Dynamics of humoral immune response in SARS-CoV-2 infected individuals with different clinical stages.

Background: The COVID-19 pandemic remains a global health problem. As in other viral infections, the humoral immune response against SARS-CoV-2 is thought to be crucial for controlling the infection. However, the dynamic of B cells in the clinical spectrum of this disease is still controversial. This study aimed to characterize B cell subsets and neutralizing responses in COVID-19 patients according to disease severity through a one-month follow-up. Methods: A cohort of 71 individuals with SARS-CoV-2 infection confirmed by RT-PCR were recruited and classified into four groups: i) asymptomatic; ii) symptomatic outpatients; iii) hospitalized in ward, and iv) intensive care unit patients (ICU). Samples were taken at days 0 (inclusion to the study), 7 and 30. B cell subsets and neutralizing antibodies were assessed using multiparametric flow cytometry and plaque reduction neutralization, respectively. Results: Older age, male gender and body mass index over 25 were common factors among hospitalized and ICU patients, compared to those with milder clinical presentations. In addition, those requiring hospitalization had more comorbidities. A significant increase in the frequencies of CD19+ cells at day 0 was observed in hospitalized and ICU patients compared to asymptomatic and symptomatic groups. Likewise, the frequency of plasmablasts was significantly increased at the first sample in the ICU group compared to the asymptomatic group, but then waned over time. The frequency of naïve B cells decreased at days 7 and 30 compared to day 0 in hospitalized and ICU patients. The neutralizing antibody titers were higher as the severity of COVID-19 increased; in asymptomatic individuals, it was strongly correlated with the percentage of IgM+ switched memory B cells, and a moderate correlation was found with plasmablasts. Conclusion: The humoral immune response is variable among SARS-CoV-2 infected people depending on the severity and time of clinical evolution. In severe COVID-19 patients, a higher plasmablast frequency and neutralizing antibody response were observed, suggesting that, despite having a robust humoral immunity, this response could be late, having a low impact on disease outcome.

Functional Profile of CD8+ T-Cells in Response to HLA-A*02:01-Restricted Mutated Epitopes Derived from the Gag Protein of Circulating HIV-1 Strains from Medellín, Colombia.

CD8+ T-cells play a crucial role in the control of HIV replication. HIV-specific CD8+ T-cell responses rapidly expand since the acute phase of the infection, and it has been observed that HIV controllers harbor CD8+ T-cells with potent anti-HIV capacity. The development of CD8+ T-cell-based vaccine against HIV-1 has focused on searching for immunodominant epitopes. However, the strong immune pressure of CD8+ T-cells causes the selection of viral variants with mutations in immunodominant epitopes. Since HIV-1 mutations are selected under the context of a specific HLA-I, the circulation of viral variants with these mutations is highly predictable based on the most prevalent HLA-I within a population. We previously demonstrated the adaptation of circulating strains of HIV-1 to the HLA-A*02 molecule by identifying mutations under positive selection located in GC9 and SL9 epitopes derived from the Gag protein. Also, we used an in silico prediction approach and evaluated whether the mutations found had a higher or lower affinity to the HLA-A*02. Although this strategy allowed predicting the interaction between mutated peptides and HLA-I, the functional response of CD8+ T-cells that these peptides induce is unknown. In the present work, peripheral blood mononuclear cells from 12 HIV-1+ HLA-A*02:01+ individuals were stimulated with the mutated and wild-type peptides derived from the GC9 and SL9 epitopes. The functional profile of CD8+ T-cells was evaluated using flow cytometry, and the frequency of subpopulations was determined according to their number of functions and the polyfunctionality index. The results suggest that the quality of the response (polyfunctionality) could be associated with the binding affinity of the peptide to the HLA molecule, and the functional profile of specific CD8+ T-cells to mutated epitopes in individuals under cART is maintained.

