Disease modifying therapies for multiple sclerosis (MS) can impair the specific immune response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Specifically, it is recognized that ocrelizumab reduces or abrogates anti-SARS-CoV-2 antibody production after natural infection or vaccination, while very little is known about T-cell responses.We developed an interferon (IFN)-γ release assay (IGRA) to detect T-cell responses specific to SARS-CoV-2 after overnight stimulation of whole blood with peptide libraries covering the immunodominant sequence domains of the Spike glycoprotein (S) and the Nucleocapsid phosphoprotein (N).Five patients with MS receiving ocrelizumab treatment for at least 1 year and recovered from SARS-CoV-2 infection were enrolled in the study. Despite the absence or the very low concentration of anti-S antibodies, a T-cell response was detectable in all the five MS patients. These results are in accordance with the marked reduction of peripheral B-lymphocyte absolute counts induced by ocrelizumab, that, conversely, did not affect peripheral blood T-lymphocyte subset absolute and relative counts and CD4/CD8 ratio.The detection of specific T-cell responses to SARS-CoV-2 in patients receiving B-cell depleting therapies represents a useful tool to improve the diagnostic approach in SARS-CoV-2 infection and to accurately assess the immunological response after natural infection or vaccination.
Our research group and others demonstrated the implication of the human endogenous retroviruses (HERVs) in SARS-CoV-2 infection and their association with disease progression, suggesting HERVs as contributing factors in COVID-19 immunopathology. To identify early predictive biomarkers of the COVID-19 severity, we analyzed the expression of HERVs and inflammatory mediators in SARS-CoV-2-positive and -negative nasopharyngeal/oropharyngeal swabs with respect to biochemical parameters and clinical outcome.Residuals of swab samples (20 SARS-CoV-2-negative and 43 SARS-CoV-2-positive) were collected during the first wave of the pandemic and expression levels of HERVs and inflammatory mediators were analyzed by qRT-Real time PCR.The results obtained show that infection with SARS-CoV-2 resulted in a general increase in the expression of HERVs and mediators of the immune response. In particular, SARS-CoV-2 infection is associated with increased expression of HERV-K and HERV-W, IL-1β, IL-6, IL-17, TNF-α, MCP-1, INF-γ, TLR-3, and TLR-7, while lower levels of IL-10, IFN-α, IFN-β, and TLR-4 were found in individuals who underwent hospitalization. Moreover, higher expression of HERV-W, IL-1β, IL-6, IFN-α, and IFN-β reflected the respiratory outcome of patients during hospitalization. Interestingly, a machine learning model was able to classify hospitalized vs not hospitalized patients with good accuracy based on the expression levels of HERV-K, HERV-W, IL-6, TNF-a, TLR-3, TLR-7, and the N gene of SARS-CoV-2. These latest biomarkers also correlated with parameters of coagulation and inflammation.Overall, the present results suggest HERVs as contributing elements in COVID-19 and early genomic biomarkers to predict COVID-19 severity and disease outcome.
There are still conflicting data on the virological effects of the SARS-CoV-2 direct antivirals used in clinical practice, in spite of the documented clinical efficacy. The aim of this monocentric retrospective study was to compare virologic and laboratory data of patients admitted due to SARS-CoV-2 infection from March to December 2020 treated with either remdesivir (R), a protease inhibitor (lopinavir or darunavir/ritonavir (PI)) or no direct antiviral drugs (NT). Viral load variation was indirectly assessed through PCR cycle threshold (Ct) values on the nasopharyngeal swab, analyzing the results from swabs obtained at ward admission and 7 (±2) days later. Overall, 253 patients were included: patients in the R group were significantly older, more frequently males with a significantly higher percentage of severe COVID-19, requiring more often intensive care admission, compared to the other groups. Ct variation over time did not differ amongst the three treatment groups and did not seem to be influenced by corticosteroid use, even after normalization of the treatment groups for disease severity. Non-survivors had lower Ct on admission and showed a significantly slower viral clearance compared to survivors. CD4 T-lymphocytes absolute count assessed at ward admission correlated with a reduced Ct variation over time. In conclusion, viral clearance appears to be slower in COVID-19 non-survivors, while it seems not to be influenced by the antiviral treatment received.
