Respuesta inmune contra SARS-CoV-2 en personas con VIH convalecientes de COVID-19 / SARS-CoV-2 immunity in PWH

Desde principios de la pandemia de SARS-CoV-2 se ha debatido el curso de la enfermedad COVID-19 en personas con VIH. Por un lado, la inmunodeficiencia derivada de la infección por VIH y la mayor prevalencia de comorbilidades estarían asociadas al desarrollo de enfermedad grave. Por otro lado, la disfunción inmunológica podría evitar una respuesta inflamatoria exacerbada. En este trabajo de revisión analizamos la evidencia disponible en cuanto a la relación entre la manifestación clínica de COVID-19 y la respuesta inmune humoral y celular contra SARS-CoV-2 en el contexto de la coinfección con VIH. La bibliografía sugiere que las personas con VIH que reciben tratamiento antirretroviral logran respuestas eficaces contra SARS-CoV-2, a pesar de presentar algunas de las funciones celulares alteradas. Esto sugiere un impacto significativo de la terapia antirretroviral, no solo en el control del VIH sino en potenciar la inmunidad para restringir otras infecciones.

Since the beginning of SARS-CoV-2 pandemic, the course of COVID-19 in people with HIV has been debated. On the one hand, the immunodeficiency derived from HIV infec-tion and the higher prevalence of comorbidities would be associated with severe disease. On the other hand, due to its immunological dysfunction, an exacerbated inflam-matory response might be avoided.In this review, we analyzed the evidence regarding the clinical manifestation of COVID-19 and the humoral and cellular immune response against SARS-CoV-2 during HIV coinfection. The literature suggests that people with HIV on antiretroviral treatment achieved effective responses against SARS-CoV-2, despite having altered cell func-tions. This indicates a remarkable impact of antiretroviral therapy, not only in controlling HIV but also in boosting immunity to restrict other infections

Macrophage Migration Inhibitory Factor (MIF) Promotes Increased Proportions of the Highly Permissive Th17-like Cell Profile during HIV Infection.

In this study, we evaluate the role of the MIF/CD74 axis in the functionality of CD4+ T lymphocytes (CD4TL) during HIV infection. MDMs from healthy donors were infected with a R5-tropic or Transmitted/Founder (T/F) HIV strain. At day 11 post-MDM infection, allogeneic co-cultures with uninfected CD4TLs plus MIF stimulus were performed. Cytokine production was evaluated by ELISA. MIF plasma levels of people with HIV (PWH) were evaluated by ELISA. The phenotype and infection rate of CD4TLs from PWH were analyzed after MIF stimulus. Intracellular cytokines and transcription factors were evaluated by flow cytometry. Data were analyzed by parametric or non-parametric methods. The MIF stimulation of HIV-infected MDMs induced an increased expression of IL-6, IL-1ß and IL-8. In CD4TL/MDM co-cultures, the MIF treatment increased IL-17A/RORγt-expressing CD4TLs. Higher concentrations of IL-17A in supernatants were also observed. These results were recapitulated using transmitted/founder (T/F) HIV-1 strains. The MIF treatment appeared to affect memory CD4TLs more than naïve CD4TLs. MIF blocking showed a negative impact on IL17A+CD4TL proportions. Higher MIF concentrations in PWH-derived plasma were correlated with higher IL-17A+CD4TL percentages. Finally, MIF stimulation in PWH-derived PBMCs led to an increase in Th17-like population. MIF may contribute to viral pathogenesis by generating a microenvironment enriched in activating mediators and Th17-like CD4TLs, which are known to be highly susceptible to HIV-1 infection and relevant to viral persistence. These observations establish a basis for considering MIF as a possible therapeutic target.

Phenotypic and functional analysis of γδ T cells in the pathogenesis of human T-cell lymphotropic virus type 1 infection.