Implicaciones de los virus Zika y Chikungunya en el semen durante la transmisión sexual / Implications of Zika and Chikungunya viruses in semen during sexual transmission

Introducción: Los brotes de enfermedades causados por los virus Zika (VZIK) y Chikungunya (VCHIK) representan un problema de salud pública para muchos países tropicales y subtropicales. Objetivo: Discutir las implicaciones del hallazgo del VZIK y del VCHIK en el semen, y su relación con la transmisión sexual y la fertilidad masculina. Métodos: Se realizó una revisión narrativa de la literatura usando artículos indexados en PubMed (Medline), Embase y Scopus. Información, análisis y síntesis: Si bien los mosquitos del género Aedes son el vector principal y transmiten ambos virus, la transmisión sexual es una vía de infección significativa del VZIK y una posible ruta alterna para el VCHIK. La diseminación de estas arbovirosis vía linfática y sanguínea contribuye a la infección de diversos tejidos, incluyendo el tracto reproductivo masculino, donde el VZIK puede persistir. La infección de los testículos y quizás también de las glándulas accesorias del sistema reproductor masculino, se asocia con síntomas genitourinarios o alteraciones espermáticas, relacionadas con la detección del virus por largos periodos. Aunque no hay evidencia contundente sobre la presencia del VCHIK en el tracto genital masculino, se ha hallado en orina y semen. Además, se ha sugerido una posible persistencia en macrófagos que pueden infiltrar diferentes tejidos periféricos y cumplir una función de reservorio. Conclusiones: Hay presencia y persistencia de los virus Zika y Chikungunya en el tracto reproductor masculino. La infección en el semen se asocia con la transmisión sexual del virus, y con la alteración en la producción y calidad de los espermatozoides, con consecuencias clínicas graves en la salud sexual y reproductiva de los hombres infectados(AU)

Introduction: Disease outbreaks caused by Zika (ZIKV) and Chikungunya (CHIKV) viruses represent a public health problem for many tropical and subtropical countries. Objective: To discuss the implications of finding ZIKV and CHIKV in semen, and their relationship to sexual transmission and male fertility. Methods: A narrative review of the literature was carried out using articles indexed in PubMed (Medline), Embase and Scopus. Information, Analysis and Synthesis: Although Aedes mosquitoes are the primary vector and transmit both viruses, sexual transmission is a significant route of infection for ZIKV and a possible alternate route for CHIKV. Spread of these arboviruses via lymphatic and blood routes contributes to infection of various tissues, including the male reproductive tract, where ZIKV may persist. Infection of the testes and probably of the accessory glands of the male reproductive system is associated with genitourinary symptoms or sperm alterations, related to the detection of the virus for long periods. Although there is no conclusive evidence of the presence of CHIKV in the male genital tract, it has been found in urine and semen. In addition, a possible persistence in macrophages that can infiltrate different peripheral tissues and function as reservoir has been suggested. Conclusions: Zika and Chikungunya viruses can be present and persist in the male reproductive tract. Infection in semen is associated with sexual transmission of the virus and with alterations in the production and quality of spermatozoa, with serious clinical consequences in the sexual and reproductive health of infected men(AU)

A Crop Modelling Strategy to Improve Cacao Quality and Productivity.

Cacao production systems in Colombia are of high importance due to their direct impact in the social and economic development of smallholder farmers. Although Colombian cacao has the potential to be in the high value markets for fine flavour, the lack of expert support as well as the use of traditional, and often times sub-optimal technologies makes cacao production negligible. Traditionally, cacao harvest takes place at exactly the same time regardless of the geographic and climatic region where it is grown, the problem with this strategy is that cacao beans are often unripe or over matured and a combination of both will negatively affect the quality of the final cacao product. Since cacao fruit development can be considered as the result of a number of physiological and morphological processes that can be described by mathematical relationships even under uncontrolled environments. Environmental parameters that have more association with pod maturation speed should be taken into account to decide the appropriate time to harvest. In this context, crop models are useful tools to simulate and predict crop development over time and under multiple environmental conditions. Since harvesting at the right time can yield high quality cacao, we parameterised a crop model to predict the best time for harvest cacao fruits in Colombia. The cacao model uses weather variables such as temperature and solar radiation to simulate the growth rate of cocoa fruits from flowering to maturity. The model uses thermal time as an indicator of optimal maturity. This model can be used as a practical tool that supports cacao farmers in the production of high quality cacao which is usually paid at a higher price. When comparing simulated and observed data, our results showed an RRMSE of 7.2% for the yield prediction, while the simulated harvest date varied between +/-2 to 20 days depending on the temperature variations of the year between regions. This crop model contributed to understanding and predicting the phenology of cacao fruits for two key cultivars ICS95 y CCN51.

