Expression profile of microRNAs related with viral infectivity, inflammatory response, and immune activation in people living with HIV.

Objective: To evaluate the serum expression of microRNAs (miRNAs) with ability to modulate the human immunodeficiency (HIV) replication or inflammatory status in people living with HIV (PLWH). Methods: Forty healthy controls and two groups of PLWH were evaluated: (a) Group 1 (n = 30), patients with detectable viral load at inclusion, analyzed before receiving antiretroviral therapy (ART) and 12 months after initiating it; (b) Group 2 (n = 55), PLWH with prolonged undetectable viral load. Intestinal barrier disruption (I-FABP) and bacterial translocation (16S rDNA) markers, inflammatory markers such as interleukin (IL)-6 and sCD163, immune activation and expression of specific miRNAs were evaluated. Results: Serum concentrations of I-FABP, 16S rDNA, IL-6, sCD163 and activated T lymphocytes were increased in PLWH. Serum miR-34a was overexpressed at inclusion and remained elevated after ART. The expression of the remaining miRNAs that modulate HIV infectivity (miR-7, mir-29a, miR-150, and miR-223) was similar in PLWH and controls. Related to miRNAs implicated in inflammation (miR-21, miR-155, and miR-210), significant overexpression were observed in miR-21 and miR-210 levels in untreated PLWH, but levels were restored in those patients treated for a long period. Conclusion: A sustained overexpression of miR-34a was detected even after prolonged HIV controlled replication. miR-21 and miR-210 can be considered new markers of inflammation with high sensitivity to its modifications.

Implication of Neutrophils Extracellular Traps in the Pathogenesis of SARS-CoV-2 pneumonia.

Peripheral blood polymorphonuclear neutrophils (PMNs) forming extracellular traps (NETs), as well as endothelial- and platelet-derived parameters, have been analyzed in patients with SARS-CoV-2 pneumonia, and their prognostic role has been evaluated. Eighty-seven consecutive patients hospitalized with SARS-CoV-2 pneumonia were prospectively selected. A sample of 30 healthy individuals served as the control group. Clinical and oxygenation (oxygen saturation to fraction of inspired oxygen ratio-SpO2/FiO2) characteristics and PMNs forming NETs, serum levels of myeloperoxidase, E-selectin, vascular cell adhesion molecule 1-VCAM1-vascular endothelial growth factor, P-selectin, platelet factor 4 and plasma concentrations of D-dimer were evaluated at hospital admission, at discharge and 14 days after discharge. Intensive care unit admission or death was the primary composite endpoint. Patients showed a higher number of PMNs forming NETs than healthy controls. The absolute number of PMNs forming NETs was inversely correlated with oxygen status (SpO2/FiO2) and positively with inflammatory (C-reactive protein, ferritin) markers and VCAM1. A decrease in, but not a normalization of NETs and endothelial-derived parameters was observed in patients who survived. In conclusion, the formation of NETs runs parallel to that of other inflammatory and endothelial activation markers, and is inverse to the oxygenation parameters, supporting a pathogenic role for PMNs in this entity.

Hepatitis C: Problems to extinction and residual hepatic and extrahepatic lesions after sustained virological response.

Loss of follow-up or reinfections hinder the expectations of hepatitis C eradication despite the existence of highly effective treatments. Moreover, the elimination of the infection does not imply the reversion of those chronic alterations derived from the previous infection by hepatitis C virus (HCV). This review analyzes the risk factors associated with loss to follow-up in diagnosis or treatment, and the possibility of reinfection. Likewise, it assesses the residual alterations induced by chronic HCV infection considering the liver alterations (inflammation, fibrosis, risk of decompensation, hepatocellular carcinoma, liver transplantation) and, on the other hand, the comorbidities and extrahepatic manifestations (cryoglobulinemia, non-Hodgkin lymphoma, peripheral insulin resistance, and lipid, bone and cognitive alterations). Peculiarities present in subjects coinfected with human immunodeficiency virus are analyzed in each section.

Modifications of liver stiffness and CXCL4, TGF-ß1 and HGF are similar in HCV- and HIV/HCV-infected patients after DAAs.

