CD86 and B7-H1, whereas mDCs from unexposed infants upregulated B7-H1, but not CD80/CD86, and adult mDCs up-regulated mainly CD80 and CD86. IFN-alpha production was similar in all groups, indicating a normal pDC function. Therefore, in utero exposure to HIV-1 induces quantitative and qualitative changes in neonatal DCs, particularly in mDCs, which might be associated with alterations observed in T cells from these EU.


Assuntos
Células Dendríticas/citologia , Células Dendríticas/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Adolescente , Adulto , Fármacos Anti-HIV/uso terapêutico , Antígenos/genética , Antígenos/metabolismo , Células Dendríticas/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica , Infecções por HIV/tratamento farmacológico , Infecções por HIV/prevenção & controle , Infecções por HIV/virologia , Humanos , Recém-Nascido , Transmissão Vertical de Doença Infecciosa , Interferon-alfa/metabolismo , Masculino , Oligodesoxirribonucleotídeos/farmacologia , Orthomyxoviridae/imunologia , Gravidez , Complicações Infecciosas na Gravidez/imunologia , Complicações Infecciosas na Gravidez/virologia , Receptores Toll-Like/agonistas , Receptores Toll-Like/metabolismo
20.
Clin Immunol ; 121(3): 251-9, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17010668

RESUMO

Immaturity of the immune system has been suggested as an underlying factor for the high rate of morbidity and mortality from infections in newborns. Functional impairment of neonatal T cells is frequently quoted as the main underlying mechanism for such immaturity. However, recent studies suggest that neonatal antigen-presenting cells (APCs) also exhibit functional alterations, which could lead to secondary defects of adaptive T-cell responses. In this review, we summarize what is known on the functionality of APC at birth and during early childhood. Compared to adults, neonatal APCs display markers of immaturity and produce low levels of cytokines. Multiple factors could be involved in neonatal APC alteration, such as intrinsic immaturity, defective interaction between APCs and T cells and regulatory T-cell-mediated inhibition. Characterization of the relative contribution of each mechanism is clearly needed to better understand the functional capability of the neonatal immune system.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/patologia , Recém-Nascido/imunologia , Animais , Células Apresentadoras de Antígenos/citologia , Diferenciação Celular , Células Dendríticas/citologia , Células Dendríticas/imunologia , Células Dendríticas/patologia , Sangue Fetal/citologia , Sangue Fetal/imunologia , Humanos , Monócitos/citologia , Monócitos/imunologia , Monócitos/patologia , Linfócitos T/imunologia
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