Chikungunya Virus and Zika Virus, Two Different Viruses Examined with a Common Aim: Role of Pattern Recognition Receptors on the Inflammatory Response.

Chikungunya virus (CHIKV) and Zika virus (ZIKV) are 2 reemerging arboviruses that have been the focus of public health institutions worldwide, since the last decades and following a spate of outbreaks in tropical and subtropical areas. The disease caused by both viruses manifests itself first as an acute stage of severe inflammation into the infected tissues, which later progresses to arthritis and chronic polyarthralgia in the case of CHIKV or congenital microcephaly and neurological disorders such as Guillain-Barré syndrome in the case of ZIKV. This review aims to summarize on current knowledge of the role of different pattern recognition receptors that leads to an elevated production and secretion of antiviral response (interferon) and severe inflammation in response to CHIKV and ZIKV infection.

Role of Monocytes in the Pathogenesis of Dengue.

Diseases caused by dengue virus (DENV) are a major public health problem worldwide, considered one of the infections with more prevalence in tropical and subtropical zones of the world. Despite the intense research in the pathogenesis of DENV, this feature is not well understood. One of the main target cells for DENV infection is monocytes; these phagocytes can play a dual role, since they are essential to control viremia, but they also participate in the induction of tissue damage during DENV infection. Monocytes produce different pro-inflammatory cytokines and chemokines in response to infection, and also mediate endothelial damage. In peripheral blood, monocytes can be divided into three different subpopulations, namely classical, intermediate and non-classical, which differ in frequency, cytokine production, among others. Studies in the last years suggest that non-classical monocytes have higher affinity for microvasculature endothelium compared to other type of monocytes, which implies that they could be more involved in the increase of endothelial permeability observed during DENV infection. This review provides a general view of the role of monocytes and their subpopulations in DENV pathogenesis and its effect in viral replication. Finally, the potential contribution of these phagocytes in the alterations of endothelial permeability is discussed.

Increase of Frequency and Modulation of Phenotype of Regulatory T Cells by Atorvastatin Is Associated with Decreased Lung Inflammatory Cell Infiltration in a Murine Model of Acute Allergic Asthma.

Regulatory T cells (Tregs) play an important role by controlling allergic inflammation of airways. Recently, it has been shown that statins have immunomodulatory properties, probably mediated by their effects on Tregs. Therefore, we evaluated the in vivo effect of atorvastatin (ATV) on Tregs and its association with the inflammatory process in a model of allergic asthma. BALB/c mice were sensitized with ovalbumin (OVA) and then challenged with intranasal OVA. ATV (40 mg/kg) was delivered by daily intraperitoneal injection for 7 or 15 days before each OVA challenge. ATV treatment for 7 days increased the frequency of Tregs in mediastinal lymph nodes (MLN) and the interleukin (IL)-10 in lungs. After 15 days of treatment, ATV increased the percentage of glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR+) and programmed cell death protein 1 (PD-1+) Tregs in the lung, without enhancing their suppressive activity, but also increased the percentage of conventional T cells expressing GITR+, PD1+, and OX-40 (tumor necrosis factor receptor superfamily member 4). Although no significant changes were observed in the number of inflammatory cells in the bronchoalveolar lavage (BAL), OVA-specific immunoglobulin E in the serum, and type 2 helper (Th2) cytokines in the lungs, there was a significant decrease of peribronchial inflammation that negatively correlated with the Tregs in MLN and the concentration of IL-10 in the lung. These results suggest that ATV has an immunomodulatory role possibly mediated by their effects on Tregs, which could contribute to the control of inflammation during allergic asthma. Further studies are necessary to elucidate the contribution of Treg to immunomodulatory action of statins in the context of allergic asthma.

