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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.
Curr HIV Res ; 2019 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-31622220

RESUMO

Background: The diversity of the HIV proteome influences the cellular response and development of an effective vaccine, particularly due to the generation of viral variants with mutations located within CD8+ T-cell epitopes. These mutations can affect the recognition of the epitopes, that may result in the selection of HIV variants with mutated epitopes (autologous epitopes) and different CD8+ T-cell functional profiles. Objective: To determine the phenotype and functionality of CD8+ T-cell from HIV-infected Colombian patients in response to autologous and consensus peptides derived from HIV-1 clade B protease and reverse transcriptase (RT). Methods: By flow cytometry, we compared the ex vivo CD8+ T-cell responses from HIV-infected patients to autologous and consensus peptides derived from HIV-1 clade B protease and RT, restricted by HLA-B*35, HLA-B*44 and HLA-B*51 alleles. Results: Although autologous peptides restricted by HLA-B*35 and HLA-B*44 did not show any differences compared with consensus peptides, we observed the induction of a higher polyfunctional profile of CD8+ T-cells by autologous peptides restricted by HLA-B*51, particularly by the production of interferon-γ and macrophage inflammatory protein-1ß. The response by different memory CD8+ T-cell populations was comparable between autologous vs. consensus peptides. In addition, the magnitude of the polyfunctional response induced by the HLA-B*51-restricted QRPLVTIRI autologous epitope correlated with low viremia. Conclusion: Autologous peptides should be considered for the evaluation of HIV-specific CD8+ Tcell responses and to reveal some relevant epitopes that could be useful for therapeutic strategies aiming to promote polyfunctional CD8+ T-cell responses in a specific population of HIV-infected patients.

3.
J Clin Virol ; 119: 17-23, 2019 Oct.
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.

4.
Salud(i)ciencia (Impresa) ; 23(5): 428-437, jun. 2019. tab., ilus.
Artigo em Espanhol | LILACS, BINACIS | ID: biblio-1025191

RESUMO

The purpose of this work was to analyze the prevalence of fetal mortality (FM) in mothers in early adolescence (10-14 years), late adolescence (15-19 years) and in adults (20-34 years), during the period 2014-2016, in the North Department of Santander-Colombia. The factors taken into account were: gestation time, fetal weight, childbirth, basic causes, area of residence, and educational level of the mothers. Method: The study was retrospective, correlational, analytical-comparative. The database was from a secondary public access source of the National Administrative Department of Statistics (DANE-Colombia). The analysis was performed using the following tests: chi-square, Kruskal-Wallis H, Cramer's V coefficient, Goodman and Kruskal's gamma, Tukey's post-hoc procedures and the Bonferroni method based on Student's t-test. Results: The prevalence of FM for the years 2014-2016 was 10.0 per 1000 live births in mothers in early adolescence, 19.2 in mothers in late adolescence and 18.6 in adult mothers. It emerged that the prevalence of FM in pregnancies of under 22 weeks was higher in adult mothers, before delivery and during childbirth (chi-square = 32.023; p = 0.021), and there was a slight negative relationship between mother's age and weight of the fetus (gamma = -0.186; p = 0.014). The prevalence of FM was higher in adult mothers residing in the municipal district (chi-square = 80.18; p = 0.000), in mothers with primary, secondary and professional-level basic education (chi-square = 105.56; p = 0.000), and greater in adult mothers due to obstetric complications and birth trauma


