Different Plasma Markers of Inflammation Are Influenced by Immune Recovery and cART Composition or Intensification in Treated HIV Infected Individuals

BACKGROUND: HIV-1 infection increases plasma levels of inflammatory markers. Combination antiretroviral therapy (cART) does not restore inflammatory markers to normal levels. Since intensification of cART with raltegravir reduced CD8 T-cell activation in the Discor-Ral and IntegRal studies, we have evaluated the effect of raltegravir intensification on several soluble inflammation markers in these studies. METHODS: Longitudinal plasma samples (0-48 weeks) from the IntegRal (n = 67, 22 control and 45 intensified individuals) and the Discor-Ral studies (44 individuals with CD4 T-cell counts<350 cells/µl, 14 control and 30 intensified) were assayed for 25 markers. Mann-Whitney, Wilcoxon, Spearman test and linear mixed models were used for analysis. RESULTS: At baseline, different inflammatory markers were strongly associated with HCV co-infection, lower CD4 counts and with cART regimens (being higher in PI-treated individuals), but poorly correlated with detection of markers of residual viral replication. Although raltegravir intensification reduced inflammation in individuals with lower CD4 T-cell counts, no effect of intensification was observed on plasma markers of inflammation in a global analysis. An association was found, however, between reductions in immune activation and plasma levels of the coagulation marker D-dimer, which exclusively decreased in intensified patients on protease inhibitor (PI)-based cART regimens (P = 0.040). CONCLUSIONS: The inflammatory profile in treated HIV-infected individuals showed a complex association with HCV co-infection, the levels of CD4 T cells and the cART regimen. Raltegravir intensification specifically reduced D-dimer levels in PI-treated patients, highlighting the link between cART composition and residual viral replication; however, raltegravir had little effect on other inflammatory markers

Glucocorticoids' treatment impairs the medium-term immunogenic response to SARS-CoV-2 mRNA vaccines in Systemic Lupus Erythematosus patients

Limited data exists on SARS-CoV-2 sustained-response to vaccine in patients with rheumatic diseases. This study aims to evaluate neutralizing antibodies (nAB) induced by SARS-CoV-2 vaccine after 3 to 6 months from administration in Systemic Lupus Erythematosus (SLE) patients, as a surrogate of sustained-immunological response. This cross-sectional study compared nAB titre of 39 SLE patients and 37 Healthy individuals with no previous SARS-CoV-2 infection, who had all received a complete regimen of a mRNA SARS-CoV-2 vaccine within the last 3 to 6 months. We included four lines of SLE treatment including Not-treated, Hydroxychloroquine, immunosuppressive drugs and biological therapy. Glucocorticoids were allowed in all groups. Healthy and Not-treated individuals showed the highest levels of nAB. Treated patients presented lower nAB titres compared to Healthy: a 73% decrease for First-Line patients, 56% for Second-Line treatment and 72% for Third-Line. A multivariate analysis pointed to Glucocorticoids as the most associated factor with declining nAB levels (75% decrease) in treated SLE. Furthermore, a significant reduction in nAB titres was observed for Rituximab-users compared to Healthy subjects (89% decrease). Medium-term response of SLE patients to SARS-CoV-2 mRNA vaccines is negatively impacted in Glucocorticoids and Rituximab users. These findings might help to inform recommendations in vaccination protocols for SLE patients

Identifying the needs of older people living with HIV (≥ 50 years old) from multiple centres over the world: a descriptive analysis

BackgroundOlder People Living with HIV (OPWH) combine both aging and HIV-infection features, resulting in ageism, stigma, social isolation, and low quality of life. This context brings up new challenges for healthcare professionals, who now must aid patients with a significant comorbidity burden and polypharmacy treatments. OPWH opinion on their health management is hardly ever considered as a variable to study, though it would help to understand their needs on dissimilar settings.MethodsWe performed a cross-sectional, comparative study including patients living with HIV aged >= 50 years old from multiple centers worldwide and gave them a survey addressing their perception on overall health issues, psychological problems, social activities, geriatric conditions, and opinions on healthcare. Data was analyzed through Chisquared tests sorting by geographical regions, age groups, or both.ResultsWe organized 680 participants data by location (Center and South America [CSA], Western Europe [WE], Africa, Eastern Europe and Israel [EEI]) and by age groups (50- 55, 56-65, 66-75, >75). In EEI, HIV serostatus socializing and reaching undetectable viral load were the main problems. CSA participants are the least satisfied regarding their healthcare, and a great part of them are not retired. Africans show the best health perception, have financial problems, and fancy their HIV doctors. WE is the most developed region studied and their participants report the best scores. Moreover, older age groups tend to live alone, have a lower perception of psychological problems, and reduced social life.ConclusionsPatients' opinions outline region- and age-specific unmet needs. In EEI, socializing HIV and reaching undetectable viral load were the main concerns. CSA low satisfaction outcomes might reflect high expectations or profound inequities in the region. African participants results mirror a system where general health is hard to achieve, but HIV clinics are much more appealing to them. WE is the most satisfied region about their healthcare. In this context, age-specific information, education and counseling programs (i.e. Patient Reported Outcomes, Patient Centered Care, multidisciplinary teams) are needed to promote physical and mental health among older adults living with HIV/AIDS. This is crucial for improving health-related quality of life and patient's satisfaction

