Statins increase the frequency of circulating CD4+ FOXP3+ regulatory T cells in healthy individuals

RESUMEN: Las estatinas se han demostrado para modular el número y la función supresora de células T CD4 + FOXP3 (Treg) en condiciones inflamatorias. Sin embargo, no está bien establecido si estatinas también podría afectar Treg en ausencia de inflamación. Para abordar esta cuestión, dieciocho sujetos masculinos normocolesterolémicos fueron tratados con lovastatina o atorvastatina al día durante 45 días. La frecuencia y el fenotipo de circulación Treg se evaluaron en los días 0, 7, 30, y 45. Los niveles de ARNm de FOXP3, IDO, TGF-β, e IL-10 se midieron en las células T CD4 +. Se encontró que tanto los que aumenta significativamente los niveles de ARNm y de frecuencia de Treg FOXP3 en el día 30. En el día 45, los números de Treg volvieron a los valores basales; Sin embargo, el TGF-β y los niveles de ARNm de FOXP3 se mantuvo alta, acompañada por el aumento de los porcentajes de CTLA-4 y GITR que expresan Treg. Treg expresión de Ki-67 se redujo tras el tratamiento con estatinas. la frecuencia de Treg correlacionó positivamente con los niveles plasmáticos de colesterol de lipoproteínas de alta densidad (HDL-C), lo que sugiere un papel para el HDL-C en la homeostasis de Treg. Por lo tanto, las estatinas parecen tener efectos inmunomoduladores inflamación independiente. Por lo tanto, el aumento de la frecuencia de Treg células probablemente contribuye a inmunomoduladores efecto de las estatinas, incluso en individuos sanos.ABSTRACT: 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-β, 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-β 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 individual

Caracterización de las células T reguladoras por citometría de flujo: estado del arte y controversias

The ability to maintain proper balance between immune activation and inhibition is required to develop an effective immune response without immunopathogenic processes associated. Different effector mechanisms that allow the elimination of exogenous agents and the presence of a regulatory system guarantee the physiological immune response and maintain the tolerance to self antigens.Among the regulatory mechanisms, the function of CD4+ T lymphocytes, in particular, the regulation exerted by natural regulatory T cells (nTreg), is important to underline. The phenotypic and functional characterization of these cells is a complex process, due to the absence of a cell marker that allows their specific identification by flow cytometry, a tool that has made possible the characterization of most of the immune cells.Currently, the combined use of monoclonal antibodies to identify CD4+/CD25high/Foxp3+/CD127low/- T lymphocytes has been proposed as the most specific alternative to determine the frequency of nTreg. For functional analysis, the identification of nTreg based on the expression of FoxP3 is not possible, since this is an intracellular molecule that requires the permeabilization of the cells for their identification. Once the cells are pure, their functional activity could be evaluated by different methods, including measuring their effect on the function of effector T lymphocytes.Based on these limitations the search for new molecules that allow a better characterization of these cells by flow cytometry continues and most likely a combination of this powerful tool with recent molecular findings (FoxP3 gene methylation pattern) will give a more precise alternative to study this cell subpopulation.La habilidad para mantener el equilibrio entre la activación y la inhibición de la respuesta inmune es un requisito necesario para evitar el desarrollo de procesos inmunopatológicos. Esto se logra gracias a la existencia de mecanismos efectores que permiten la eliminación de agentes extraños al organismo y a la presencia de un sistema regulador que limita las respuestas efectoras y mantiene la tolerancia de los antígenos propios.Entre los mecanismos reguladores se destaca la función ejercida por los linfocitos T (LT) CD4+, en particular, por la subpoblación de LT reguladores naturales (nTreg). La caracterización fenotípica y funcional de estas células es compleja, por la ausencia de un marcador que permita su identificación específica por citometría de flujo, herramienta que ha hecho posible la caracterización de la gran mayoría de células del sistema inmune.Actualmente, se propone que el uso combinado de anticuerpos monoclonales que permitan la identificación de LT CD4+/CD25alto/Foxp3+/CD127bajo/- es la alternativa más específica para determinar la frecuencia de estas células. Para estudios funcionales se requiere eliminar, de la combinación anterior; la detección de FoxP3 por ser una molécula intracelular cuya detección requiere la permeabilización celular. Una vez están purificadas las nTreg, la actividad funcional se evalúa por diferentes métodos que, en su mayoría, miden el efecto que tienen sobre la función de los LT efectores