La lepra es una enfermedad infecciosa crónica causada por Mycobacterium leprae, la cual tiene una notoria afinidad por la piel y los troncos nerviosos periféricos. Esta enfermedad se caracteriza por tener una clínica polimorfa que depende de la respuesta inmune del hospedero. La inmunopatogénesis de esta enfermedad aún representa un reto para los investigadores, y un eslabón faltante en su comprensión es el estudio de los micronutrientes, los cuales se ha demostrado que tienen la capacidad de modular la respuesta inmune innata y adaptativa. El objetivo de esta revisión es describir y relacionar algunos nutrientes, como las vitaminas A, D, E, C y B6, el folato, el zinc y el hierro, con la respuesta inmune en la lepra. Además, proponemos que algunos micronutrientes (vitaminas A, D y C y zinc) serían importantes para mitigar la aparición de reacciones lepróticas por medio de la modulación de la respuesta inmune en el hospedero infectado por M. leprae, y que micronutrientes como las vitaminas A, D, B6 y D, el folato, el hierro y el zinc serían importantes para reducir la incidencia de la lepra, dado que promoverían una mejor respuesta inmune en convivientes. Por lo tanto, el estudio del estado nutricional y el aporte suplementario con micronutrientes en convivientes y en afectados con lepra sería clave en la eliminación de esta enfermedad que ha deformado cuerpos y ha destruido sueños a lo largo de los siglos.


Assuntos
Humanos , Vitaminas , Linfócitos , Estado Nutricional , Estresse Oxidativo , Micronutrientes , Imunidade , Inflamação , Hanseníase
5.
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.

6.
Pathog Dis ; 76(6)2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30052986

RESUMO

Leprosy is a chronic infectious disease caused by Mycobacterium leprae. This disease is characterized by skin and peripheral nerve trunk damage. The mechanisms responsible for the observed nerve damage in leprosy could be directly related to the ability of M. leprae to infect Schwann cells, leading to triggering of signaling events. Therefore, we hypothesize that in response to M. leprae infection, activation of the Notch signaling pathway in Schwann cells could play a crucial role in glial cell dedifferentiation. On the other hand, nerve damage evidenced in this disease may be additionally explained by indirect mechanisms such as the immune response and genetic susceptibility of the host. The understanding of the mechanisms leading to nerve damage induced by M. leprae infection will allow us to generate valuable tools for the early detection of leprosy as well as for the mitigation of the effects of this disabling disease.

7.
Med Hypotheses ; 109: 162-169, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29150278

RESUMO

Leprosy is a chronic infectious disease caused by Mycobacterium leprae mainly affecting skin and peripheral nerves. Leprosy has a broad range of clinical manifestations that range from mild (tuberculoid leprosy) to severe (lepromatous leprosy) forms, and are highly dependent on the host's immune response. Among the immune response elements involved in the pathogenesis of leprosy are the Toll-like receptors (TLRs), vitamin D receptor (VDR), natural killer cells (NK), and T cells. These innate and adaptive immune response elements may be related to the Notch signaling pathway, which is involved in immune cell growth, differentiation, and proliferation. We hypothesize that failure in Notch signaling in leprosy patients may be associated to: 1) compromising NK cell maturation, lysing of infected cells, and CD4+ Th1 differentiation. 2) VDR alterations and TLR polymorphisms may affect expression of Notch Delta-like ligands (DLL) in antigen presenting cells (APCs). 3) altered DLL expression by APCs could compromise CD4+ T cell differentiation towards the Th1 and Th17 effector phenotypes; and finally 4) expression of Notch Jagged ligands would induce CD4+ T cell differentiation towards Th2 effector phenotype and alternative activation of macrophages. Altogether, these signaling failures could favor proliferation of M. leprae in the host. Therefore, evidence of the proposed immunologic failures in leprosy patients would be essential for the better understanding of immunopathogenesis of this disease, and would ultimately enable detection of susceptible individuals, providing a valuable tool for prevention of this debilitating disease.


