COVID-19 in Colombia endpoints. Are we different, like Europe?

The infection by the new coronavirus (SARS-CoV-2) has taken the dimension of a pandemic, affecting more than 160 countries in a few weeks. In Colombia, despite the implementation of the rules established by the national government, exists an elevate concern both for mortality and for the limited capacity of the health system to respond effectively to the needs of patients infected. For Colombia, assuming a case fatality rate among people infected with SARS-CoV-2 of 0.6% (average data from the information reported for Latin American countries for March 18) (Table 1), the number of deaths, in one or two weeks, could be 16 and 243, respectively. These estimates differ markedly from those documented in countries such as Spain and Italy, in which COVID-19 case fatality rates exceed 8% (case of Italy) and from the percentage of patients who have required intensive care, which has ranged from 9% to 11% of patients in Mediterranean European countries. These differences could be explained due to: a) the percentage of the population at risk (individuals older than 60 years); b) a higher epidemiological exposure to viral respiratory infections associated with more frequent exposure to them, due to geographic and climatic conditions; c) less spread of the virus by location in the tropical zone; and d) earlier preventive measures to contain the spread of SARS-CoV-2 infection. Therefore, it is possible to establish that the situation in this country will be different from in European Mediterranean and that Colombia could have different endpoints from Spain and Italy.

Higher Frequency of NK and CD4+ T-Cells in Mucosa and Potent Cytotoxic Response in HIV Controllers.

HIV infection induces immune alterations, mainly in gut mucosa, where the main target cells reside. However, the evolution of the infection is variable among infected individuals, as evidenced by HIV controllers who exhibit low or undetectable viral load in the absence of treatment. The aim of this study was to evaluate the frequency, phenotype and activity of T and NK cells in peripheral blood and gut mucosa in a cohort of Colombian HIV controllers. Blood and gut biopsies were included. The frequency and the activation status of T and NK cells were performed by flow cytometry. In addition, Gag-stimulated CD8+ T-cells and cytokine-stimulated NK cells were tested for cytotoxic activity. Finally, microbial translocation was measured by plasma lipopolysaccharide quantification. Compared with HIV-progressors, HIV controllers exhibited higher frequency of CD4+ T and NK cells, and lower expression of activation molecules in blood and mucosal immune cells, as well as lower microbial translocation. An increased production of molecules associated with cytotoxic activity of CD8+ T-cells in blood and mucosa and a higher percentage of polyfunctional CD8+ T cells in blood were also observed in HIV controllers. In addition, an increased activity of NK cells was observed in blood. These findings suggest that HIV controllers have a potent immune response, mainly mediated by cytotoxic cells that control HIV replication, which contribute to reducing alterations at the gut mucosa.

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.

In vitro human immunodeficiency virus and sperm cell interaction mediated by the mannose receptor.

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.

Actividad inmunomoduladora y anti-VIH de las estatinas / Immunomodulatory and anti-HIV activity of statins

Las estatinas son fármacos hipolipemiantes usados para controlar la aterogénesis y las enfermedades cardiovasculares originadas por hipercolesterolemia. Recientemente, se describieron varios efectos pleótropos de las estatinas, dependientes e independientes de la inhibición de la síntesis del colesterol, que van desde la regulación de la respuesta inmunitaria hasta la inhibición de la infección y la replicación viral. El tratamiento antirretroviral contra el VIH inhibe su replicación en las células infectadas, disminuyendo hasta niveles indetectables las copias del ARN viral en el plasma. Esto se asocia al incremento de los linfocitos T CD4+ circulantes y la disminución en la incidencia de infecciones oportunistas y en la mortalidad. Sin embargo, el costo y la complejidad del esquema antirretroviral, además de los efectos colaterales y la aparición de cepas resistentes, indican la necesidad de nuevos tratamientos para la infección por VIH. Como el VIH requiere del colesterol y las balsas de lípidos de la membrana celular para infectar las células blanco y cumplir su ciclo de replicación, se postula que las estatinas pueden ser una alternativa efectiva para ayudar al control de esta infección. La actividad anti-VIH de las estatinas no va dirigida contra las proteínas virales, muy variables por la mutabilidad del virus, sino que se centra en las células afectadas, bloqueando la infección por VIH y modulando su respuesta funcional; desde esta perspectiva, las estatinas evitarían la resistencia por mutaciones virales e intervendrían modulando la respuesta inmunitaria ampliamente alterada por el VIH.