Modulación de la expresión de la L-selectina por agentes quimiotácticos y GM-CSF

L-selectin is an adhesion molecule with constitutive expression located on the membrane of granulocytes, monocytes and lymphocytes. It is involved in the early stages of migration of these cells toward either the sites of inflammation or lymphoid tissues. After the cells are activated, Lselectin is down-regulated with shedding of a soluble fragment. Flow cytometry was used to measure L-selectin expression levels on the granulocyte surface, after incubation with a phorbol esther (PMA), two chemotactic factors (fMLP and LTB4) and a cytokine (GM-CSF). Under basal conditions, the expression of L-selectin was found in a high percentage (95.0 ± 0.7) of granulocytes; PMA stimulation led to a marked decrease in expression (3.2 ± 0.6). Chemotactic factors also led to a significant decrease in L-selectin expression (69.9 ± 5.0 for LTB4, and 53.70 ± 4.3 for fMLP), whereas the incubation with GM-CSF produced no significant changes (89.1 ± 4.8). When all the conditions were compared, the PMA effect was significantly higher than those observed with other stimuli; furthermore, the expression upon incubation with fMLP and LTB4 was statistically significant. These results suggest that the level of activation reached by granulocytes is directly related to their capacity for shedding L-selectin from the cell surface, and that these levels are lowered after the stimulation by chemotactic factors. GM-CSF activates several important functions of granulocyte cells, however it does not induce L-selectin shedding.La L-selectina es una molécula de adhesión que se expresa constitutivamente en la membrana de los granulocitos, monocitos y linfocitos, células en las cuales interviene en los procesos iniciales de migración hacia los sitios de inflamación y órganos linfoides. Una vez que dichas células son activadas, la L-selectina experimenta un proceso de regulación negativa con la liberación de un fragmento soluble. Con el objetivo de analizar el efecto de algunos agentes quimiotácticos fisiológicos y un estimulante artificial sobre la expresión de la L-selectina en la superficie de los granulocitos de sangre periférica, se evaluó ésta por citometría de flujo en leucocitos no estimulados y luego de su incubación con un éster de forbol (PMA), dos agentes quimiotácticos (fMLP y LTB4) y una citocina (GM-CSF). En condiciones basales, la expresión de la L-selectina se encontró en un porcentaje alto (95,03 ± 0,67); la estimulación con PMA indujo una disminución notable en la expresión de esta molécula (3,16 ± 0,63). Los factores quimiotácticos llevaron también a una reducción significativa (69,89 ± 4,96 para LTB4 y 53,70 ± 4,30 para fMLP), mientras que la incubación con GM-CSF no produjo cambios significativos con respecto a la expresión basal (89,08 ± 4,81). Al comparar las diferentes condiciones de estimulación entre ellas, se observó que el efecto del PMA fue significativamente mayor que los demás estímulos; además, cuando se comparó la reducción de la expresión generada por el fMLP y el LTB4 también se encontró que entre ellas existía una diferencia estadísticamente significativa. Estos resultados sugieren que el grado de activación alcanzado por los granulocitos se relaciona directamente con la capacidad para liberar la L-selectina desde su superficie, siendo ésta menos intensa después de la acción de estímulos fisiológicos como los agentes quimiotácticos; si bien el GM-CSF activa funciones importantes en la fisiología de los granulocitos, no induce la pérdida de la L-selectina desde la membrana celular

Caracterización inmunológica de un grupo familiar colombiano con infección por SARS-CoV-2

