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om as , F e r na n d o G on zález Candelas, SeqCOVID-SPAIN consortium, Tanja Stadler & Richard A. NeherThis is a PDF file of a peer-reviewed paper that has been accepted for publication. Although unedited, the content has been subjected to preliminary formatting. Nature is providing this early version of the typeset paper as a service to our authors and readers. The text and figures will undergo copyediting and a proof review before the paper is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers apply.

We derived a total of 146 T lymphocyte lines specific for human myelin basic protein (MBP) from the peripheral blood of 20 MS patients and from a control group of 12 healthy donors, and determined the reactivities of T cell lines by [3H]thymidine incorporation on exposure to MBP and MBP peptides 1-44, 45-89, and 90-170. We defined HLA restriction of the T lines by using monoclonal antibodies against monomorphic determinants on human HLA-DR, HLA-DQ, and HLA-DP molecules. MBP-specific T cell lines could be isolated with a comparable efficiency from MS patients and healthy individuals. In both groups, MBP-specific T lymphocytes recognized at least 4 different epitopes in the MBP molecule, and specificities showed comparable patterns for different MBP peptides. MBP-specific T cell lines derived from MS patients and controls were restricted by DR products of the human major histocompatibility class II locus. Notable phenotypic differences of T cell lines existed between the 2 groups. Lines isolated from MS patients expressed predominantly the CD3+ CD4+ CD8- phenotype, while some control lines were composed of up to 87% CD3+CD4+CD8+ T lymphocytes. These findings illustrate the presence of MBP-specific T cells in MS patients and controls that are similarly sensitized to MBP and restricted by HLA-DR products.

Multiple sclerosis (MS) is an autoimmune disease in which myelin proteins have been implicated as autoantigens recognized by pathogenic autoreactive T cells. To study the relationship between human myelin basic protein (hMBP) and HLA alleles associated to MS susceptibility, such as DRB1*1501, the binding of synthetic peptides spanning the entire hMBP sequence to 10 purified HLA-DR molecules was determined. All the hMBP peptides tested showed binding affinity for at least one of the DR molecules analyzed, but three hMBP peptides, included in sequences 13-32,84-103, and 144-163 were found capable of binding to three or more DR molecules. The hMBP peptide 84-103 was the most degenerate in binding, in that it bound to 9 out of 10 DR molecules tested. Interestingly, it bound with highest affinity to DRB1*1501 molecules. To correlate the binding pattern of hMBP peptides to HLA class II molecules with their recognition by T cells, 61 hMBP-specific T cell lines (TCL) were established from the peripheral blood of 20 MS patients, who were homozygous, heterozygous, or negative for DRB1*1501. Analysis of hMBP epitopes recognized by these TCL and their HLA restriction demonstrated a very good correlation between binding data and T cell proliferation to hMBP peptides. Although virtually all hMBP peptides tested could be recognized by at least one TCL from MS patients, three immunodominant T cell epitopes were apparent among the TCL examined, corresponding exactly to the hMBP peptides capable of binding to several DR molecules. No major difference could be detected in the recognition of immunodominant hMBP peptides by TCL from DRB1*1501 positive or negative MS patients. These results have implications for the role of hMBP as relevant autoantigen, and of DRB1*1501 as susceptibility allele in MS. (J. Clin. Invest. 1993. 91:616-628.) Key words: immunodominance -human histocompatibilDr. Valli is currently at

The replication kinetics of nonpathogenic anelloviruses belonging to the Alphatorquevirus genus (such as torque teno virus) might reflect the overall state of posttransplant immunosuppression. We analyzed 221 kidney transplant (KT) recipients in whom plasma alphatorquevirus DNA load was quantified by real-time polymerase chain reaction at baseline and regularly through the first 12 posttransplant months. Study outcomes included posttransplant infection and a composite of opportunistic infection and/or de novo malignancy (immunosuppression-related adverse event [iRAE]). Alphatorquevirus DNA loads at month 1 were higher among patients who subsequently developed posttransplant infection (P = .023) or iRAE (P = .009). Likewise, those with iRAE beyond months 3 and 6 also exhibited higher peak viral loads over the preceding periods. Areas under the curve for log 10 alphatorquevirus DNAemia estimated by months 1 or 6 were significantly higher in patients experiencing study outcomes. Alphatorquevirus DNA loads above 3.15 and 4.56 log 10 copies/mL at month 1 predicted the occurrence of posttransplant infection (adjusted hazard ratio [aHR]: 2.88; 95% confidence interval [CI]: 1.13-7.36; P = .027) and iRAE (aHR: 5.17; 95% CI: 2.01-13.33; P = .001). In conclusion, posttransplant monitoring of plasma alphatorquevirus DNA kinetics may be useful to identify KT recipients at increased risk of immunosuppression-related complications. K E Y W O R D S biomarker, clinical research/practice, complication: infectious, complication: malignant, infection and infectious agents, infection and infectious agents -viral, infectious disease, kidney transplantation/nephrology

Until an effective vaccine is available, interruption of community circulation of SARS-CoV-2 is crucial to control virus spread. To this end, systematic testing of large population groups by RT-PCR is mandatory to case identification and contact tracing thereby minimizing the likelihood of resurgence in contagion. 1 This approach faces a variety of obstacles, most notably the limited availability of reagents resources. Sample pooling for RT-PCR has been effectively used for screening of blood donors for Human immunodeficiency virus-1 and Hepatitis C virus in lowprevalence setttings. 2 This strategy has also been applied to detect community

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Monitoring the human virome has been recently suggested as a promising and novel area of research for identifying new biomarkers which would help physicians in the management of transplant patients. Imbalance of the immune system in transplant recipients has a significant impact on replication of Torquetenovirus (TTV), the most representative and abundant virus of human virome. TTV kinetic was studied by real-time PCR in 280 liver or kidney transplant recipients who underwent different drug regimens to maintain immunosuppression. During one-year post-transplant follow-up, TTV viremia fluctuated irrespective of transplanted organ type but consistent with the immunosuppression regimen. TTV kinetic in patients who manifested cytomegalovirus (CMV) reactivation within the first four months post-transplant differed from that observed in patients who did not experience CMV complications. Importantly, plasma TTV load measured between day 0 and 10 post-transplant was significantly higher in CMV DNA positive than in CMV DNA negative patients. TTV viremia above 3.45 log DNA copies/ml within the first 10 days post-transplant correlates with higher propensity to CMV reactivation following transplantation. This study provides further evidence for using early post-transplant TTV viremia to predict CMV reactivation in liver or kidney transplant recipients.