Increased frequency of NK and gamma delta 1 T cells in a cohort of patients with sepsis * / Incremento en la frecuencia de células NK y células T gamma delta 1 en una cohorte de pacientes con sepsis

Introduction: The mechanisms involved in the immunopathogenesis of sepsis are not well established. The clinical and therapeutic relevance of several soluble mediators has been described and the contribution of cellular components with immunoregulatory roles has begun to be elucidated. Objective: To describe changes in the frequency and production of IFN- γ and IL-10 occurring in NK cells and γδ T lymphocytes in a cohort of patients with different manifestations of septic syndrome. Materials and methods: This was a prospective cohort study. Patients with sepsis (n=26), and severe sepsis (n=83) from adult emergency rooms and intensive care units, as well as healthy volunteers (n=8), were included. For all participants, the frequency and phenotype of NK cells and γδ T lymphocytes and the percentage of IFN- γ and IL-10 positive NK and γδ T cells were evaluated by flow cytometry. The NK cells were phenotyped based on the expression of CD56 and CD16 and the γδ T cells on the expression of d 1 and d 2 chains. Results: Patients with sepsis and severe sepsis exhibited an increase in the frequency of NK cells with changes in the proportion of the CD56 bright /CD16¯, CD56 bright /CD16 dim and CD56 dim CD16¯ subpopulations; these cells showed a proinflammatory cytokine profile. A decrease in the V d 2 subset of γδ T lymphocyte s was also observed. Conclusions: Our results indicate a role for NK and γδ T cells during sepsis, however, their exact contribution in the pathogenesis of sepsis syndrome requires further studies.

Introducción: Los mecanimos involucrados en la inmunopatogénesis de las sepsis no han sido claramente establecidos. La importancia clínica y terapéutica de diferentes mediadores solubles ha sido descrita y la contribución de componentes celulares con propiedades inmunorreguladoras ha empezado a dilucidarse. Objetivo: Describir los cambios en la frecuencia y en la producción de IFN- γ e IL-10 que se observa en células NK y linfocitos T γδ en una cohorte de pacientes con diferentes manifestaciones del síndrome séptico. Materiales y métodos: Estudio de cohorte prospectiva, donde pacientes con sepsis (n = 26) y sepsis grave (n = 83) provenientes de las salas de emergencias y unidades de cuidado intensivo, y controles sanos (n = 8) fueron incluidos. Tanto la frecuencia y fenotipo de las células NK y T γδ como el porcentaje de células IFN- γ+ e IL-10+ fueron evaluados mediante citometría de flujo. Las células NK fueron fenotipificadas con base en la expresión de las moléculas CD56 y CD 16 y los T γδ con base en la expresión de las cadenas δ1 y δ2. Resultados: En los pacientes con sepsis y sepsis grave se observó un incremento en la frecuencia de las células NK con cambios en las proporciones de las subpoblaciones CD56 bright /CD 16 ¯, CD56 bright /CD16 dim y CD56 dim CD16¯; en estas células se observó un perfil de citocinas proinflamarias. Se observó una reducción en el porcentaje de células Vδ2. Conclusiones: Los resultados sugieren un papel de las células NK y linfocitos T γδ durante la sepsis; sin embargo, su contribución en la patogénesis de este síndrome requiere estudios adicionales.

Chronically HIV-1 Infected Patients Exhibit Low Frequencies of CD25+ Regulatory T Cells.

The characterization of regulatory T cells (Treg) during HIV infection has become of particular interest considering their potential role in the pathogenesis of the acquired immunodeficiency syndrome. Different reports on Tregs in HIV-infected patients vary greatly, depending on the state of disease progression, anatomical compartment, and the phenotypic markers used to define this cell subpopulation. To determine the frequency of Tregs we included paired samples from peripheral blood and rectal biopsies from controls and chronic HIV patients with or without detectable viral load. Tregs were determined by flow cytometry using three different protocols: CD4(+)Foxp3(+); CD4(+)Foxp3(+)CD127(Low/-), and CD4(+)CD25(+)CD127(Low/-). In addition, and with the purpose to compare the different protocols we also characterized Tregs in peripheral blood of HIV negative individuals with influenza like symptoms. Here, we report that Treg characterization in HIV-infected patients as CD4(+)Foxp3(+) and CD4(+)Foxp3(+)CD127(Low/-) cells was similar, indicating that both protocols represent a suitable method to determine the frequency of Tregs in peripheral blood mononuclear cells (PBMC) and gut associated lymphoid tissue (GALT). In contrast, in HIV but not in flu-like patients, detection of Tregs as CD4(+)CD25(+)CD127(Low/- )cells resulted in a significantly lower percentage of these cells. In both, HIV patients and controls the frequency of Treg was significantly higher in GALT compared to PBMC. The frequency of Tregs in PBMC and GALT using CD4(+)Foxp3(+) and CD4(+)Foxp3(+)CD127(Low/-) was higher in HIV patients than in controls. Similarly, the frequency of Treg using any protocol was higher in flu-like patients compared to controls. The results suggest that relying on the expression of CD25 could be unsuitable to characterize Tregs in PBMC and GALT samples from a chronic infection such as HIV.