Introduction: Immunological markers have been described during COVID-19 and persist after recovery. These immune markers are associated with clinical features among SARSCoV-2 infected individuals. Nevertheless, studies reporting a comprehensive analysis of the immune changes occurring during SARS-CoV-2 infection are still limited.Objective: To evaluate the production of proinflammatory cytokines, the antibody response, and the phenotype and function of NK cells and T cells in a Colombian family cluster with SARS-CoV-2 infection.Materials and methods: Proinflammatory cytokines were evaluated by RT-PCR and ELISA. The frequency, phenotype, and function of NK cells (cocultures with K562 cells) and T-cells (stimulated with spike/RdRp peptides) were assessed by flow cytometry. Anti-SARS-CoV-2 antibodies were determined using indirect immunofluorescence and plaque reduction neutralization assay.Results: During COVID-19, we observed a high proinflammatory-cytokine production and a reduced CD56bright-NK cell and cytotoxic response. Compared with healthy controls, infected individuals had a higher frequency of dysfunctional CD8+ T cells CD38+HLA-DR-. During the acute phase, CD8+ T cells stimulated with viral peptides exhibited a monofunctional response characterized by high IL-10 production. However, during recovery, we observed a bifunctional response characterized by the co-expression of CD107a and granzyme B or perforin.Conclusion: Although the proinflammatory response is a hallmark of SARS-CoV-2 infection, other phenotypic and functional alterations in NK cells and CD8+ T cells couldbe associated with the outcome of COVID-19. However, additional studies are required to understand these alterations and to guide future immunotherapy strategies.Introducción. Se han descrito diferentes marcadores inmunológicos durante la COVID-19, los cuales persisten incluso después de la convalecencia y se asocian con los estadios clínicos de la infección. Sin embargo, aún son pocos los estudios orientados al análisis exhaustivo de las alteraciones del sistema inmunológico en el curso de la infección.Objetivo. Evaluar la producción de citocinas proinflamatorias, la reacción de anticuerpos, y el fenotipo y la función de las células NK y los linfocitos T en una familia colombiana con infección por SARS-CoV-2.Materiales y métodos. Se evaluaron las citocinas proinflamatorias mediante RT-PCR y ELISA; la frecuencia, el fenotipo y la función de las células NK (en cocultivos con células K562) y linfocitos T CD8+ (estimulados con péptidos spike/RdRp) mediante citometría de flujo, y los anticuerpos anti-SARS-CoV-2, mediante inmunofluorescencia indirecta y prueba de neutralización por reducción de placa.Resultados. Durante la COVID-19 hubo una producción elevada de citocinas proinflamatorias, con disminución de las células NK CD56bright y reacción citotóxica. Comparados con los controles sanos, los individuos infectados presentaron con gran frecuencia linfocitos T CD8+ disfuncionales CD38+HLA-DR-. Además, en los linfocitos T CD8+ estimulados con péptidos virales, predominó una reacción monofuncional con gran producción de IL-10 durante la fase aguda y una reacción bifuncional caracterizada por la coexpresión de CD107a y granzima B o perforina durante la convalecencia.Conclusión. Aunque la reacción inflamatoria caracteriza la infección por SARS-CoV-2, hay otras alteraciones fenotípicas y funcionales en células NK y linfocitos T CD8+ que podrían asociarse con la progresión de la infección. Se requieren estudios adicionales para entender estas alteraciones y guiar futuras estrategias de inmunoterapia

HIV-Induced T-Cell Activation/Exhaustion in Rectal Mucosa Is Controlled Only Partially by Antiretroviral Treatment