Assuntos
Hanseníase/imunologia , Hanseníase/metabolismo , Receptores Notch/metabolismo , Transdução de Sinais , Imunidade Adaptativa , Animais , Linfócitos T CD4-Positivos/citologia , Diferenciação Celular , Citocinas/metabolismo , Humanos , Células Matadoras Naturais/metabolismo , Hanseníase/fisiopatologia , Ligantes , Camundongos , Modelos Teóricos , Mycobacterium leprae , Fenótipo , Polimorfismo Genético , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo
8.
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
9.
Biores Open Access ; 4(1): 115-20, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26309788

RESUMO

Numerous reports have focused on consensus peptides to determine CD8+ T-cell responses; however, few studies evaluated the functional profile using peptides derived from circulating strains of a specific region. We determined the effector profile and maturation phenotype of CD8+ T-cells targeting the consensus APPEESFRS (AS9) epitope and its variant APPEESFRF (AF9), previously identified. The free energy of binding, maturation phenotype, and polyfunctional profile of both peptides were similar. The magnitude of CD8+ T-cell responses to AF9 was greater than the one elicited by AS9, although the difference was not significant. The polyfunctional profile of AF9 was characterized by CD107a/interleukin-2 (IL-2)/macrophage inflammatory protein beta (MIP1ß) and by interferon gamma (IFNγ)/MIP1ß/tumor necrosis factor alpha (TNFα) in response to AS9. TNFα production was significantly higher in response to AF9 than to AS9, and there was a negative correlation between the absolute number of CD8+ T-cell-producing TNFα and the plasma human immunodeficiency virus (HIV) load, suggesting a role of this cytokine in the control of HIV replication.

10.
Viruses ; 7(3): 1313-31, 2015 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-25803098

RESUMO

One of the main characteristics of the human immunodeficiency virus is its genetic variability and rapid adaptation to changing environmental conditions. This variability, resulting from the lack of proofreading activity of the viral reverse transcriptase, generates mutations that could be fixed either by random genetic drift or by positive selection. Among the forces driving positive selection are antiretroviral therapy and CD8+ T-cells, the most important immune mechanism involved in viral control. Here, we describe mutations induced by these selective forces acting on the pol gene of HIV in a group of infected individuals. We used Maximum Likelihood analyses of the ratio of non-synonymous to synonymous mutations per site (dN/dS) to study the extent of positive selection in the protease and the reverse transcriptase, using 614 viral sequences from Colombian patients. We also performed computational approaches, docking and algorithmic analyses, to assess whether the positively selected mutations affected binding to the HLA molecules. We found 19 positively-selected codons in drug resistance-associated sites and 22 located within CD8+ T-cell epitopes. A high percentage of mutations in these epitopes has not been previously reported. According to the docking analyses only one of those mutations affected HLA binding. However, algorithmic methods predicted a decrease in the affinity for the HLA molecule in seven mutated peptides. The bioinformatics strategies described here are useful to identify putative positively selected mutations associated with immune escape but should be complemented with an experimental approach to define the impact of these mutations on the functional profile of the CD8+ T-cells.


Assuntos
Epitopos de Linfócito T/genética , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/genética , HIV-1/imunologia , Seleção Genética , Produtos do Gene pol do Vírus da Imunodeficiência Humana/genética , Antirretrovirais/uso terapêutico , Sítios de Ligação , Linfócitos T CD8-Positivos/imunologia , Colômbia , Biologia Computacional , Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , Transcriptase Reversa do HIV/genética , Antígenos HLA/metabolismo , Humanos , Mutação de Sentido Incorreto , Ligação Proteica
11.
CES med ; 28(1): 91-106, ene.-jun. 2014. tab
Artigo em Espanhol | LILACS-Express | ID: lil-729434

RESUMO

Una de las principales características del virus de la inmunodeficiencia humana es la alta diversidad genética, dada, en parte, por la baja fidelidad de la transcriptasa reversa, lo cual lleva a la generación de variantes virales con mutaciones asociadas a evasión de la respuesta inmune, cambio del tropismo celular o resistencia a medicamentos antirretrovirales. La terapia antirretroviral altamente activa es un esquema farmacológico contra el virus que utiliza dos o más familias de antirretrovirales, que pretende llevar la replicación viral a niveles indetectables, reduciendo entonces la morbimortalidad y aumentando la calidad y expectativa de vida de los individuos infectados. Las mutaciones que confieren resistencia a estos fármacos pueden ser fijadas en el genoma viral y ser transmitidas a nuevos hospederos, aportando así a la circulación de una población viral resistente a estos medicamentos que resulta en falla virológica. En esta revisión se describen los mecanismos más comunes asociados con resistencia a antirretrovirales y las mutaciones reportadas en la literatura.