Statins are hypolipemiant drugs used for controlling atherogenesis and cardiovascular diseases caused by hypercholesterolemia. Recently, several pleiotropic effects of statins have been reported, whereas dependent or independent of downregulating cholesterol synthesis; these effects range from immune response modulation to inhibition of the infection and viral replication. The antiretroviral therapy against HIV inhibits viral replication in infected cells, decreasing to undetectable levels the number of viral RNA copies in plasma. Consequently, there is an increase in circulating CD4+ T-cell count, and a decrease in the incidence of opportunistic infections and mortality. However, the cost and complexity of antiretroviral regimens, the frequent side effects and the emergence of resistant strains, indicate the need of new approaches for HIV infection. Since HIV virions require of cholesterol in their envelope and the integrity of host membrane lipid rafts, in order to infect target cells and to perform several steps of their replication cycle, it has been proposed that the use of statins in HIV-1 infected patients can be an effective alternative to help control this infection. The anti-HIV activity of statins is not directed against viral proteins, which are highly variable due to viral mutations, but instead it focuses on cellular targets blocking their infection and regulating their functional responses. From this point of view, statins could avoid the emergence of resistant viral strains and intervene in the modulation of the highly altered immune responses.

Papel de las prtteínas reguladoras y accesorias del vih-1 en la patogénesis de esa infección / Role of the regulatory and accesory proteins of HIV- 1 in its pathogenisis

Desde el descubrimiento del virus de inmunodeficiencia humana tipo 1 (VIH-1) como agente etiológico del síndrome de inmunodeficiencia adquirida (SIDA) se han descrito los procesos más importantes que hacen parte del ciclo replicativo del virus y que a su vez participan de la fisiopatología tan compleja que caracteriza a esta infección. A pesar de los avances realizados en el desarrollo de medicamentos antirretrovirales y de los logros alcanzados en el control de la replicación viral, hechos que se reflejan en un aumento en la expectativa y calidad de vida de los individuos infectados, la terapia actual no permite una reconstitución inmunológica total y está acompañada de efectos tóxicos secundarios y de la aparición de resistencia viral. Esto ha obligado a mantener la búsqueda constante de nuevos blancos terapéuticos que ofrezcan alternativas en la lucha contra esta pandemia. Hasta hace pocos años se creía que las proteínas accesorias y reguladoras del VIH1 no ejercían un papel significativo en el ciclo replicativo del virus y en la patogénesis de la infección; sin embargo, estudios recientes indican que estas proteínas ejercen funciones esenciales en diferentes etapas del proceso replicativo y por ende son responsables de muchos efectos asociados a la patogénesis viral. Por estos hallazgos, las proteínas accesorias y reguladoras del VIH-1 constituyen un blanco promisorio en el desarrollo de nuevos medicamentos que complementen los antirretrovirales disponibles en la actualidad. En esta revisión se describe la función de las proteínas reguladoras y accesorias del VIH-1 en el ciclo replicativo viral y su participación en el proceso patogénico de esta infección.

Since the discovery of HIV-1 as the etiological agent of the acquired immunodeficiency syndrome (AIDS), the main processes involved in its replication cycle and responsible for the complex physiopathology of this infection have been described. Despite the advances in the development of new antiretrovirals and their impact in the quality and life expectancy of infected individuals, the current therapy does not allow a complete immune reconstitution and is also associated with deleterious side effects and the appearance of viral resistance. Therefore the search for new therapeutic targets is required to face this pandemic. The role of the accessory and regulatory proteins of the HIV- 1 in the replication cycle and in the pathogenesis of the infection has been ignored for several years now; however, recent studies indicated that these proteins play essential roles in the replication cycle, being responsible for several processes associated to viral pathogenesis. These findings have underlined the importance of these proteins as promissory targets in the development of new therapeutic agents. In this review, we detailed the role of each one of the HIV-1’s regulatory and accessory proteins in the replicative cycle and in the pathogenesis of this infection.