Peripheral blood T-cells from untreated HIV-1-infected patients exhibit reduced immune responses, usually associated with a hyperactivated/exhausted phenotype compared to HAART treated patients. However, it is not clear whether HAART ameliorates this altered phenotype of T-cells in the gastrointestinal-associated lymphoid tissue (GALT), the main site for viral replication. Here, we compared T-cells from peripheral blood and GALT of two groups of chronically HIV-1-infected patients: untreated patients with active viral replication, and patients on suppressive HAART. We characterized the T-cell phenotype by measuring PD-1, CTLA-4, HLA-DR, CD25, Foxp3 and granzyme A expression by flow cytometry; mRNA expression of T-bet, GATA-3, ROR-γt and Foxp3, and was also evaluated in peripheral blood mononuclear cells and rectal lymphoid cells. In HIV-1+ patients, the frequency of PD-1+ and CTLA-4+ T-cells (both CD4+ and CD8+ T cells) was higher in the GALT than in the blood. The expression of PD-1 by T-cells from GALT was higher in HIV-1-infected subjects with active viral replication compared to controls. Moreover, the expression per cell of PD-1 and CTLA-4 in CD4+ T-cells from blood and GALT was positively correlated with viral load. HAART treatment decreased the expression of CTLA-4 in CD8+ T cells from blood and GALT to levels similar as those observed in controls. Frequency of Granzyme A+ CD8+ T-cells in both tissues was low in the untreated group, compared to controls and HAART-treated patients. Finally, a switch towards Treg polarization was found in untreated patients, in both tissues. Together, these findings suggest that chronic HIV-1 infection results in an activated/exhausted T-cell phenotype, despite T-cell polarization towards a regulatory profile; these alterations are more pronounced in the GALT compared to peripheral blood, and are only partiality modulated by HAART

NEOTROPICAL XENARTHRANS: a data set of occurrence of xenarthran species in the Neotropics

Xenarthrans – anteaters, sloths, and armadillos – have essential functions for ecosystem maintenance, such as insect control and nutrient cycling, playing key roles as ecosystem engineers. Because of habitat loss and fragmentation, hunting pressure, and conflicts with 24 domestic dogs, these species have been threatened locally, regionally, or even across their full distribution ranges. The Neotropics harbor 21 species of armadillos, ten anteaters, and six sloths. Our dataset includes the families Chlamyphoridae (13), Dasypodidae (7), Myrmecophagidae (3), Bradypodidae (4), and Megalonychidae (2). We have no occurrence data on Dasypus pilosus (Dasypodidae). Regarding Cyclopedidae, until recently, only one species was recognized, but new genetic studies have revealed that the group is represented by seven species. In this data-paper, we compiled a total of 42,528 records of 31 species, represented by occurrence and quantitative data, totaling 24,847 unique georeferenced records. The geographic range is from the south of the USA, Mexico, and Caribbean countries at the northern portion of the Neotropics, to its austral distribution in Argentina, Paraguay, Chile, and Uruguay. Regarding anteaters, Myrmecophaga tridactyla has the most records (n=5,941), and Cyclopes sp. has the fewest (n=240). The armadillo species with the most data is Dasypus novemcinctus (n=11,588), and the least recorded for Calyptophractus retusus (n=33). With regards to sloth species, Bradypus variegatus has the most records (n=962), and Bradypus pygmaeus has the fewest (n=12). Our main objective with Neotropical Xenarthrans is to make occurrence and quantitative data available to facilitate more ecological research, particularly if we integrate the xenarthran data with other datasets of Neotropical Series which will become available very soon (i.e. Neotropical Carnivores, Neotropical Invasive Mammals, and Neotropical Hunters and Dogs). Therefore, studies on trophic cascades, hunting pressure, habitat loss, fragmentation effects, species invasion, and climate change effects will be possible with the Neotropical Xenarthrans dataset

Guía de práctica clínica para la prevención, diagnóstico, tratamiento y rehabilitación de la falla cardiaca en población mayor de 18 años, clasificación B, C y D

La falla cardíaca es un síndrome clínico caracterizado por síntomas y signos típicos de insuficiencia cardíaca, adicional a la evidencia objetiva de una anomalía estructural o funcional del corazón. Guía completa 2016. Guía No. 53Población mayor de 18 añosN/