One of the main characteristics of HIV is its high genetic diversity given in part by the low fidelity of the reverse transcriptase, which leads to the generation of viral variants bearing mutations associated with the evasion of the immune response, changes in the cellular tropism and/or antiretroviral resistance. Highly active antiretroviral therapy (HAART) is a pharmacologic scheme against HIV, which comprises two or more antiretroviral drug families, HAART aims to suppress viral replication which in turn decrease the morbidity and mortality of infected individuals, and increase their life expectancy and improve their quality of life. Mutations that confer resistance to antiretrovirals can be fixed in the viral genome and be transmitted to new hosts contributing to the movement of a viral population resistant to these drugs that results in virologic failure. In this review we describe the most common mechanisms associated with antiretroviral resistance, mutations reported in the literature and bioinformatics tools used for their determination.

12.
Iatreia ; 25(1): 54-64, ene. 2012. tab
Artigo em Espanhol | LILACS | ID: lil-619994

RESUMO

El curso clínico de la infección por el virus de inmunodeficiencia humana tipo 1 es un proceso variable y complejo que depende de componentes virales y del hospedero. En la mayoría de los individuos infectados, la respuesta inmune generada en las fases iniciales de la infección logra controlar la replicación viral por mecanismos efectores innatos, de anticuerpos neutralizantes específicos y particularmente de la actividad de los linfocitos T CD8+ (LT CD8+). A pesar de generarse una respuesta inmune específica, esta se vuelve ineficaz en las etapas crónicas de la infección debido a cambios en los péptidos virales blanco, los cuales conducen a una pérdida del reconocimiento del antígeno presentado; dichos cambios son dados por la baja fidelidad de la transcriptasa reversa y la selección de cuasi-especies por la presión inmunológica. Durante la activación de los LT CD8+ es importante la señal ejercida por el péptido viral, el cual se presenta en el contexto de una molécula del complejo mayor de histocompatibilidad clase I (CMH-I). Estudios de correlación entre el CMH-I y la resistencia/susceptibilidad (R/S) al VIH se han centrado en cuatro aspectos: 1) la expresión de alelos específicos; 2) el grado de homocigocidad/heterocigocidad; 3) la exposición a diversos aloantígenos; 4) la relación con receptores KIR. En esta revisión se aborda el fenómeno de resistencia/susceptibilidad a la infección por el VIH-I relacionado con el CMH-I, cuyo entendimiento favorecerá el desarrollo de herramientas novedosas de intervención terapéutica.


The clinical course of infection with human immunodeficiency virus type-1 (HIV-1) is a variable and complex process that depends on viral and host components. In the majority of infected individuals, the immune response is generated from the initial phases of infection, achieving the control of the viral replication through innate effector mechanisms, neutralizing specific antibodies and particularly through cytotoxic CD8+T cell activity. Despite the generation of these specific cellular and humoral responses, it becomes ineffective in chronic stages of infection because of changes in viral peptide targets, the low fidelity of the reverse transcriptase and the immune pressure. During the activation of CD8+ T cells, the signal delivered by the viral peptide presented in the context of the class I major histocompatibility complex (MHC-I) molecules, is essential. Correlation studies between the MHC-I and the resistance/ susceptibility (R/S) to HIV infection have focused on four aspects, namely: 1) the expression of specific alleles; 4) the degree of homozygosity/heterozygosity; 3) the degree of exposure to different alloantigens; 4) the relation with KIR receptors. In this review, we focus on resistance/susceptibility to HIV-1 infection, particularly related to the MHC, hoping to have a better understanding of this phenomenon that may allow the development of novel therapeutic intervention tools.


Assuntos
Humanos , Predisposição Genética para Doença , HIV , Antígenos HLA , Isoantígenos , Linfócitos T Citotóxicos
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