Presence of HIV-1 DNA in spermatozoa from HIV-positive patients: changes in the semen parameters.

Although very inefficient, sexual transmission of HIV-1 is responsible for more than 80% of infections worldwide. Yet, the presence of HIV in spermatozoa has been a matter of debate. The aim of this study was to evaluate the presence of HIV nucleic acids and the distribution of mannose receptors in sperm cells, and to determine the semen parameters and cytokine levels in ejaculates from HIV-positive patients. The presence of non-seminal cells in purified sperm was revealed by light microscopy, flow cytometry and RT-PCR. HIV nucleic acids were evaluated by nested PCR; the distributions of mannose receptors on the surface of the sperm and cytokine levels in ejaculates were determined by fluorescence microscopy and flow cytometry respectively. Sperm characteristics were determined by conventional methods. HIV DNA was detected in 69.2% of purified sperm from HIV-positive men; in contrast all purified sperm were negative for HIV RNA. The distribution of mannose receptors and cytokine levels in HIV-1-positive men were similar to uninfected individuals. Using the Principal Component Analysis (PCA) method, it was possible to determine that semen parameters of HIV-positive men exhibit different distributions compared to HIV-negative individuals. Finally, these results indicate that viral DNA is present in purified sperm from HIV-positive men and that HIV infection of spermatozoa could be associated with lower seminal parameters as demonstrated by the PCA method. The similar distribution of mannose receptors between infected and uninfected individuals suggests that sperm cells from infected individuals interact normally with oocytes.

Frequency and function of circulating invariant NKT cells in autoimmune diabetes mellitus and thyroid diseases in Colombian patients.

The frequency and functionality of peripheral blood invariant (iNKT) cells and their subsets, as well as other regulatory T-cell subsets, were evaluated in patients with type 1A diabetes mellitus (DM1), Hashimoto's disease, and Graves' disease. In addition to healthy individuals (HC), patients with type 2 diabetes mellitus (DM2) were included as controls because this disease has a different physiopathology. A similar frequency of total iNKT cells, as well as their subsets, existed among HC and the different study groups. Similar results were reported when we compared the frequency of CD4(+)/CD25(high) T cells, CD8(+)/CD28(negative) T cells, and gamma-delta T cells among HC and study groups, whereas patients with DM2 exhibited a higher frequency of CD8(+)/CD28(negative) T cells compared with HC and DM1. Also, patients with DM2 exhibited a lower frequency of CD4(negative) and CD4(+) iNKT cells expressing tumor necrosis factor-alpha (TNF-alpha) than HC. We did not observe significant differences in the frequency of iNKT cells expressing interleukin-4 or interferon-gamma among study groups and controls. Our findings support a normal frequency and function of peripheral blood iNKT cells in different endocrine autoimmune diseases, but an abnormal expression of TNF-alpha by circulating iNKT cells from patients with DM2.

Infección labial por citomegalovirus en un paciente infectado con VIH-1 / Labial cytomegalovirus infection in a patient infected with HIV-1

En pacientes infectados con el virus de la inmunodeficiencia humana tipo 1 (VIH-1), la infección por citomegalovirus (CMV) ocurre principalmente en estadios avanzados de la enfermedad, especialmente cuando el recuento de células T CD4+ en sangre periférica se encuentra por debajo de 100 células/mm3, lo cual favorece la progresión al sida y aumenta la probabilidad de muerte. El compromiso de la retina es la manifestación más común de esta coinfección, pero existen otras manifestaciones, como la radiculopatía periférica, la encefalopatía y el compromiso gastrointestinal; en raras ocasiones se observa neumonitis. Esta coinfección también puede presentarse como un cuadro fatal, asociado con una viremia alta y persistente, y con un compromiso grave de varios órganos. La infección cutánea por CMV es una manifestación muy rara en los pacientes positivos para VIH-1, la cual se observa cuando el recuento de células T CD4+ es menor de 50/mm3 y cursa con úlceras crónicas en la piel o las mucosas.Se presentan las características clínicas e inmunológicas de un caso de infección cutánea por CMV en un paciente positivo para VIH-1, y se revisa la literatura.

