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Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte-macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A). GenOMICC was funded by Sepsis Research (the Fiona Elizabeth Agnew Trust), the Intensive Care Society, a Wellcome Trust Senior Research Fellowship (to J.K.B., 223164/Z/21/Z), the Department of Health and Social Care (DHSC), Illumina, LifeArc, the Medical Research Council, UKRI, a BBSRC Institute Program Support Grant to the Roslin Institute (BBS/E/D/20002172, BBS/E/D/10002070 and BBS/E/D/30002275) and UKRI grants MC_PC_20004, MC_PC_19025, MC_PC_1905 and MRNO2995X/1. A.D.B. acknowledges funding from the Wellcome PhD training fellowship for clinicians (204979/Z/16/Z), the Edinburgh Clinical Academic Track (ECAT) programme. This research is supported in part by the Data and Connectivity National Core Study, led by Health Data Research UK in partnership with the Office for National Statistics and funded by UK Research and Innovation (grant MC_PC_20029). Laboratory work was funded by a Wellcome Intermediate Clinical Fellowship to B.F. (201488/Z/16/Z). We acknowledge the staff at NHS Digital, Public Health England and the Intensive Care National Audit and Research Centre who provided clinical data on the participants; and the National Institute for Healthcare Research Clinical Research Network (NIHR CRN) and the Chief Scientist’s Office (Scotland), who facilitate recruitment into research studies in NHS hospitals, and to the global ISARIC and InFACT consortia. GenOMICC genotype controls were obtained using UK Biobank Resource under project 788 funded by Roslin Institute Strategic Programme Grants from the BBSRC (BBS/E/D/10002070 and BBS/E/D/30002275) and Health Data Research UK (HDR-9004 and HDR-9003). UK Biobank data were used in the GSMR analyses presented here under project 66982. The UK Biobank was established by the Wellcome Trust medical charity, Medical Research Council, Department of Health, Scottish Government and the Northwest Regional Development Agency. It has also had funding from the Welsh Assembly Government, British Heart Foundation and Diabetes UK. The work of L.K. was supported by an RCUK Innovation Fellowship from the National Productivity Investment Fund (MR/R026408/1). J.Y. is supported by the Westlake Education Foundation. SCOURGE is funded by the Instituto de Salud Carlos III (COV20_00622 to A.C., PI20/00876 to C.F.), European Union (ERDF) ‘A way of making Europe’, Fundación Amancio Ortega, Banco de Santander (to A.C.), Cabildo Insular de Tenerife (CGIEU0000219140 ‘Apuestas científicas del ITER para colaborar en la lucha contra la COVID-19’ to C.F.) and Fundación Canaria Instituto de Investigación Sanitaria de Canarias (PIFIISC20/57 to C.F.). We also acknowledge the contribution of the Centro National de Genotipado (CEGEN) and Centro de Supercomputación de Galicia (CESGA) for funding this project by providing supercomputing infrastructures. A.D.L. is a recipient of fellowships from the National Council for Scientific and Technological Development (CNPq)-Brazil (309173/2019-1 and 201527/2020-0). We thank the members of the Banco Nacional de ADN and the GRA@CE cohort group; and the research participants and employees of 23andMe for making this work possible. A full list of contributors who have provided data that were collated in the HGI project, including previous iterations, is available online (https://www.covid19hg.org/acknowledgements). Sí