The human T-cell leukemia virus type 1 (HTLV-1) is the cause of serious malignant and inflammatory diseases, including adult T-cell leukemia and lymphoma and tropical spastic paraparesis. The potential protective role of γδ T cells in HTLV-1 infection remains unclear. Here, demonstrate that there is a decrease in the amount of Vγ9Vδ2 T cells in patients with HTLV-1, especially in those with HTLV-1 associated pathologies. This suggests that γδ T cells could be involved in controlling the virus. Indeed, we found that Vγ9Vδ2 T cells, expanded from non-infected individuals, can kill cells expressing the viral proteins HBZ and Tax and this phenotype is reversed in the presence of mevastatin. Cytotoxicity by Vγ9Vδ2 T cells was not associated with an increase of INF-γ production. In sharp contrast, killing by NK cells was reduced by Tax expression. Thus, our study provides initial evidence for a potential protective role of Vγ9Vδ2 T cells against HTLV-1 infection. Therapeutic exploitation of these insights is feasible with current technologies of T-cell therapies and could provide novel tools to prevent and treat HTLV-1-associated malignancies and neurologic complications.

Creación de la colección COVID-19 del Biobanco de Enfermedades Infecciosas en Argentina / Establishment of a COVID-19 collection within the Biobank of Infectious Diseases in ArgentinaEsta obra está bajo una licencia de CreativeCommons Reconocimiento-NoComercial 4.0Internacionalhttps://creativecommons.org/licenses/by-nc/4.0/i

La pandemia de COVID-19 ha puesto en jaque a los sistemas de salud en el mundo; la vinculación entre la investigación biomédica y la práctica asistencial ha probado ser un requisito fundamental para dar respuesta a la misma de manera eficiente y rápida. En este sentido, los biobancos se constituyen como un componente clave ya que favorecen el almacenamiento de grandes volúmenes de muestras biológicas gestionadas en base a criterios que garanticen su óptima calidad, armonización y seguridad, respetando requisitos éticos y legales que aseguran los derechos de los ciudadanos. La cesión de estas muestras a distintos grupos de investigación promueve el desarrollo de nuevas herramientas diagnósticas y terapéuticas y vacunas. Frente a la llegada del SARS-CoV-2 a la Argentina, el Biobanco de Enfermedades Infecciosas estableció rápidamente la colección COVID-19 constituida por muestras de plasma, suero y células mononucleares de sangre periférica de personas cursando la enfermedad o recuperadas. En solo seis meses se enrolaron 825 donantes, lo que significa alrededor de 14.000 viales de material biológico almacenados y a disposición de los investigadores que lo soliciten. A tal efecto, se realizaron seis actos de cesión a diversos grupos pertenecientes a instituciones de investigación, mientras que tres se encuentran en evaluación. Las muestras cedidas han permitido, por ejemplo, el desarrollo de kits serológicos de producción nacional; lo que pone de manifiesto que el rápido establecimiento de esta colección, bajo un sistema de gestión eficiente, constituye una herramienta muy valiosa en la respuesta a esta nueva enfermedad

The COVID-19 pandemic has driven an unprecedented health crisis. Cooperation between biomedical research and healthcare practice has been shown to be a fundamental requirement to provide an efficient and timely response. In this regard, biobanks are key components since they allow the storage of large volumes of biological samples with guaranteed optimum quality, harmonization and safety, ensuring ethical and legal requirements which protect citizen rights. The transfer of these samples to different research groups fosters the development of new diagnostic and therapeutic tools as well as vaccines. Upon SARS-CoV-2 arrival to Argentina, the Biobank of Infectious Diseases rapidly established the COVID-19 collection comprised by plasma, serum and peripheral blood mononuclear cells samples obtained from people within the acute phase of the infection or who have already recovered. In only 6 months, 825 donors were enrolled, representing around 14,000 vials of biological material stored and available to researchers who might require it. In this line, 6 transfer agreements have been already performed to different groups belonging to national research institutions, while 3 are under evaluation. The transferred samples have allowed, for instance, the development of nationally produced serologic kits, which shows that the rapid establishment of this collection, under an efficient management system, represents a highly valuable tool in the response to this new disease.