In patients infected with the type 1-human immunodeficiency virus (HIV-1), the cytomegalovirus (CMV) infection occurs mainly in advanced stages of the disease, especially when the CD4+ T-cell count in under 100 cells/millilitre, which accelerates the progression to AIDS and increases the risk of death. The retina compromise is the most frequent manifestation of the CMV infection associated to HIV-1. Other manifestations include peripheralpolyradiculopathy, encephalopathy, andgastrointestinal compromise. Pneumonitis is rarely observed. In addition, this coinfection can be presented as a fatal disease associated with high and persistent viremia and severe compromise of several organs. The cutaneous CMV infection is a very rare manifestation in HIV-1-infected patients, which is observed when the CD4+ T-cell count is under 50 cells/millilitre, and course with chronicskin and mucosal ulcers. We present the clinic and immunological characteristicsof an HIV-1-infected individual with aCMV cutaneous infection, making a comprehensive review of literature published.

[Effect of opportunistic infections on the frequency of leukocyte subpopulations from type-1 human immunodeficiency virus infected individuals]. / Efecto de las infecciones oportunistas sobre las subpoblaciones de leucocitos en individuos infectados con el virus de inmunodeficiencia humana tipo 1.

INTRODUCTION: The presence of opportunistic infections in patients with acquired immunodeficiency syndrome favors the progression of HIV-1 infection. Despite the key role that several leukocyte subpopulations exhibit during the anti-infectious response, few studies have focused on the role of these cells in HIV-1-infected patients with active opportunistic infections. OBJECTIVE: The quantity of several innate and adaptive cell subpopulations was evaluated in whole peripheral blood of HIV-1-infected patients, with and without a history of opportunistic infections. MATERIALS AND METHODS: The absolute number of each leukocyte subpopulation was evaluated by flow cytometry, and for each cell subpopulation, this number was correlated with viral load, CD4+ T cell count and the expression of activation markers on CD4+ and CD8+ T lymphocytes. RESULTS: Chronically HIV-1 infected patients exhibited a quantitative deficiency in several leukocyte subpopulations; this effect was more pronounced in individuals suffering an active opportunistic infection. This indicated that the coinfection by HIV-1 and opportunistic microorganisms potentiated the immunodeficiency by reducing significantly the frequency of different subpopulations of leukocytes. CONCLUSIONS: This finding underlines the importance of an early diagnose of HIV-1 infection, and the need for the rational use of antiretroviral medications to avoid the development of opportunistic infections. In addition, it points to the necessity of developing immunotherapy strategies for HIV-1-infected patients in order to re-establish the immune competence.

Efecto de las infecciones oportunistas sobre las subpoblaciones de leucocitos en individuos infectados con el virus de inmunodeficiencia humana tipo 1 / Effect of opportunistic infections on the frequency of leukocyte subpopulations from type-1 human immunodeficiency virus infected individuals

Introducción. La presencia de infecciones por patógenos oportunistas en pacientes con síndrome de inmunodeficiencia adquirida representa un coestímulo para acelerar la progresión de la infección por el VIH-1. A pesar del papel preponderante que varias subpoblaciones de leucocitos tienen en la respuesta antiinfecciosa, poco se ha estudiado el comportamiento de esas células en pacientes positivos para VIH-1 que presentan infecciones oportunistas. Objetivo. Evaluar cuantitativamente las subpoblaciones celulares más importantes de la inmunidad innata y adaptativa en sangre periférica de adultos infectados con el VIH-1 (con antecedentes de infecciones oportunistas y sin ellos). Materiales y métodos. El número absoluto de las diferentes subpoblaciones de leucocitos fue determinado por citometría de flujo; para cada subpoblación, este número se correlacionó con la carga viral, el recuento de linfocitos T CD4+ y la expresión de marcadores de activación inmunológica en células T CD4+ y CD8+. Resultados. Los pacientes crónicamente infectados por el VIH-1 presentan deficiencia cuantitativa de varias subpoblaciones de leucocitos, que es más significativa en aquellos pacientes con una infección oportunista activa al momento de la evaluación, lo cual indica que la coinfección VIH-1/agentes oportunistas puede potenciar la inmunodeficiencia al asociarse con una reducción significativa de las diferentes subpoblaciones de leucocitos. Conclusiones. Estos hallazgos sugieren la necesidad de hacer un diagnóstico temprano de la infección por el VIH-1 y un uso racional de la terapia antirretroviral de manera que se impida que los pacientes lleguen a desarrollar infecciones oportunistas, así como la necesidad de establecer estrategias de inmunoterapia para pacientes positivos para VIH-1 con el fin de reestablecer más integralmente la competencia inmune.