AMPc: una molécula clave en los eventos de regulación inmune y en el control de la replicación del VIH / cAMP: A keymolecule in events of immune regulation and in the control of HIV replication

El monofosfato de adenosina cíclico (AMPc) induce la activación de la proteína cinasa A, la cual regula negativamente la activación, la proliferación celular y la producción de IL-2, en células T. En células infectadas con el virus de inmunodeficiencia humana, el monofosfato de adenosina cíclico suprime la actividad de transcripción del promotor del virus y el paso del ADN viral del citoplasma al núcleo. El incremento del monofosfato de adenosina cíclico mediado por células T reguladoras CD4+, empleando la inyección de esta molécula en células blanco a través de las uniones comunicantes o empleando el eje CD39-CD73 para generar adenosina es utilizado para suprimir otras poblaciones celulares. En esta revisión se propone que la modulación del monofosfato de adenosina cíclico por las células T reguladoras CD4+ podría tener un papel dual durante la evolución de la infección por el virus de inmunodeficiencia humana. Su papel benéfico se centraría principalmente en el control de la replicación viral y factores de transcripción, o evitando la infección de nuevas células blanco por disminución en la expresión de los receptores virales. Paradójicamente, la segunda posibilidad es que el aumento del monofosfato de adenosina cíclico podría tener un papel perjudicial, debido al efecto negativo sobre la proliferación, activación, respuesta citotóxica y en la producción de citocinas que se observa durante la infección viral.

Cyclic adenosine monophosphate induces the activation of protein kinase A, which negatively regulates activation, proliferation and IL-2 production in T cells. In cells infected with human immunodeficiency virus, cyclic adenosine monophosphate suppresses the transcriptional activity of long terminal repeats and the amount of viral DNA from the cytoplasm to the nucleus. The increase in cyclic adenosine monophosphate mediated by CD4+ regulatory T cells, using either the influx of this molecule in target cells through the GAP junctions or by CD39-CD73 to generate adenosine, is used by CD4+ regulatory T cells to suppress other cell populations. In this review, we suggest that modulation of cyclic adenosine monophosphate by CD4+ regulatory T cells may have a dual role during the evolution of human immunodeficiency virus infection. The beneficial role would be mainly focused on the control of viral replication and transcription factors to replicate the virus, and/or preventing the infection of new target cells, decreasing the expression of the viral co-receptors. Paradoxically to this beneficial role, the second possibility is that increased cyclic adenosine monophosphate could have a detrimental role, due to the negative effect on proliferation, activation, cytotoxic response and cytokine production, which occurs during viral infection.

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.

Regulación inmune durante la coinfección por el virus de la inmunodeficiencia humana y el Mycobacterium tuberculosis / Immune regulation during Human Immunodeficiency Virus and mycobacterium tuberculosis coinfection

Durante las infecciones crónicas la regulación inmune constituye un mecanismo esencial para controlar los procesos inflamatorios; sin embargo, la excesiva regulación impide el desarrollo de una respuesta efectora adecuada. Las células T reguladoras, las células dendríticas y algunas moléculas inhibitorias, como CTLA-4, PD-1, IL-10, TGF-ß dioxigenasa, participan en la modulación de la respuesta inmune contra el virus de la inmunodeficiencia humana (VIH) y Mycobacterium tuberculosis. La mayoría de los hallazgos sustentan un efecto negativo de la regulación durante ambas infecciones, debido a que permiten la replicación de los patógenos. La acumulación de células T reguladoras funcionales y la expresión de estas moléculas se han asociado a un mecanismo compensador, en respuesta a la hiperactivación celular y a una inducción directa por parte de los microorganismos. En la coinfección, el VIH favorece la reactivación de M. tuberculosis y el desarrollo de formas extrapulmonares de la enfermedad. La infección por M. tuberculosis facilita la entrada del virus a la célula blanco y su replicación. Asimismo, se evidencia un aumento del estado de hiperactivación inmune, junto a una menor respuesta efectora. Aunque la inmunopatogénesis durante la coinfección ha sido poco estudiada, es probable que el estado proinflamatorio y de hiperactivación, característico de ambas infecciones, facilita el desarrollo de mecanismos de regulación que alteren aún más el equilibrio de la respuesta protectora durante la coinfección y facilitan la gravedad de la enfermedad.