Seroprevalencia de COVID 19 en personas viviendo con VIH en el Area Metropolitana / COVID-19 Seroprevalence and PLHIV

Se desconoce si las personas que viven con el VIH (PVV) tienen un mayor riesgo de contraer la infección por SARS-CoV-2. Los estudios serológicos prospectivos pueden permitir análisis de seroincidencia. Este estudio prospectivo incluyó a PVV sin antecedentes de vacunación contra SARS-CoV-2 de la Ciudad Autónoma de Buenos Aires (CABA) y Gran Buenos Aires (GBA) que concurrieron entre marzo y junio de 2021 a realizar sus controles al instituto INBIRS. La tasa de seroprevalencia de anticuerpos contra la proteína espiga del SARS-CoV-2 fue del 33,3% (IC 24,9-42,5%) para la población estudiada. Esta prevalencia fue significativamente mayor a la reportada previamente para la población general de la misma región geográfica. No se observó una asociación entre el recuento de linfocitos T CD4+ con los niveles de IgG específica. En conclusión, el hallazgo de una alta seroprevalencia de anticuerpos contra SARS-CoV-2 entre las PVV en CABA y GBA puede sugerir una mayor susceptibilidad a la infección por este virus; sin embargo, puede ser también un marcador subrogante que indica la tasa de seroprevalencia en población general se encuentra subestimada

It is not known whether people living with HIV (PLHIV) are at increased risk of acquiring SARS-CoV-2 infection. Prospective serological studies can allow seroincidence analysis. This prospective study included PLHIV, without a history of vaccination against SARS-CoV-2, from the Autonomous City of Buenos Aires (CABA) and Buenos Aires surroundings (GBA), who attended INBIRS Institute between March and June 2021 to carry out their controls. The seroprevalence rate of antibodies against the SARS-CoV-2 spike protein was 33.3% (CI 24.9-42.5%) for the study population. This prevalence was significantly higher than that previously reported for the general population of the same geographic region. No association was found between CD4+ T-cell counts with levels of SARS-CoV-2 specific IgG. In conclusion, the finding of a high seroprevalence of antibodies against SARS-CoV-2 among PLHIV in CABA and GBA may suggest a greater susceptibility to infection; however, it can also be a surrogate marker that the seroprevalence rate in the general population is underestimated.

Expression of IL-33 Receptor Is Significantly Up-Regulated in B Cells During Pregnancy and in the Acute Phase of Preterm Birth in Mice.

Interleukin-33 (IL-33) is a mucosal alarmin belonging to the IL-1 cytokine family and is now recognized to have a key role in innate and adaptive immunity, contributing to tissue homeostasis and response to environmental stresses. In addition, IL-33 has also been shown to work as a positive regulator that initiates and maintains a Th2 immune response. In the context of pregnancy, it has been recently demonstrated that upon certain stress conditions, such as an infection induced inflammation, IL-33 is released from the uterine mucosa and triggers decidual B cells to produce anti-inflammatory molecules, which in turn restore immune homeostasis and prevents the development of preterm birth. In this study we therefore performed a detailed characterization of IL-33 receptor (Il1rl1 or ST2) expression in B cells during normal pregnancy, as well as in a mouse model of preterm birth. We observed that splenic B cells significantly up-regulate the expression of Il1rl1 during pregnancy and identified the B1 B cell population as the main ST2-expressing B cell subset. A further kinetic analysis showed that percentages of ST2-expressing B1 B cells are significantly augmented on days 12 and 14 of pregnancy, both in the spleen and peritoneal cavity of pregnant mice, and then drop toward the end of pregnancy to the levels observed in non-pregnant animals. Furthermore, using a mouse model of LPS-induced preterm birth, we demonstrated that not only are the percentages of ST2-expressing B1 B cells significantly enlarged in the spleen during the acute phase of preterm birth, but decidual B cells also significantly up-regulate ST2 expression as compared to term-pregnant mice. Overall, our results suggest a functional role of ST2 expression in B cells during pregnancy and reinforce the importance of the IL-33/ST2 axis in B cells as a critical mechanism to control inflammation-induced preterm birth.