The objective of this work was to identify predictive factors of fibrosis regression after direct antiviral agents (DAAs) in HCV-monoinfected and HIV/HCV-coinfected patients. This was a prospective study of HCV-monoinfected (n = 20), HIV/HCV-co-infected (n = 66) patients and healthy controls (n = 15). Patients had started DAAs and achieved sustained virological response. Liver stiffness (LS) and serum concentrations of profibrotic transforming growth factor (TGF)-ß1 and CXC chemokine ligand 4 (CXCL4) and antifibrotic HGF hepatocyte growth factor (HGF) were analyzed at baseline (M0) and 12 months after starting DAAs (M12). A M12 LS achievement of ≤ 9.5 kPa was considered the cutoff point to discharge from a liver clinic. The LS decrease from M0 to M12 was 34%. No significant differences were observed in LS decline between HCV- and HIV/HCV-infected individuals. Changes of serum CXCL4, TGF-ß1 and HGF levels did not correlate with LS improvement. 16 out from 56 patients (28%) with a baseline LS > 9.5 achieved a M12 LS ≤ 9.5. HCV-monoinfected and HIV/HCV coinfected patients experienced a significant reduction of LS after sustained virological response. This improvement did not correlate with changes in serum profibrotic or antifibrotic markers. A 29% of those with a baseline LS > 9.5 achieved a LS under this cutoff point.

Modifications of CD4 T cells, CD4/CD8 ratio and serum levels of soluble CD14 in HIV-HCV-coinfected patients after sustained HCV response induced by direct-acting antiviral agents: influence of liver cirrhosis.

To analyze the modifications of CD4 T cell, CD4/CD8 ratio, and serum levels of soluble CD14 (sCD14) in HIV/HCV-coinfected patients after treatment with direct anti-HCV antiviral agents. Consecutive cases of HIV/HCV-coinfected patients, attended at the University Hospital, who achieved sustained virological responses with interferon-free hepatitis C antiviral drugs, were analyzed. Thirty-five percent of patients (n = 39) had been diagnosed with liver cirrhosis. The evaluation criteria were changes in CD4 T-cell counts and percentages and inflammation (measured by serum sCD14 levels) or immune activation indexes (determined by CD4/CD8 ratio) from beginning anti-HCV therapy to 12 months later. One hundred twelve patients were included (87% male; median age, 54 years; median time from the infection diagnosis, 22 years; previous drug users, 87%). Significant increases in CD4 T cell count and percentage were detected only in individuals without liver cirrhosis. No significant differences in CD4/CD8 ratios or sCD14 levels were observed in patients with or without cirrhosis. The proportion of patients with less than 500 CD4 T cell/mm3 before therapy who achieved more than 500 CD4 T cell/mm3 after it increased only in the group without liver cirrhosis. The finding that CD4 T cell count and percentage were improved only in patients without liver cirrhosis supports the idea that treatment against HCV in HIV/HCV-coinfected patients is needed in the early phases of liver disease.

Similarities and differences between HIV and SARS-CoV-2.

In the last 50 years we have experienced two big pandemics, the HIV pandemic and the pandemic caused by SARS-CoV-2. Both pandemics are caused by RNA viruses and have reached us from animals. These two viruses are different in the transmission mode and in the symptoms they generate. However, they have important similarities: the fear in the population, increase in proinflammatory cytokines that generate intestinal microbiota modifications or NETosis production by polymorphonuclear neutrophils, among others. They have been implicated in the clinical, prognostic and therapeutic attitudes.

Neutrophil Expression of T and B Immunomodulatory Molecules in HIV Infection.

Objective: Evaluate the expression of B and T cell immunomodulatory molecules in polymorphonuclear neutrophils (PMN) in HIV-infected patients. Methods: HIV load, bacterial translocation and neutrophils' expression of T [programmed death ligand, interleukin-10+, arginase 1+] and B [BAFF, APRIL] molecules were analyzed in different cohorts and time points: a control group of 25 healthy individuals and two groups of HIV-infected patients. Group 1 of patients included 35 untreated patients, studied at baseline and after antiretroviral therapy (ART). Group 2 was composed of 25 patients with undetectable viral load after a median of 101 months of ART prior to inclusion in the study. Results: Compared with the control group, group 1 patients showed increased bacterial translocation and their PMN had a significantly higher expression of T and B-cell immunomodulatory molecules, both at baseline and after 12 months of ART. Group 2 patients showed reduced bacterial translocation levels when compared with group 1 patients after 12 months of treatment. PMN expression of B-cell modulators was similar between group 2 patients and healthy controls, although the expression of T-cell modulators remained increased. Conclusion: In HIV-infected patients, the expression of B-cell stimulatory and T-cell suppressive molecules by neutrophils was increased at baseline and after a limited time of therapy. After a prolonged period of ART, only PMNs expression of T-cell immunosuppressive molecules remained elevated.

Antiretroviral therapy partially improves the abnormalities of dendritic cells and lymphoid and myeloid regulatory populations in recently infected HIV patients.