Characterization of quantitative and functional innate immune parameters in HIV-1-infected Colombian children receiving stable highly active antiretroviral therapy.

BACKGROUND: The immunological benefits of highly active antiretroviral therapy (HAART) in HIV-1-infected children include reconstitution of CD4+ T-cell count and functional activity. The effect of HAART on innate immune cells has not been well established. AIM: To characterize innate immune responses in HAART-treated HIV-1-infected children. PATIENTS AND METHODS: 23 HIV-1-infected children on stable HAART and 23 uninfected children were evaluated. The frequency of innate immune cells in peripheral blood was determined by flow cytometry and functional activity was evaluated using Toll-like receptor agonists. RESULTS: Compared with uninfected children, HAART-treated HIV-1-infected children exhibited a significant decrease in the frequency of plasmacytoid dendritic cells and natural killer and T-cell receptor (TCR)-invariant CD1d-restricted T cells. This deficiency of innate immune cells was observed mainly in children with detectable viral load. We also compared the magnitude of the quantitative restoration of those cells comparing HIV-1-infected children with HIV-1-infected adults and found a partial effect of HAART on immune restoration that was independent of age. In both pediatric and adult subjects Toll-like receptor agonists induced expression of costimulatory molecules and production of proinflammatory cytokines by dendritic cells. Peripheral blood mononuclear cells of HIV-1-infected children produced significantly reduced amounts of interferon-alpha compared with uninfected children. CONCLUSIONS: HAART administration to HIV-1-infected children does not lead to a complete increase of circulating innate immune cells, particularly in patients with incomplete suppression of HIV.

Las células dendríticas en la infección por el VIH-1 / Dendritic cells during the HIV-1 infection

Las células dendríticas son un componente de la inmunidad innata que cumple con la función crucial de activar los linfocitos T vírgenes. Son una de las células blanco de la infección por el VIH-1, aunque la replicación de este virus en las células dendríticas es muy inferior a la observada en los linfocitos T CD4+. Sin embargo, las células dendríticas almacenan viriones por largo tiempo, para transmitirlos después a otras células susceptibles, y se convierten en uno de los reservorios más importantes del VIH-1. Durante esta infección, las células dendríticas hacen parte inicialmente de la respuesta inmune contra el VIH-1, pero luego exhiben alteraciones cuantitativas y funcionales que potencian la inmunodeficiencia característica de esa infección. El papel que cumplen las células dendríticas en la inducción de la respuesta inmune innata y adaptativa indica que tienen un potencial terapéutico interesante en el desarrollo de vacunas e inmunoterapia para la infección por el VIH-1.

Dendritic cells are components of the innate immunity crucial for activating naïve T cells. They are one of the target cells for HIV-1 infection, but their ability to replicate HIV-1 is much more limited than that exhibited by CD4+ T cells. However, they have the capacity to store the virus for long periods of time which are able to infect susceptible cells later on. Therefore, dendritic cells are considered as one of the most important reservoirs for the HIV-1. At early stages of this infection, dendritic cells also contribute with the anti-HIV-1 immune response, but then they exhibit quantitative and functional alterations enhancing the severe immunodeficiency characteristic of this infection. The important role of dendritic cells in inducing innate and adaptive immune responses indicates that these cells have a promising therapeutic potential for the development of vaccines and immunotherapy for HIV-1 infection.

[The role of toll-like receptors in viral infections: HIV-1 as a model]. / Papel de los receptores tipo toll en las infecciones virales: el VIH-1 como modelo.

