The APPEESFRS Peptide, Restricted by the HLA-B*35:01 Molecule, and the APPEESFRF Variant Derived from an Autologous HIV-1 Strain Induces Polyfunctional Responses in CD8+ T Cells.

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.

Selection pressure in CD8⁺ T-cell epitopes in the pol gene of HIV-1 infected individuals in Colombia. A bioinformatic approach.

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.

Resistencia a antirretrovirales: bases moleculares e implicaciones farmacológicas / Resistance to antiretrovirals: molecular bases and pharmacological implications

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.

Variaciones alélicas en los genes de citocinas proinflamatorias y antiinflamatorias, y su asociación con la susceptibilidad y el curso clínico de la sepsis / Allelic variations in genes of pro-inflammatory and anti-inflammatory cytokines, and their association with the susceptibility to sepsis and its clinical course

Se considera que la sepsis es la principal causa de mortalidad en las unidades de cuidado intensivo, por lo cual ha sido objeto de numerosas investigaciones que aún no se han traducido en avances terapéuticos significativos. El balance entre los fenómenos proinflamatorios y antiinflamatorios característicos de este síndrome es el que puede determinar el desenlace del paciente; además, la complejidad del desarrollo de estrategias terapéuticas en sepsis está relacionada con la naturaleza heterogénea de la respuesta inmune; se destaca la importancia de los factores genéticos que regulan el componente inmune durante la respuesta inflamatoria. Con base en tales conocimientos, esta revisión se centra en genes de citocinas importantes en el curso clínico de la sepsis, en la información sobre sus variantes genéticas en la población con sepsis y en su impacto sobre la función del gen. Estos factores son de importancia crítica y un mejor conocimiento acerca de ellos podría ayudar a evaluar el riesgo de desarrollar sepsis y a definir su asociación con la evolución clínica de este síndrome.

Sepsis is the main cause of mortality in intensive care units. Therefore, many efforts to develop therapeutic approaches have been made without significant progress. The balance between the pro-inflammatory and anti-inflammatory responses during the course of sepsis may determine the clinical outcome of patients; besides, the complexity of developing successful treatments in sepsis may be related to the heterogeneous nature of immune responses; the importance of genetic factors that regulate the immune component during the inflammatory response is emphasized. Based on such facts, this review focuses on genes of cytokines involved in the clinical course of sepsis; on information about their allelic variants found in the population with sepsis, and on their impact on gene expression. These factors are of critical importance, and a better knowledge about them could help to evaluate the risk of developing sepsis, and to define their association with the clinical evolution of this syndrome.

Antígenos leucocitarios humanos y su asociación con resistencia/susceptibilidad a la infección por el VIH-1 / Human leukocyte antigens associated to resistance/susceptibility to HIV infection

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.

Actividad inmunomoduladora de las estatinas y su efecto potencial sobre las células T reguladoras FOXP3+ / Immunomodulatory activity of statins and their potential effect on the FOXP3+ regulatory T cells

Las estatinas constituyen un grupo de fármacos inhibidores de la enzima 3-hidroxi-3- metilglutaril-coenzima A reductasa, que limitan la síntesis de colesterol y la producción de compuestos isoprenoides, fenómenos responsables de la reducción de la enfermedad aterosclerótica en individuos con hipercolesterolemia. Debido a la amplia prescripción y uso de estos fármacos, se han observado efectos benéficos adicionales, relacionados principalmente con la disminución de la síntesis de compuestos isoprenoides. Parte de estos efectos se asocia con la modulación del sistema inmune; sin embargo, su acción sobre las células T reguladoras (Treg) ha sido poco estudiada, a pesar de que estas células son fundamentales para regular la intensidad de la respuesta inmune y mantener la homeostasis inmunológica. En esta revisión abordamos las vías comunes por las cuales las estatinas y las células Treg pueden interactuar para regular la respuesta inmune. Aunque los resultados de las primeras investigaciones muestran que las estatinas aumentan la frecuencia y, posiblemente, la capacidad supresora de las células Treg, se requieren más estudios que permitan dilucidar si esta relación tiene consecuencias benéficas o perjudiciales para la regulación inmune, en diferentes contextos clínicos.

Statins are a group of drugs that inhibit the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase, which limits cholesterol synthesis and production of isoprenoid compounds, phenomena responsible for the reduction of atherosclerotic disease in individuals with hypercholesterolemia. Due to the wide prescription and use of these drugs, some additional beneficial effects have been observed in various clinical settings, mainly related to the decreased production of isoprenoid compounds. Some of these effects have been associated with the modulation of the immune system, but their effect on regulatory T cells (Treg) has not been well studied, despite the fact these cells are crucial to regulate the intensity of the immune response and to preserve immune homeostasis. This review focuses on the common pathways through which statins and Treg cells interact to regulate the immune response. Although the results from early investigations show that statins increase the frequency and suppressive capacity of Treg cells, further research is required to determine whether that relationship produces beneficial or harmful consequences for the immune regulation in different clinical settings.