7-oxo-DHEA enhances impaired M. tuberculosis-specific T cell responses during HIV-TB coinfection.

BACKGROUND: Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB), affecting approximately one third of the world's population. Development of an adequate immune response will determine disease progression or progress to chronic infection. Risk of developing TB among human immunodeficiency virus (HIV)-coinfected patients (HIV-TB) is 20-30 times higher than those without HIV infection, and a synergistic interplay between these two pathogens accelerates the decline in immunological functions. TB treatment in HIV-TB coinfected persons is challenging and it has a prolonged duration, mainly due to the immune system failure to provide an adequate support for the therapy. Therefore, we aimed to study the role of the hormone 7-oxo-dehydroepiandrosterone (7-OD) as a modulator of anti-tuberculosis immune responses in the context of HIV-TB coinfection. METHODS: A cross-sectional study was conducted among HIV-TB patients and healthy donors (HD). We characterized the ex vivo phenotype of CD4 + T cells and also evaluated in vitro antigen-specific responses by Mtb stimulation of peripheral blood mononuclear cells (PBMCs) in the presence or absence of 7-OD. We assessed lymphoproliferative activity, cytokine production and master transcription factor profiles. RESULTS: Our results show that HIV-TB patients were not able to generate successful anti-tubercular responses in vitro compared to HD, as reduced IFN-γ/IL-10 and IFN-γ/IL-17A ratios were observed. Interestingly, treatment with 7-OD enhanced Th1 responses by increasing Mtb-induced proliferation and the production of IFN-γ and TNF-α over IL-10 levels. Additionally, in vitro Mtb stimulation augmented the frequency of cells with a regulatory phenotype, while 7-OD reduced the proportion of these subsets and induced an increase in CD4 + T-bet+ (Th1) subpopulation, which is associated with clinical data linked to an improved disease outcome. CONCLUSIONS: We conclude that 7-OD modifies the cytokine balance and the phenotype of CD4 + T cells towards a more favorable profile for mycobacteria control. These results provide new data to delineate novel treatment approaches as co-adjuvant for the treatment of TB.

PD-1/PD-L1 Pathway Modulates Macrophage Susceptibility to Mycobacterium tuberculosis Specific CD8+ T cell Induced Death.

CD8+T cells contribute to tuberculosis (TB) infection control by inducing death of infected macrophages. Mycobacterium tuberculosis (Mtb) infection is associated with increased PD-1/PD-L1 expression and alternative activation of macrophages. We aimed to study the role of PD-1 pathway and macrophage polarization on Mtb-specific CD8+T cell-induced macrophage death. We observed that both PD-L1 on CD14+ cells and PD-1 on CD8+T cells were highly expressed at the site of infection in pleurisy TB patients' effusion samples (PEMC). Moreover, a significant increase in CD8+T cells' Mtb-specific degranulation from TB-PEMC vs. TB-PBMC was observed, which correlated with PD-1 and PDL-1 expression. In an in vitro model, M1 macrophages were more susceptible to Mtb-specific CD8+T cells' cytotoxicity compared to M2a macrophages and involved the transfer of cytolytic effector molecules from CD8+T lymphocytes to target cells. Additionally, PD-L1 blocking significantly increased the in vitro Ag-specific CD8+T cell cytotoxicity against IFN-γ-activated macrophages but had no effect over cytotoxicity on IL-4 or IL-10-activated macrophages. Interestingly, PD-L1 blocking enhanced Mtb-specific CD8+ T cell killing of CD14+ cells from human tuberculous pleural effusion samples. Our data indicate that PD-1/PD-L1 pathway modulates antigen-specific cytotoxicity against M1 targets in-vitro and encourage the exploration of checkpoint blockade as new adjuvant for TB therapies.