The toll-like receptors are an essential component of the innate and adaptive immune response. They are responsible for the recognition of different pathogens agents and trigger responses directed at eliminating the pathogens as well as the development of immunological long-term memory. During viral infections, several different toll-like receptors are activated. These generally induce a protective immune response, but at the same time, can also be part of the pathogenic mechanisms of the viral infection. One of the viral infections in which toll-like receptors participate is the HIV-1 infection. Here, several receptors are activated to develop antiviral responses mediated by interferon type I; however virus replication and spreading dissemination are also favoured by signals derived from stimulation of the toll-like receptors. Individuals co-infected with opportunistic microorganisms are particularly affected, promoting the progression of HIV-1 infection. An integral understanding of the behavior of toll-like receptors during viral infections will allow the design of prophylactic and/or therapeutic strategies, based on the modulation of the expression and function of these receptors. Agonists of these receptors can be used effectively to control these viral infections.

Papel de los receptores tipo toll en las infecciones virales: el VIH-1 como modelo / The role of toll-like receptors in viral infections: HIV-1 as a model

Los receptores tipo toll son un componente esencial de la respuesta inmune innata y adaptativa, pues se encargan del reconocimiento de los diferentes agentes patógenos y desencadenan respuestas dirigidas a eliminarlos y a desarrollar memoria inmunológica. Durante las infecciones virales se activan diferentes receptores tipo toll que, generalmente, inducen una respuesta inmune protectora pero, también, pueden hacer parte de los mecanismos patogénicos del virus. Una de las infecciones virales en la que los receptores tipo toll participan de esta respuesta dual, es la infección por el VIH-1, en la cual varios de estos receptores se activan para desarrollar respuestas antivirales dirigidas por los interferones tipo 1; pero, la replicación y la diseminación del virus también se favorecen por las señales derivadas de la estimulación de dichos receptores, en particular, por las infecciones asociadas con microorganismos oportunistas, lo cual favorece la progresión de la infección por el VIH-1. Un entendimiento integral del comportamiento de estos receptores durante las infecciones virales, permitirá diseñar estrategias profilácticas o terapéuticas basadas en la modulación de su expresión y función, en particular, utilizando agonistas de estos receptores que sean eficaces en la lucha por el control de las infecciones virales.

The toll-like receptors are an essential component of the innate and adaptive immune response. They are responsible for the recognition of different pathogens agents and trigger responses directed at eliminating the pathogens as well as the development of immunological long-term memory. During viral infections, several different toll-like receptors are activated. These generally induce a protective immune response, but at the same time, can also be part of the pathogenic mechanisms of the viral infection. One of the viral infections in which toll-like receptors participate is the HIV-1 infection. Here, several receptors are activated to develop antiviral responses mediated by interferon type I; however virus replication and spreading dissemination are also favoured by signals derived from stimulation of the toll-like receptors. Individuals co-infected with opportunistic microorganisms are particularly affected, promoting the progression of HIV- 1 infection. An integral understanding of the behavior of toll-like receptors during viral infections will allow the design of prophylactic and/or therapeutic strategies, based on the modulation of the expression and function of these receptors. Agonists of these receptors can be used effectively to control these viral infections.

[Soluble factors with inhibitory activity against type 1 Human Immunodeficiency Virus]. / Factores solubles con actividad inhibitoria contra el virus de la inmunodeficiencia humana tipo 1.

Soluble factors with inhibitory activity against type 1 Human Immunodeficiency Virus The pathogenesis of HIV-1 infection is a complex process that depends on multiple factors, including viral and host immune and genetic characteristics. This leads to a variable pattern of disease progression among those HIV-1-exposed individuals who become infected, while there are a number of individuals who remain healthy and HIV-1 seronegative despite being serially exposed to HIV-1. These variable outcomes of HIV-1 exposure suggest that there are mechanisms of natural resistance to HIV-1 infection. Although several genetic and adaptive immune mechanisms of resistance have been reported in some exposed seronegative and long-term non-progressor individuals, the mechanisms involved in controlling the establishment and progression of HIV-1 infection are not fully understood. Several soluble factors, such as defensins, chemokines, interferons and ribonucleases, among others, produced by cells of the immune system and epithelial tissues, have a broad anti-viral activity that might play a role as protective mechanisms during HIV-1 exposure. A better understanding of the mechanisms and role of these soluble factors during the natural resistance to HIV-1 infection may have important implications for the design of novel therapeutic strategies to combat the morbidity and mortality associated with the HIV-1 pandemic.