Abstract: Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system, caused by the polyomavirus JC and occurring almost exclusively in the context of severe immune depression. AIDS represents the most common predisposing condition for PML development. Antiretroviral treatment has reduced PML incidence in HIV-infected subjects, but the disease remains a severe and life-threatening complication of AIDS, considering thus far the lack of an effective anti-JC virus (JCV) direct-acting antiviral drug. In the last decade, the use of monoclonal antibodies for treating immune-based diseases evidenced new predisposing conditions for PML development, promoting a renewed interest in PML pathogenesis. In this article, we review the current knowledge on JCV epidemiology and AIDS-associated PML incidence, JCV viral cycle, pathogenesis, and the interplay with HIV infection. We give an updated overview of diagnostic and prognostic tools available for PML diagnosis and describe past and current therapeutic approaches, including new strategies for PML cure. Keywords: PML, JCV, NeuroAIDS, IRIS, diagnosis, therapy
The recent epidemic in the Americas caused by Zika virus (ZIKV), Asian lineage, spurred the research towards a better understanding of how ZIKV infection affects the host immune response. The aim of this study was to evaluate the effects of Asian and East African ZIKV strain infection on the induction of IFN and proinflammatory and Th2 cytokines in human PBMC. We reported a slight modulation of type II IFN in PBMC exposed to Asian strain, but not to African strain, and a complete lack of type I and III IFN induction by both strains, suggesting the ability of ZIKV to evade the IFN system not only inhibiting the antiviral IFN response but also IFN production. Moreover, we highlighted a polyfunctional immune activation only in PBMC exposed to Asian strain, due to the induction of an inflammatory profile (IL-6, IL-8) and of a Th9 (IL-9) response. Overall, our data show a different ability of the ZIKV Asian strain, with respect to the African strain, to activate host immune response that may have pathogenetic implications for virus spread in vivo, including mother-to-child transmission and induction of severe fetal complications, as birth defects and neurological disorders.
Abstract Background Post COVID-19 condition (PCC) affects 10–40% of patients and is characterized by persisting symptoms at ≥ 4 weeks after SARS CoV-2 infection. Symptoms can last 7 or even more months. How long PCC persists and any changes in its clinical phenotypes over time require further investigation. We investigated PCC trajectories and factors associated with PCC persistence. Material and methods We included both hospitalized COVID-19 patients and outpatients from February 2020 to June 2023, who underwent at least one follow-up visit after acute infection at San Paolo Hospital, University of Milan. Follow-up visits were conducted at the post COVID-19 clinic or via telemedicine. During each follow-up examination, patients completed a short version of the WHO CRF for ongoing symptoms, the Hospital Anxiety and Depression Scale (HADS), and a screening tool for Post-Traumatic Stress Disorder (PTSD). Statistical analyses involved Chi-square, Mann-Whitney, Kruskal-Wallis tests, and logistic regression analysis. Results We enrolled 853 patients (median age 62, IQR 52–73; 41% females). 551/853 (64.6%), 152/418 (36.4%) and 21/69 (30.4%) presented PCC at median follow up of 3 (IQR 2–3), 7 (IQR 6–10) and 26 (IQR 20–33) months, respectively (p < 0.001). The main clinical phenotypes were fatigue, respiratory sequelae, brain fog and chronic pain; anosmia/dysgeusia was observed mostly in the first post-acute period. Female sex, acute disease in 2020, a longer hospital stay and no COVID-19 vaccination were associated with persistence or resolution of PCC compared to never having had PCC. Anxiety, depression and PTSD were more common in PCC patients. By fitting a logistic regression analysis, acute infection in 2020 remained independently associated with persistent PCC, adjusting for age, sex, preexisting comorbidities and disease severity (AOR 0.479 for 2021 vs 2020, 95%CI 0.253–0.908, p = 0.024; AOR 0.771 for 2022 vs 2020, 95%CI 0.259–2.297, p = 0.641; AOR 0.086 for 2023 vs 2020, 95%CI 0.086–3.830, p = 0.565). Conclusions There was a reduction in the PCC burden 7 months following the acute phase; still, one third of patients experienced long-lasting symptoms. The main clinical presentations of PCC remain fatigue, respiratory symptoms, brain fog, and chronic pain. Having had SARS CoV-2 infection during the first pandemic phases appears to be associated with persistent PCC.