15 Pág., Background: Although human immunodeficiency virus type 1 (HIV-1) reservoir size is very stable under antiretroviral therapy (ART), individuals exposed to the Hepatitis C virus (HCV) (chronically coinfected and spontaneous clarifiers) show an increase in HIV reservoir size and in spliced viral RNA, which could indicate that the viral protein regulator Tat is being more actively synthesized and, thus, could lead to a higher yield of new HIV. However, it is still unknown whether the effect of HCV elimination with direct-acting antivirals (DAAs) could modify the HIV reservoir and splicing. Methods: This longitudinal study (48 weeks’ follow-up after sustained virological response) involves 22 HIV+-monoinfected individuals, 17 HIV+/HCV- spontaneous clarifiers, and 24 HIV+/HCV+ chronically infected subjects who eliminated HCV with DAAs (all of them aviremic, viral load < 50). Viral-spliced RNA transcripts and proviral DNA copies were quantified by qPCR. Paired samples were analyzed using a mixed generalized linear model. Results: A decrease in HIV proviral DNA was observed in HIV+/HCV- subjects, but no significant differences were found for the other study groups. An increased production of multiple spliced transcripts was found in HIV+ and HIV+/HCV+ individuals. Conclusions: We conclude that elimination of HCV by DAAs was unable to revert the consequences derived from chronic HCV infection for the reservoir size and viral splicing, which could indicate an increased risk of rapid HIV-reservoir reactivation. Moreover, spontaneous clarifiers showed a significant decrease in the HIV reservoir, likely due to an enhanced immune response in these individuals., Financial support was provided by the Instituto de Salud Carlos III to V.B. and A.F.-R. (PI15CIII/00031 and PI18CIII/00020) and the SPANISH AIDS Research Network (RD16CIII/0002/0001 and RD16CIII/0002/0002—ISCIII—FEDER). A.F.-R. is supported by the Miguel Servet program from Fondo de Investigación Sanitaria (ISCIII) (CP14/CIII/00010). Financial support was provided by the National Institutes of Health (NIH) (Grant R01AI143567) for M.C. The work of M.R.L.-H. is financed by the NIH (Grant R01AI143567). C.P. is funded by FCT—Fundação para a Ciência e a Tecnologia, I.P. (national funding), under a contract program as defined by DL No. 57/2016 and Law No. 57/2017.

Gender-specific consequences after HCV eradication are unexplored. MicroRNAs (miRNAs) play a crucial role in the immune response against viral infections. However, few have highlighted miRNA role in sex-biased disease or therapy response. We aim to assess gender differences reflected in the miRNA expression of HIV/HCV-coinfected patients who achieve sustained virological response (SVR) with direct acting antivirals (DAAs). We conducted a prospective study of miRNA expression in PBMCs from 28 chronic HIV/HCV-coinfected patients (HIV/HCV) at baseline and after achieving SVR with DAAs. Sixteen HIV-monoinfected patients (HIV) and 36 healthy controls (HC) were used as controls. Identification of significant differentially expressed (SDE) miRNAs was performed with generalized linear model and mixed GLMs. We also explored putative dysregulated biological pathways. At baseline, the HIV/HCV patients showed differences in the miRNA profile concerning the HIV group (165 and 102 SDE miRNAs for males and females, respectively). Gender-stratified analysis of HIV/HCV group at baseline versus at SVR achievement showed higher differences in males (80 SDE miRNAs) than in females (55 SDE miRNAs). After SVR, HIV/HCV group showed similar values to HIV individuals, especially in females (1 SDE miRNA). However, ten miRNAs in males remained dysregulated, which were mainly involved in cancer, fatty acid, and inflammatory pathways. Taken together, our results show gender-biased dysregulation in the miRNA expression profile of PBMCs after HCV eradication with DAAs. These differences were normalized in females, while miRNA profile and their target-related pathways in males lack of normalization, which may be related to a high-risk of developing liver-related complications. This work has been supported by grants from Institute of Health Carlos III, Spain [PI15CIII/00031 and PI18CIII/00020/ to AFR and VB] and the Foundation Universidad Alfonso X el Sabio-Santander, Spain [Grant no. 1.010.932 to AFR]. AFR is supported by the Miguel Servet programme from Fondo de Investigación Sanitaria (ISCIII), Spain [CP14/CIII/00010 and CPII20CIII/0001]. This study has been conducted within the Spanish AIDS Research Network (RIS), The SPANISH AIDS Research Network – funded by the Institute of Health Carlos III (ISCIII) [RD16CIII/0002/0002]. Sí

Background: A better understanding of the evolution of cirrhosis after hepatitis C virus (HCV) clearance is essential since the reversal of liver injury may not happen. We aimed to assess the evolution of plasma metabolites after direct-acting antivirals (DAAs) therapy and their association with liver disease scores in HIV/HCV-coinfected patients with advanced HCV-related cirrhosis. Methods: We performed a prospective study in 49 cirrhotic patients who started DAAs therapy. Data and samples were collected at baseline and 36 weeks after SVR. Metabolomics analysis was carried out using gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry. Inflammation-related biomarkers were analyzed using ProcartaPlex Immunoassays. Results: At 36 weeks after SVR, patients experienced significant decrease in taurocholic acid, 2,3-butanediol, and LPC(18:0); while several phosphatidylcholines (LPC(16:1), LPC(18:1), LPC(20:4), and PC(16:0/9:0(CHO))/PC(16:0/9:0(COH)), 2-keto-n-caproic acid/2-keto-isocaproic acid and N-methyl alanine increased, compared to baseline. The plasma decrease in taurocholic acid was associated with a reduction in Child-Turcotte-Pugh (CTP) (AMR=3.39; q-value=0.006) and liver stiffness measurement (LSM) (AMR=1.06; q-value