Factores solubles con actividad inhibitoria contra el virus de la inmunodeficiencia humana tipo 1 / Soluble factors with inhibitory activity against type 1 Human Immunodeficiency Virus

La patogénesis de la infección por el VIH-1 es un proceso complejo que depende de múltiples factores, incluyendo los de origen viral, la respuesta inmune y los factores genéticos del hospedero. Debido a esto, se observa que en los individuos infectados por el VIH-1 existen diferentes patrones de progresión de la enfermedad, mientras que algunos individuos que se exponen repetidamente al virus permanecen sanos y seronegativos. Esta variabilidad luego de la exposición al VIH-1 sugiere que existen mecanismos de resistencia natural contra esta infección. Si bien en algunos individuos expuestos seronegativos y en infectados no progresores a largo término, se ha podido determinar que la resistencia se da por mecanismos genéticos o inmunológicos, existe un porcentaje importante de casos de resistencia para los cuales no ha sido posible establecer el mecanismo protector. Varios factores solubles, como las defensinas, las quimiocinas, los interferones y las ribonucleasas, entre otros, producidos por células del sistema inmune y por células de varios tejidos epiteliales, tienen una reconocida actividad antiviral que podría estar involucrada en la protección del hospedero durante la exposición al VIH-1. Conocer adecuadamente los mecanismos de acción de estos factores y su papel en la resistencia natural a la infección por el VIH-1 puede ser útil al momento de diseñar nuevas estrategias terapéuticas para combatir la morbilidad y mortalidad asociadas con la pandemia por el VIH-1.

The pathogenesis of HIV-1 infection is a complex process that depends on multiple factors, including viral and host immune and genetic characteristics. This leads to a variable pattern of disease progression among those HIV-1-exposed individuals who become infected, while there are a number of individuals who remain healthy and HIV-1 seronegative despite being serially exposed to HIV-1. These variable outcomes of HIV-1 exposure suggest that there are mechanisms of natural resistance to HIV-1 infection. Although several genetic and adaptive immune mechanisms of resistance have been reported in some exposed seronegative and long-term non-progressor individuals, the mechanisms involved in controlling the establishment and progression of HIV-1 infection are not fully understood. Several soluble factors, such as defensins, chemokines, interferons and ribonucleases, among others, produced by cells of the immune system and epithelial tissues, have a broad anti-viral activity that might play a role as protective mechanisms during HIV-1 exposure. A better understanding of the mechanisms and role of these soluble factors during the natural resistance to HIV-1 infection may have important implications for the design of novel therapeutic strategies to combat the morbidity and mortality associated with the HIV-1 pandemic.

Papel de las células nkt invariantes en la respuesta inmune anti-viral: [revisión] / Role of invariant nkt cells in the anti-viral immune response: [review]

Las células T asesinas naturales con receptor de células T invariante y restringidas por la molécula CD1d (iNKT) son un subgrupo de linfocitos con potente actividad inmunorreguladora; su respuesta casi inmediata y la capacidad de producir citoquinas tanto Th1 como Th2 son factores determinantes en el desarrollo de la respuesta inmune innata y adaptativa. El papel fisiológico de las células iNKT se ha documentado ampliamente en la respuesta anti-tumoral, el desarrollo de la tolerancia en los órganos inmunoprivilegiados y el control de las reacciones autoinmunes. A pesar de la demostrada potencia inmunomoduladora de las células iNKT, hasta el momento se conoce poco de su acción en la respuesta inmune anti-infecciosa, en particular en el ser humano y contra los virus patógenos. Este artículo sintetiza los resultados de una búsqueda en las principales bases de datos biomédicas (Pubmed, Medline y OVID), e incluye los estudios realizados para caracterizar estas células y evaluar su papel en la interacción del hospedero con los virus. Las células iNKT participan en la respuesta inmune antiviral, aunque de una manera diferente según el tipo de virus; incluso, podrían estar comprometidas en los daños mediados por mecanismos inmunes. En el ser humano, las células iNKT son aparentemente esenciales en la respuesta inmune contra el virus Varicela Zoster, mientras que todavía hay controversia sobre su función en el control de otros virus. Los modelos animales han aportado las primeras evidencias sobre el potencial de la manipulación terapéutica específica de este subgrupo de linfocitos.