Behavioral responses of terrestrial mammals to COVID-19 lockdowns

DATA AND MATERIALS AVAILABILITY : The full dataset used in the final analyses (33) and associated code (34) are available at Dryad. A subset of the spatial coordinate datasets is available at Zenodo (35). Certain datasets of spatial coordinates will be available only through requests made to the authors due to conservation and Indigenous sovereignty concerns (see table S1 for more information on data use restrictions and contact information for data requests). These sensitive data will be made available upon request to qualified researchers for research purposes, provided that the data use will not threaten the study populations, such as by distribution or publication of the coordinates or detailed maps. Some datasets, such as those overseen by government agencies, have additional legal restrictions on data sharing, and researchers may need to formally apply for data access. Collaborations with data holders are generally encouraged, and in cases where data are held by Indigenous groups or institutions from regions that are under-represented in the global science community, collaboration may be required to ensure inclusion.COVID-19 lockdowns in early 2020 reduced human mobility, providing an opportunity to disentangle its effects on animals from those of landscape modifications. Using GPS data, we compared movements and road avoidance of 2300 terrestrial mammals (43 species) during the lockdowns to the same period in 2019. Individual responses were variable with no change in average movements or road avoidance behavior, likely due to variable lockdown conditions. However, under strict lockdowns 10-day 95th percentile displacements increased by 73%, suggesting increased landscape permeability. Animals’ 1-hour 95th percentile displacements declined by 12% and animals were 36% closer to roads in areas of high human footprint, indicating reduced avoidance during lockdowns. Overall, lockdowns rapidly altered some spatial behaviors, highlighting variable but substantial impacts of human mobility on wildlife worldwide.The Radboud Excellence Initiative, the German Federal Ministry of Education and Research, the National Science Foundation, Serbian Ministry of Education, Science and Technological Development, Dutch Research Council NWO program “Advanced Instrumentation for Wildlife Protection”, Fondation Segré, RZSS, IPE, Greensboro Science Center, Houston Zoo, Jacksonville Zoo and Gardens, Nashville Zoo, Naples Zoo, Reid Park Zoo, Miller Park, WWF, ZCOG, Zoo Miami, Zoo Miami Foundation, Beauval Nature, Greenville Zoo, Riverbanks zoo and garden, SAC Zoo, La Passarelle Conservation, Parc Animalier d’Auvergne, Disney Conservation Fund, Fresno Chaffee zoo, Play for nature, North Florida Wildlife Center, Abilene Zoo, a Liber Ero Fellowship, the Fish and Wildlife Compensation Program, Habitat Conservation Trust Foundation, Teck Coal, and the Grand Teton Association. The collection of Norwegian moose data was funded by the Norwegian Environment Agency, the German Ministry of Education and Research via the SPACES II project ORYCS, the Wyoming Game and Fish Department, Wyoming Game and Fish Commission, Bureau of Land Management, Muley Fanatic Foundation (including Southwest, Kemmerer, Upper Green, and Blue Ridge Chapters), Boone and Crockett Club, Wyoming Wildlife and Natural Resources Trust, Knobloch Family Foundation, Wyoming Animal Damage Management Board, Wyoming Governor’s Big Game License Coalition, Bowhunters of Wyoming, Wyoming Outfitters and Guides Association, Pope and Young Club, US Forest Service, US Fish and Wildlife Service, the Rocky Mountain Elk Foundation, Wyoming Wild Sheep Foundation, Wild Sheep Foundation, Wyoming Wildlife/Livestock Disease Research Partnership, the US National Science Foundation [IOS-1656642 and IOS-1656527, the Spanish Ministry of Economy, Industry and Competitiveness, and by a GRUPIN research grant from the Regional Government of Asturias, Sigrid Rausing Trust, Batubay Özkan, Barbara Watkins, NSERC Discovery Grant, the Federal Aid in Wildlife Restoration act under Pittman-Robertson project, the State University of New York, College of Environmental