Methylation regulation of Antiviral host factors, Interferon Stimulated Genes (ISGs) and T-cell responses associated with natural HIV control

GWAS, immune analyses and biomarker screenings have identified host factors associated within vivoHIV-1 control. However, there is a gap in the knowledge about the mechanisms that regulate the expression of such host factors. Here, we aimed to assess DNA methylation impact on host genome in natural HIV-1 control. To this end, whole DNA methylome in 70 untreated HIV-1 infected individuals with either high (>50,000 HIV-1-RNA copies/ml, n = 29) or low (<10,000 HIV-1-RNA copies/ml, n = 41) plasma viral load (pVL) levels were compared and identified 2,649 differentially methylated positions (DMPs). Of these, a classification random forest model selected 55 DMPs that correlated with virologic (pVL and proviral levels) and HIV-1 specific adaptive immunity parameters (IFNg-T cell responses and neutralizing antibodies capacity). Then, cluster and functional analyses identified two DMP clusters: cluster 1 contained hypo-methylated genes involved in antiviral and interferon response (e.g.PARP9,MX1, andUSP18) in individuals with high viral loads while in cluster 2, genes related to T follicular helper cell (Tfh) commitment (e.g.CXCR5andTCF7) were hyper-methylated in the same group of individuals with uncontrolled infection. For selected genes, mRNA levels negatively correlated with DNA methylation, confirming an epigenetic regulation of gene expression. Further, these gene expression signatures were also confirmed in early and chronic stages of infection, including untreated, cART treated and elite controllers HIV-1 infected individuals (n = 37). These data provide the first evidence that host genes critically involved in immune control of the virus are under methylation regulation in HIV-1 infection. These insights may offer new opportunities to identify novel mechanisms ofin vivovirus control and may prove crucial for the development of future therapeutic interventions aimed at HIV-1 cure. Author summary The infection with the human immunodeficiency virus (HIV), as for other viral infections, induce global DNA Methylation changes in the host genome. Herein, we identified for first time the methylation impact on host genome in untreated HIV-1 infection with different degrees ofin vivovirus control. Specifically, we observed that individuals with a better HIV-1 control showed a hypermethylation of genes associated with antiviral and interferon pathways and the hypomethylation of genes associated with the differentiation process of T follicular helper cells. Interestingly, these epigenetic imprints in host genome were strongly correlated with virus content and HIV-specific T cell responses. Therefore, we propose DNA Methylation as the regulation mechanism of host genes involved in immune HIV-1 control that could interfere in the efficacy of cure strategies. We also highlight the importance of DNA Methylation to regulate immune responses not only in HIV-1 but also in chronic infections or other pathologic situations associated with a sustained activation of the immune system

Kinetics of immune responses elicited after three mRNA COVID-19 vaccine doses in predominantly antibody-deficient individuals

Mass vaccination campaigns reduced COVID-19 incidence and severity. Here, we evaluated the immune responses developed in SARS-CoV-2-uninfected patients with predominantly antibody-deficiencies (PAD) after three mRNA-1273 vaccine doses. PAD patients were classified based on their immunodeficiency: unclassified primary antibody-deficiency (unPAD, n = 9), common variable immunodeficiency (CVID, n = 12), combined immunodeficiency (CID, n = 1), and thymoma with immunodeficiency (TID, n = 1). unPAD patients and healthy controls (HCs, n = 10) developed similar vaccine-induced humoral responses after two doses. However, CVID patients showed reduced binding and neutralizing titers compared to HCs. Of interest, these PAD groups showed lower levels of Spike-specific IFN-γ-producing cells. CVID individuals also presented diminished CD8+T cells. CID and TID patients developed cellular but not humoral responses. Although the third vaccine dose boosted humoral responses in most PAD patients, it had limited effect on expanding cellular immunity. Vaccine-induced immune responses in PAD individuals are heterogeneous, and should be immunomonitored to define a personalized therapeutic strategies.info:eu-repo/semantics/publishedVersio