Background: Vitamin D is a fundamental regulator of host defenses by activating genes related to innate and adaptive immunity. In this study, we analyzed the association among single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) gene, with clinical patterns of AIDS progression in antiretroviral treatment (ART)-naive HIV-infected patients. Methods: We conducted a retrospective study in 667 HIV-infected patients, who were classified within three groups according to their AIDS progression pattern (183 long-term non-progressors (LTNPs), 334 moderate progressors (MPs), and 150 rapid progressors (RPs)). Five VDR SNPs (rs11568820, rs4516035, rs2228570, rs1544410, and rs7975232) were genotyped using Agena Bioscience's MassARRAY platform. Results: Significant association results were found for rs2228570. Within all HIV patients, the presence of T allele at VDR rs2228570 SNP was protective against AIDS progression (ordinal outcome) under additive (adjusted odds ratio (aOR) = 0.75; p = 0.009), dominant (aOR = 0.69; p = 0.015), and codominant (aOR = 0.56; p = 0.017) inheritance models. In addition, the same allele was protective under additive and codominant inheritance models when we compared with LTNPs vs. RPs [aOR = 0.64 (p = 0.019) and aOR = 0.37 (p = 0.018), respectively] and when we compared MPs vs. RPs [aOR = 0.72 (p = 0.035) and aOR = 0.45 (p = 0.028), respectively]. Conclusions: The VDR rs2228570 T allele was related to a lower AIDS progression pattern in ART-naive HIV-infected patients. These findings expand upon the knowledge about HIV pathogenesis in untreated HIV-infected patients with different clinical outcomes., This work has been (partially) funded by the RD16/0025/0019 and RD16CIII/0002/0002, projects as part of Accion Estrategica en Salud, Plan Nacional de Investigacion Cientifica, Desarrollo e Innovacion Tecnologica (2013-2016) and cofinanced by Instituto de Salud Carlos III (Subdireccion General de Evaluacion) and Fondo Europeo de Desarrollo Regional (FEDER), RETIC PT17/0015/0042, Fondo de Investigacion Sanitaria (FIS) (grant number PI16/01863, PI17/01115, PI17CIII/00003), EPIICAL Project and Comunidad de Madrid B2017/BMD-3703. Programa de Investigacion de la Consejeria de Sanidad de la Comunidad de Madrid to JLJ. CIBER-BBN is an initiative funded by the VI National R& D& i Plan 2008-2011, Iniciativa Ingenio 2010, the Consolider Program, and CIBER Actions and financed by the Instituto de Salud Carlos III with assistance from the European Regional Development Fund. COST CA17140 Cancer Nanomedicine-Front the Bench to Bebside. AFR are supported and funded by Instituto de Salud Carlos III [grant number CP14/0010].

UNLABELLED: There is growing evidence that vitamin D is related to chronic hepatitis C (CHC) pathogenicity. We analyzed the relationship of vitamin D status with advanced liver fibrosis (ALF) in CHC treatment-naïve patients and sustained virologic response (SVR) in CHC patients on pegylated interferon alpha plus ribavirin (pegIFNα/ribavirin) therapy. We performed a meta-analysis of all eligible studies published to date (April, 2014) in PubMed, SCOPUS, LILACS, and the Cochrane Library, assessing plasma/serum vitamin D levels related to ALF and/or SVR. Pooled odds ratios (ORs) were estimated by either fixed or random effects models. Fourteen studies were selected from the literature search, seven for ALF (1,083 patients) and 11 for SVR (2,672 patients). For liver fibrosis, low vitamin D status was related to a diagnosis of ALF, with the cutoffs of 10 ng/mL (OR=2.37, 95% confidence interval [CI]=1.20, 4.72) and 30 ng/mL (OR=2.22, 95% CI=1.24, 3.97) being significant, and a near-significance for 20 ng/mL (OR=1.44, 95% CI=0.99, 2.12). Regarding SVR, a significant heterogeneity among studies was found (P