Science and Forestry, the Ministry of Education, Youth and Sport of the Czech Republic, the Ministry of Agriculture of the Czech Republic, Rufford Foundation, an American Society of Mammalogists African Graduate Student Research Fund, the German Science Foundation, the Israeli Science Foundation, the BSF-NSF, the Ministry of Agriculture, Forestry and Food and Slovenian Research Agency (CRP V1-1626), the Aage V. Jensen Naturfond (project: Kronvildt - viden, værdier og værktøjer), the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy, National Centre for Research and Development in Poland, the Slovenian Research Agency, the David Shepherd Wildlife Foundation, Disney Conservation Fund, Whitley Fund for Nature, Acton Family Giving, Zoo Basel, Columbus, Bioparc de Doué-la-Fontaine, Zoo Dresden, Zoo Idaho, Kolmården Zoo, Korkeasaari Zoo, La Passarelle, Zoo New England, Tierpark Berlin, Tulsa Zoo, the Ministry of Environment and Tourism, Government of Mongolia, the Mongolian Academy of Sciences, the Federal Aid in Wildlife Restoration act and the Illinois Department of Natural Resources, the National Science Foundation, Parks Canada, Natural Sciences and Engineering Research Council, Alberta Environment and Parks, Rocky Mountain Elk Foundation, Safari Club International and Alberta Conservation Association, the Consejo Nacional de Ciencias y Tecnología (CONACYT) of Paraguay, the Norwegian Environment Agency and the Swedish Environmental Protection Agency, EU funded Interreg SI-HR 410 Carnivora Dinarica project, Paklenica and Plitvice Lakes National Parks, UK Wolf Conservation Trust, EURONATUR and Bernd Thies Foundation, the Messerli Foundation in Switzerland and WWF Germany, the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie Actions, NASA Ecological Forecasting Program, the Ecotone Telemetry company, the French National Research Agency, LANDTHIRST, grant REPOS awarded by the i-Site MUSE thanks to the “Investissements d’avenir” program, the ANR Mov-It project, the USDA Hatch Act Formula Funding, the Fondation Segre and North American and European Zoos listed at http://www.giantanteater.org/, the Utah Division of Wildlife Resources, the Yellowstone Forever and the National Park Service, Missouri Department of Conservation, Federal Aid in Wildlife Restoration Grant, and State University of New York, various donors to the Botswana Predator Conservation Program, data from collared caribou in the Northwest Territories were made available through funds from the Department of Environment and Natural Resources, Government of the Northwest Territories. The European Research Council Horizon2020, the British Ecological Society, the Paul Jones Family Trust, and the Lord Kelvin Adam Smith fund, the Tanzania Wildlife Research Institute and Tanzania National Parks. The Eastern Shoshone and Northern Arapahoe Fish and Game Department and the Wyoming State Veterinary Laboratory, the Alaska Department of Fish and Game, Kodiak Brown Bear Trust, Rocky Mountain Elk Foundation, Koniag Native Corporation, Old Harbor Native Corporation, Afognak Native Corporation, Ouzinkie Native Corporation, Natives of Kodiak Native Corporation and the State University of New York, College of Environmental Science and Forestry, and the Slovenia Hunters Association and Slovenia Forest Service. F.C. was partly supported by the Resident Visiting Researcher Fellowship, IMéRA/Aix-Marseille Université, Marseille. This work was partially funded by the Center of Advanced Systems Understanding (CASUS), which is financed by Germany’s Federal Ministry of Education and Research (BMBF) and by the Saxon Ministry for Science, Culture and Tourism (SMWK) with tax funds on the basis of the budget approved by the Saxon State Parliament. This article is a contribution of the COVID-19 Bio-Logging Initiative, which is funded in part by the Gordon and Betty Moore Foundation (GBMF9881) and the National Geographic Society.https://www.science.org/journal/sciencehj2023Mammal Research InstituteZoology and Entomolog

Mecanismos de resistencia natural al VIH en seres humanos: un resumen de 10 años de investigación en población colombiana

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