Background MicroRNAs (miRNAs) have a crucial role in regulating immune response against infectious diseases, showing changes early in disease onset and before the detection of the pathogen. Thus, we aimed to analyze the plasma miRNA profile at COVID-19 onset to identify miRNAs as early prognostic biomarkers of severity and survival. Methods and results Plasma miRNome of 96 COVID-19 patients that developed asymptomatic/mild, moderate and severe disease was sequenced together with a group of healthy controls. Plasma immune-related biomarkers were also assessed. COVID-19 patients showed 200 significant differentially expressed (SDE) miRNAs concerning healthy controls, with upregulated putative targets of SARS-CoV-2, and inflammatory miRNAs. Among COVID-19 patients, 75 SDE miRNAs were observed in asymptomatic/mild compared to symptomatic patients, which were involved in platelet aggregation and cytokine pathways, among others. Moreover, 137 SDE miRNAs were identified between severe and moderate patients, where miRNAs targeting the SARS CoV-2 genome were the most strongly disrupted. Finally, we constructed a mortality predictive risk score (miRNA-MRS) with ten miRNAs. Patients with higher values had a higher risk of 90-days mortality (hazard ratio = 4.60; p -value < 0.001). Besides, the discriminant power of miRNA-MRS was significantly higher than the observed for age and gender (AUROC = 0.970 vs. 0.881; p = 0.042). Conclusions SARS-CoV-2 infection deeply disturbs the plasma miRNome from an early stage of COVID-19, making miRNAs highly valuable as early predictors of severity and mortality.

Antiretroviral therapy (ART) allows suppressed viremia to reach less than 50 copies/mL in most treated persons living with HIV (PLWH). However, the existence of PLWH that show events of persistent low-level viremia (pLLV) between 50 and 1000 copies/mL and with different virological consequences have been observed. PLLV has been associated with higher virological failure (VF), viral genotype resistance, adherence difficulties and AIDS events. Moreover, some reports show that pLLV status can lead to residual immune activation and inflammation, with an increased risk of immunovirological failure and a pro-inflammatory cytokine level which can lead to a higher occurrence of non-AIDS defining events (NADEs) and other adverse clinical outcomes. Until now, however, published data have shown controversial results that hinder understanding of the true cause(s) and origin(s) of this phenomenon. Molecular mechanisms related to viral reservoir size and clonal expansion have been suggested as the possible origin of pLLV. This review aims to assess recent findings to provide a global view of the role of pLLV in PLWH and the impact this status may cause on the clinical progression of these patients.

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Coinfection with hepatitis C virus (HCV) influences HIV reservoir size. However, it is unknown whether this coinfection also induces a higher provirus transcription. Viral transcription is promoted by synergy between cellular factors such as NF-κB and the viral regulator Tat. The impact of HCV coinfection on HIV provirus transcription was analyzed in resting (r)CD4 T+ cells (CD3+CD4+CD25-CD69-HLADR-) and rCD4 T cells-depleted PBMCs (rCD4 T- PBMCs) from a multicenter cross-sectional study of 115 cART-treated HIV patients: 42 HIV+/HCV+ coinfected individuals (HIV+/HCV+), 34 HIV+ patients with HCV spontaneous clearance (HIV+/HCV−) and 39 HIV patients (HIV+). Viral transcription was assessed in total RNA through the quantification of unspliced, single spliced, and multiple spliced viral mRNAs by qPCR. Linear correlations between viral reservoir size and viral splicing were determined. A 3-fold increase of multiple spliced transcripts in rCD4 T+ cells of HIV+/HCV+ patients was found compared to HIV+ individuals (p < 0.05). As Tat is synthesized by multiple splicing, the levels of Tat were also quantified in these patients. Significant differences in single and multiple spliced transcripts were also observed in rCD4 T- PBMCs. Levels of multiple spliced mRNAs were increased in rCD4 T+ cells isolated from HIV+/HCV+ subjects, which could indicate a higher Tat activity in these cells despite their resting state.

Background: Co-infection with Hepatitis C virus (HCV) and Human Immunodeficiency Virus (HIV) increase immune activation, inflammation and oxidative stress that could lead to premature senescence. Different HCV infection, either acute or chronic infection, could lead to distinct premature cellular senescence in people living with HIV (PLWHIV). Methods: Observational study in 116 PLWHIV with different HCV status: i) n=45 chronically infected with HCV (CHC); ii) n=36 individuals who spontaneously clarify HCV (SC); iii) n= 35 HIV controls. Oxidative stress biomarkers were analysed at lipid, DNA, protein, and nitrates levels, as well as total antioxidant capacity and glutathione reductase enzyme. Replicative senescence was evaluated by relative telomere length (RTL) measurement. Additionally, twenty-six markers of senescence-associated secretory phenotype (SASP) were analysed by Multiplex Immunoassay (Luminex xMAP technology). Differences were evaluated by generalized linear model (GLMs) adjusted by most significant covariates. Results: The SC group had a senescence signature similar to the HIV control group and slightly lower SASP levels. However, significant differences were observed with respect to CHC group, where an increase in the nitrate concentration [aAMR=1.73 (1.27-2.35), p<0.001, q=0.009]) and the secretion of 13 SASP-associated factors (GM-CSF, IFN-γ, IL-1β, IL-2, IL-8, IL-13, TNF-α, IL-1α, IL-1RA, IL-7, IL-15, IP-10, SCF; q<0.1) was detected. CHC group also showed higher values of IL-1α, IP-10 and PIGF-1 than HIV controls. Conclusion: SC showed slightly lower senescence profile to HIV group indicating a more efficient control of viral-induced senescence. Chronic HCV infection in PLWHIV lead to nitrate accumulation and elevated plasma SASP biomarkers favouring the establishment of vial persistence.