Biomarker candidates for progression and clinical management of COVID-19 associated pneumonia at time of admission

COVID-19 pathophysiology is currently not fully understood, reliable prognostic factors remain elusive, and few specific therapeutic strategies have been proposed. In this scenario, availability of biomarkers is a priority. MS-based Proteomics techniques were used to profile the proteome of 81 plasma samples extracted in four consecutive days from 23 hospitalized COVID-19 associated pneumonia patients. Samples from 10 subjects that reached a critical condition during their hospital stay and 10 matched non-severe controls were drawn before the administration of any COVID-19 specific treatment and used to identify potential biomarkers of COVID-19 prognosis. Additionally, we compared the proteome of five patients before and after glucocorticoids and tocilizumab treatment, to assess the changes induced by the therapy on our selected candidates. Forty-two proteins were differentially expressed between patients' evolution groups at 10% FDR. Twelve proteins showed lower levels in critical patients (fold-changes 1.20-3.58), of which OAS3 and COG5 found their expression increased after COVID-19 specific therapy. Most of the 30 proteins over-expressed in critical patients (fold-changes 1.17-4.43) were linked to inflammation, coagulation, lipids metabolism, complement or immunoglobulins, and a third of them decreased their expression after treatment. We propose a set of candidate proteins for biomarkers of COVID-19 prognosis at the time of hospital admission. The study design employed is distinctive from previous works and aimed to optimize the chances of the candidates to be validated in confirmatory studies and, eventually, to play a useful role in the clinical practice

Adaptación argentina de la Escala Toronto de Alexitimia (TAS-20) e investigación de la validez del puntaje total y de sus factores

En los términos en que fuera originalmente definida por Sifneos, Nemiah y col. (1976) la alexitimia es un constructo multifacético que comprende a) la dificultad para diferenciar los sentimientos y distinguirlos de las sensaciones corporales b) la dificultad para comunicar y describir los propios sentimientos a otras personas, c) una vida de fantasía empobrecida y d) un estilo cognitivo orientado a intereses en el mundo externo. Inicialmente se conceptualizó la alexitimia como característica de las enfermedades psicosomáticas (asma, úlcera, colitis, hipertensión, artritis, eccema, hipertiroidismo, trastornos de la alimentación, patologías oncológicas, colagenopatías, nuevas patologías autoinmunes, la psoriasis, etcétera) sin embargo recientemente (Taylor, Bagby y Parker ,1997) la definen como “un desorden de la regulación de los afectos”, que se encuentra en muchos cuadros de difícil tratamiento como las psicopatías, las adicciones y la vulnerabilidad crónica o traumática al estrés. Existen teorizaciones neurológicas, psicodinámicas y culturales para explicar la alexitimia. Se han desarrollado, también, numerosos instrumentos de medición de la alexitimia. En 1990 se adaptó en Argentina (Casullo y Wiater) uno de los instrumentos de evaluación de mayor mérito psicométrico: la Alexithymia Toronto Scale (TAS26). En nuestro proyecto de investigación (1997-1999, Sistema de Incentivos, UNLP) investigamos la confiabilidad y validez de la adaptación argentina, la validez de su puntaje total y de sus factores y las variables que afectan la evaluación de la alexitimia. En el nivel internacional el constructo alexitimia y su evaluación han seguido concitando el máximo interés. Se diseñó la versión TAS-20 (1994) con aun mayor confiabilidad y se ha probado su validez factorial en 18 diferentes lenguas y culturas. Los hallazgos afirman la propiedad del uso de la TAS-20 en investigaciones transculturales y postulan a la alexitimia como un rasgo universal que trasciende las diferencias culturales (2003).Eje temático: Técnicas y Procesos de Evaluación PsicológicaFacultad de Psicologí

Adaptación argentina de la Escala Toronto de Alexitimia (TAS-20) e investigación de la validez del puntaje total y de sus factores