Natural killer T cells with an invariant T-cell receptor and restricted by CD1d (iNKT) are a subgroup of lymphocytes with a very strong immunoregulatory potential; their quick response and their ability to produce Th1 and Th2 cytokines are determinant factors that influence the development of innate and adaptive immune responses. The physiological role of iNKT cells has been well documented in anti-tumor immune responses, the development of tolerance in immune-privileged organs and the control of autoimmune diseases. Despite the fact that the immunoregulatory potential of these cells has been well documented, less is known regarding their role in the immune response against infectious agents, in particular to human pathogenic viruses. This paper synthesizes the search in the most important biomedical data bases (Pubmed, Medline, OVID), including studies on the phenotypic characterization of these cells and functional studies that evaluated their role in the interaction between hosts and viruses. iNKT cells have a heterogeneous participation during the anti-viral immune responses, depending on the type of virus; indeed, in some instances the iNKT-cell responses can be involved in the tissue damage associated to the anti-viral responses. In humans, iNKT cells are apparently essential for an effective immune response against Varicella Zoster virus, while it is still controversial their role in the control of other viral infections. Studies in animal models have shown the first evidences on the therapeutic potential of this lymphocyte subpopulation.

Increased IFN-gamma production by NK and CD3+/CD56+ cells in sexually HIV-1-exposed but uninfected individuals.

The mechanisms involved in controlling the establishment of HIV-1 infection are not fully understood. In particular, the role of innate immunity in natural resistance exhibited by individuals who are continuously exposed to HIV-1 but remain seronegative (ESN) has not been thoroughly evaluated. We determined the frequency and function of peripheral blood innate immune cells (plasmacytoid and myeloid dendritic cells, monocytes, NK cells, CD3+/CD56+ cells and invariant NKT cells) in ESN, chronically HIV-1-infected and low-risk HIV-1 seronegative individuals. ESN demonstrated a similar frequency of innate immune cells in comparison to controls and a higher frequency of dendritic cells, NK and invariant NKT cells compared to HIV-1-infected subjects. Incubation of mononuclear cells with stimulatory CpG ODN induced CD86 and CD69 up-regulation to a similar degree on innate cells from the three study groups. CpG ODN-stimulated secretion of cytokines was also similar between ESN and controls, while secretion of IFN-alpha was significantly decreased in HIV-1+ individuals. Importantly, expression of IFN-gamma by PMA/Ionomycin-activated CD56(bright) NK cells and CD3+/CD56+ cells was significantly higher in ESN when compared with controls. The anti-viral effects of IFN-gamma are well established, and so our results suggest that IFN-gamma production by innate immune cells might be one of the multiple factors involved in controlling the establishment of sexually transmitted HIV-1 infection.

Análisis de laboratorio en los pacientes que presentan infección recurrente y pueden sufrir de inmunodeficiencia / Analysis of laboratory in the patients who has recurrent infection and can suffer of immunodeficiency

The syndrome of recurrent infection constitutes an important cause of morbidity and mortality, both indeveloped and non-developed countries, which implies high social and economic costs for the health services.Practically all individuals with an appropriate immune response have important periods of recurrentinfections, which we can consider as normal. These infectious processes allow that the immune system learnshow to respond against an environment that is plenty of microorganisms with capacity to produce infectionsin an immunocompetent subject. Nevertheless recurrent infections associated with certain characteristicsmight reflect an abnormal increase of the susceptibility of an individual to certain infectious processes. Oncethe study of a patient with recurrent infection syndrome begins, it is fundamental to establish if an underlyinginmunological defect exists, which might explain the development of severe infections. The laboratoryevaluation is an important step in the goal to establish a specific diagnosis of an immunodeficiency disease. Aprecise diagnosis besides to the accelerated development of the immunotherapy, opens the possibility ofprescribing an opportune and rational treatment. An appropriate treatment must have as main goal to avoidthe relapse of infections and the development of sequels and at the same time to improve the quality of life ofthe patient and her or his family. In this article we would show a sequential scheme for the study ofthe immune response in patients that present abnormal recurrent infections. This algorithm will helpthe clinician to establish a soon phenotypic diagnosis and laterly to make a molecular characterizationof the immunodeficiency that has been identified.