This study aimed to evaluate the effects of antiretroviral therapy on plasmacytoid (pDC) and myeloid (mDC) dendritic cells as well as regulatory T (Treg) and myeloid-derived suppressor (MDSC) cells in HIV-infected patients. Forty-five HIV-infected patients (20 of them with detectable HIV load -10 recently infected and 10 chronically infected patients-, at baseline and after antiretroviral therapy, and 25 with undetectable viral loads) and 20 healthy controls were studied. The influence of HIV load, bacterial translocation (measured by 16S rDNA and lipopolysaccharide-binding protein) and immune activation markers (interleukin -IL- 6, soluble CD14, activated T cells) was analyzed. The absolute numbers and percentages of pDC and mDC were significantly increased in patients. Patients with detectable viral load exhibited increased intracellular expression of IL-12 by mDCs and interferon -IFN- α by pDCs. Activated population markers were elevated, and the proportion of Tregs was significantly higher in HIV-infected patients. The MDSC percentage was similar in patients and controls, but the intracellular expression of IL-10 was significantly higher in patients. The achievement of undetectable HIV load after therapy did not modify bacterial translocation parameters, but induce an increase in pDCs, mDCs and MDSCs only in recently infected patients. Our data support the importance of early antiretroviral therapy to preserve dendritic and regulatory cell function in HIV-infected individuals.

Soluble membrane receptors, interleukin 6, procalcitonin and C reactive protein as prognostic markers in patients with severe sepsis and septic shock.

BACKGROUND: The objective of this study was to explore the diagnostic and prognostic value of soluble triggering receptor expressed on myeloid cell 1 (sTREM-1), soluble cluster of differentiation 14 (sCD14), soluble cluster of differentiation 163 (sCD163), interleukin-6 (IL-6), procalcitonin (PCT), and C-reactive protein (CRP) serum levels for patients with severe sepsis and septic shock in an intensive care unit (ICU). METHODS: Fifty patients admitted at the ICU with the diagnosis of severe sepsis or septic shock were studied. SOFA and APACHE II scores as well as serum biomarkers were measured at days 0, 2 and 5. The influence of these variables on 28-day mortality was analyzed. Twenty healthy individuals served as controls. RESULTS: Baseline serum concentrations of sTREM-1, sCD163, IL-6 and PCT correlated with SOFA score. Only sTREM-1 levels correlated with APACHE II score. The 28-day mortality rate for all patients was 42%. The absence of risk factors for infection, presence of septic shock, baseline values of sCD14 and decrease of PCT and IL-6 from baseline to day 5 were variables associated to mortality in the univariate analysis. The unique independent factor associated to mortality in the multivariate analysis was a decrease of PCT higher than 50% from days 0 to 5. CONCLUSIONS: Serum levels of sTREM-1 are correlated with the severity of sepsis. A 50% decrease of PCT was the unique variable associated with survival in the multivariate analysis.

Liver fibrosis, host genetic and hepatitis C virus related parameters as predictive factors of response to therapy against hepatitis C virus in HIV/HCV coinfected patients.

OBJECTIVE: To establish the role of liver fibrosis as a predictive tool of response to pegylated interferon alpha (Peg-IFN) and ribavirin (RBV) treatment in human immunodeficiency (HIV)/hepatitis C virus (HCV) coinfected patients, in addition to recognized predictive factors (HCV load, HCV genotype, IL-28B polymorphism). PATIENTS AND METHODS: A sample of 267 HIV/HCV coinfected patients was treated with Peg-IFN and RBV. Predictive factors of rapid (RVR) and sustained (SVR) virological response were analyzed. Independent variables were age, sex, IL28B, -238 TNF-α and -592 IL-10 polymorphisms, HCV genotype, HCV-RNA levels, significant fibrosis or cirrhosis and CD4+ T cell count. RESULTS: Patients infected by HCV genotype 1 (n = 187) showed RVR and SVR in 12% and 39% of cases, respectively. The parameters associated with RVR were IL28B genotype CC and plasma HCV-RNA levels <600,000 IU/ml. Advanced liver fibrosis was negatively associated with SVR in patients without RVR. A SVR was obtained in 42% of subjects with HCV genotype 4, and the independent factors associated with SVR were IL28B genotype CC and an HCV-RNA <600,000 IU/ml. A SVR was obtained in 66% of patients with HCV genotypes 2/3; in this case, the independent parameter associated with SVR was the absence of significant liver fibrosis. TNF-α and IL-10 polymorphisms were not associated with SVR, although a significantly higher percentage of -238 TNF-α genotype GG was detected in patients with significant liver fibrosis. CONCLUSIONS: In HIV/HCV coinfected patients with HCV genotypes 1 or 4, RVR, mainly influenced by genotype IL28B and HCV-RNA levels, reliably predicted SVR after 4 weeks of therapy with Peg-IFN plus RBV. In patients infected by HCV genotype 3, an elevated relapse rate compromised the influence of RVR on SVR. Relapses were related to the presence of advanced liver fibrosis. Liver cirrhosis was associated with a -238 TNF-α polymorphism in these patients.