En los términos en que fuera originalmente definida por Sifneos, Nemiah y col. (1976) la alexitimia es un constructo multifacético que comprende a) la dificultad para diferenciar los sentimientos y distinguirlos de las sensaciones corporales b) la dificultad para comunicar y describir los propios sentimientos a otras personas, c) una vida de fantasía empobrecida y d) un estilo cognitivo orientado a intereses en el mundo externo. Inicialmente se conceptualizó la alexitimia como característica de las enfermedades psicosomáticas (asma, úlcera, colitis, hipertensión, artritis, eccema, hipertiroidismo, trastornos de la alimentación, patologías oncológicas, colagenopatías, nuevas patologías autoinmunes, la psoriasis, etcétera) sin embargo recientemente (Taylor, Bagby y Parker ,1997) la definen como “un desorden de la regulación de los afectos”, que se encuentra en muchos cuadros de difícil tratamiento como las psicopatías, las adicciones y la vulnerabilidad crónica o traumática al estrés. Existen teorizaciones neurológicas, psicodinámicas y culturales para explicar la alexitimia. Se han desarrollado, también, numerosos instrumentos de medición de la alexitimia. En 1990 se adaptó en Argentina (Casullo y Wiater) uno de los instrumentos de evaluación de mayor mérito psicométrico: la Alexithymia Toronto Scale (TAS26). En nuestro proyecto de investigación (1997-1999, Sistema de Incentivos, UNLP) investigamos la confiabilidad y validez de la adaptación argentina, la validez de su puntaje total y de sus factores y las variables que afectan la evaluación de la alexitimia. En el nivel internacional el constructo alexitimia y su evaluación han seguido concitando el máximo interés. Se diseñó la versión TAS-20 (1994) con aun mayor confiabilidad y se ha probado su validez factorial en 18 diferentes lenguas y culturas. Los hallazgos afirman la propiedad del uso de la TAS-20 en investigaciones transculturales y postulan a la alexitimia como un rasgo universal que trasciende las diferencias culturales (2003).Eje temático: Técnicas y Procesos de Evaluación PsicológicaFacultad de Psicologí

Stable neutralizing antibody levels 6 months after mild and severe COVID-19 episodes

Background. Understanding mid-term kinetics of immunity to SARS-CoV-2 is the cornerstone for public health control of the pandemic and vaccine development. However, current evidence is rather based on limited measurements, losing sight of the temporal pattern of these changes. Methods. We conducted a longitudinal analysis on a prospective cohort of COVID-19 patients followed up for >6 months. Neutralizing activity was evaluated using HIV reporter pseudoviruses expressing SARS-CoV-2 S protein. IgG antibody titer was evaluated by ELISA against the S2 subunit, the receptor binding domain (RBD), and the nucleoprotein (NP). Statistical analyses were carried out using mixed-effects models. Findings. We found that individuals with mild or asymptomatic infection experienced an insignificant decay in neutralizing activity, which persisted 6 months after symptom onset or diagnosis. Hospitalized individuals showed higher neutralizing titers, which decreased following a 2-phase pattern, with an initial rapid decline that significantly slowed after day 80. Despite this initial decay, neutralizing activity at 6 months remained higher among hospitalized individuals compared to mild symptomatic. The slow decline in neutralizing activity at mid-term contrasted with the steep slope of anti-RBD, S2, or NP antibody titers, all of them showing a constant decline over the follow-up period. Conclusions. Our results reinforce the hypothesis that the quality of the neutralizing immune response against SARS-CoV-2 evolves over the post-convalescent stage.info:eu-repo/semantics/acceptedVersio

SARS-CoV-2 infection elicits a rapid neutralizing antibody response that correlates with disease severity

The protective effect of neutralizing antibodies in SARS-CoV-2 infected individuals is not yet well defined. To address this issue, we have analyzed the kinetics of neutralizing antibody responses and their association with disease severity. Between March and May 2020, the prospective KING study enrolled 72 COVID-19+ participants grouped according to disease severity. SARS-CoV-2 infection was diagnosed by serological and virological tests. Plasma neutralizing responses were assessed against replicative virus and pseudoviral particles. Multiple regression and non-parametric tests were used to analyze dependence of parameters. The magnitude of neutralizing titers significantly increased with disease severity. Hospitalized individuals developed higher titers compared to mild-symptomatic and asymptomatic individuals, which together showed titers below the detection limit in 50% of cases. Longitudinal analysis confirmed the strong differences in neutralizing titers between non-hospitalized and hospitalized participants and showed rapid kinetics of appearance of neutralizing antibodies (50% and 80% of maximal activity reached after 11 and 17 days after symptoms onset, respectively) in hospitalized patients. No significant impact of age, gender or treatment on the neutralizing titers was observed in this limited cohort. These data identify a clear association of humoral immunity with disease severity and point to immune mechanisms other than antibodies as relevant players in COVID-19 protection.info:eu-repo/semantics/publishedVersio