During chronic infections, the immune regulation is an important mechanism to control inflammatory processes; however, the excessive regulation prevents the development of an appropriate effector immune response. The regulatory T cells (Treg), dendritic cells (DC) and some inhibitory molecules such as CTLA- 4, PD-1, IL-10, TGF-ß e IDO take part in the modulation of the immune response against the human immunodeficiency virus (HIV) and the Mycobacterium tuberculosis (M.tb). Most of the evidence supports a negative effect of the immune regulation during both infections, due to the fact that they allow the active replication of the pathogens. The accumulation of functional Treg cells and the expression of these molecules have been associated with a compensating mechanism, in response to a cellular hyper-activation and to these microorganisms direct induction. During the co-infection, the HIV favors the reactivation of M.tb and the development of extra-pulmonary TB forms. The M.tb infection promotes the entry of the virus into target cells and its replication. Likewise, an increase of the immune hyper-activation state has been reported along with low effector responses. Although the immune-pathogenesis during the co-infection has not been extensively studied, most likely the pro-inflammatory and immunological hyper-activation state, typical of both infections, promotes the development of immune regulatory mechanisms that further disturb the balance between the protective and pathogenic responses during co-infection, favoring the illness severity.

Factores que influyen en el curso de la infección por el virus de la inmunodeficiencia humana tipo 1en individuos sin progresión a largo plazo / Factors influencing the course of type one human immunodeficiency virus infection in individuals classified as long term non-progressors

La historia natural de la infección por el virus de la inmunodeficiencia humana tipo 1 (VIH-1) es un proceso variable que ha permitido identificar individuos con diferentes patrones de progresión de la infección. Entre estos individuos, existe un grupo de personas catalogadas como, sin progresión a largo plazo, las cuales se caracterizan por permanecer asintomáticas por largos periodos, sin evidencia de deterioro inmunológico y con cargas virales bajas o indetectables, en ausencia de tratamiento antirretroviral. Diferentes factores inmunológicos, genéticos y virales se han asociado con el patrón de progresión exhibido por estos individuos. Los factores inmunológicos contemplan mecanismos tanto de la inmunidad innata como de la adaptativa; los factores genéticos están relacionados con los genes que codifican los receptores de quimiocinas y sus ligandos naturales y genes del complejo mayor de histocompatibilidad. Por otro lado, los factores virales están relacionados con la variabilidad genética del virus y con su capacidad de replicación. De la forma en que estos factores se interrelacionen, dependen la capacidad infecciosa del virus, la respuesta inmune anti-VIH que pueda establecer el hospedero y, por consiguiente, el patrón de progresión que se establezca.

The natural history of type one human immunodeficiency virus infection (HIV-1) is a variable process that has allowed identifying different patterns of progression. Among them, there is a group of individuals known as long-term non-progressors (LTNP). LTNP are characterized for being asymptomatic for long periods of time, showing no evidence of immune deterioration and having low or undetectable viral loads in absence of antiretroviral treatment. Different immunologic, genetic and viral factors have been associated with the pattern of progression. Immunological factors include both, innate and adaptive mechanisms; genetic factors are related with genes of the chemokines family as well as genes of the major histocompatibility complex. On the other hand, viral factors are related to the genetic variability and replication ability of the virus. The disease pattern that is established depends on the interrelations of all these factors, which finally account for the type of anti- HIV-1 immune response developed and the infectious capacity of the virus.

HIV-1-driven regulatory T-cell accumulation in lymphoid tissues is associated with disease progression in HIV/AIDS.

Regulatory T (Treg) cells accumulate in the lymphoid tissues of human immunodeficiency virus (HIV)-infected individuals, contributing to the inability of the immune system to control virus replication. We investigate here Treg-cell numbers and functional markers (FOXP3, CTLA-4, IDO, and TGF-beta1) in lymphoid tissues from untreated infected hosts with progressive or nonprogressive disease (HIV-infected humans and simian immunodeficiency virus [SIV]-infected macaques). We found that increased numbers of FOXP3(+) T cells as well as increased expression of Treg-cell-associated functional markers were detected only during progressive disease. Such increases were not correlated with immune activation. Of importance, a high-perforin/FOXP3 ratio was associated with nonprogressive disease, suggesting that the immune control of virus replication represents a balance between cell-mediated immune responses and Treg-cell-mediated counter regulation of such responses. Furthermore, using an in vitro model of Treg-cell-HIV interactions, we showed that exposure of Treg cells to HIV selectively promoted their survival via a CD4-gp120-dependent pathway, thus providing an underlying mechanism for the accumulation of Treg cells in infected hosts with active viral replication. Considered together, our findings imply that therapeutic manipulation of Treg-cell number and/or function could improve immune control of HIV infection.

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.

[Evaluation as a function of granulocytes in hyperimmunoglobulinemia E syndrome with recurrent infections]. / Evaluación de la función de los granulocitos en el síndrome de hiperinmunoglobulinemia E con infecciones recurrentes.

The hyper-IgE syndrome with recurrent infections (HIESRI) is characterized by skin and respiratory infections due to Staphylococcus aureus and several fungi infections which are frequently associated with tissue damage. A deficiency in the chemotaxis of phagocytic cells has been documented to explain these findings; however, the expression of adhesion molecules, the secretion of cytokines that activate granulocytes and the production of oxygen reactive molecules have not been evaluated in HIESRI. Six HIESRI patients were evaluated for the following parameters: (1) secretion of GM-CSF and IL-5 by mitogen and antigen-activated mononuclear cells, (2) the chemotactic response of FMLP-activated granulocytes, (3) the respiratory burst of PMA-activated granulocytes, and (4) the expression of L-selectin and CD11b in PMA-activated granulocytes. Human recombinant GM-CSF and culture supernatants were evaluated for capacity to modulate granulocytic function. Compared to controls, HIESRI patients showed a normal production of GM-CSF and an increase in the basal secretion of IL-5. No significant differences were observed for chemotaxis, respiratory burst or L-selectin and CD11b expression. The GM-CSF did not modulate these functions in granulocytes from HIESRI patients, but culture supernatants applied to granulocytes inhibited chemotaxis, increased respiratory burst and caused the shedding of L-selectin from the granulocyte surface. The 6 HIESRI patients were nonsymptomatic during the time of this research due to a program of continued treatment; findings suggest that granulocytes are activated more easily in response to proinflammatory factors and that production of these factors is higher in HIESRI.

Evaluación de la función de los granulocitos en el síndrome de hiperinmunoglobulinemia E con infecciones recurrentes / Evaluation of granulocyte function in the hyper immunoglobulin E syndrome associated with recurrent infections

El síndrome de hiper-IgE con infecciones recurrentes (SHIEIR) se caracteriza por infecciones de la piel y el aparato respiratorio causadas especialmente por Staphylococcus aureus y algunos hongos, infecciones que se asocian frecuentemente con daño tisular. Para explicar esta evolución clínica se ha documentado en el SHIEIR una deficiencia en la quimiotaxis de las células fagocíticas, pero no se ha evaluado la expresión de las moléculas de adhesión que regulan este fenómeno. Además, a pesar del daño tisular observado en este trastorno, no se ha estudiado la producción de citocinas activadoras de los granulocitos ni la producción de moléculas reactivas derivadas del oxígeno. En seis pacientes con SHIEIR se evaluó la secreción de GM-CSF e IL-5 de las células mononucleares cultivadas con mitógenos y antígenos, la quimiotaxis de los granulocitos inducida por el N-formil-metionil-leucina-fenilalania (FMLP) bajo gel de agarosa, la explosión respiratoria de los granulocitos después de la activación con forbol-miristato-acetato (PMA) determinada por citometría de flujo y la expresión de las moléculas de superficie L-selectina y CD11b en los granulocitos activados con PMA. Además, se determinó la modulación ejercida sobre estas funciones de los granulocitos por el GM-CSF y los sobrenadantes de cultivos. Con respecto a los controles, los pacientes con SHIEIR presentaron una producción normal de GMCSF y un aumento en la secreción basal de IL-5, mientras que no existieron diferencias significativas en la quimiotaxis, la explosión respiratoria y la expresión de L-selectina y CD11b.