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SARS-CoV-2 specific T-cell response has been associated with disease severity, immune memory and heterologous response to endemic coronaviruses. However, an integrative approach combining a comprehensive analysis of the quality of SARS-CoV-2 specific T-cell response with antibody levels in these three scenarios is needed. In the present study we found that, in acute infection, while mild disease was associated with high T-cell polyfunctionality biased to IL-2 production and inversely correlated with anti-S IgG levels, combinations only including IFN-γ with absence of perforin production predominated in severe disease. Seven months after infection, both non-hospitalized and previously hospitalized patients presented robust anti-S IgG levels and SARS-CoV-2 specific T-cell response. In addition, only previously hospitalized patients showed a T-cell exhaustion profile. Finally, combinations including IL-2 in response to S protein of endemic coronaviruses, were the ones associated with SARS-CoV-2 S-specific T-cell response in pre-COVID-19 healthy donors’ samples. These results have implications for protective immunity against SARS-CoV-2 and recurrent COVID-19 and may help for the design of new prototypes and boosting vaccine strategies.

Viral and host immune kinetics during acute COVID-19 and after remission of acute symptoms need better characterization. SARS-CoV-2 RNA, anti-SARS-CoV-2 IgA, IgM, and IgG antibodies, and proinflammatory cytokines were measured in sequential samples from hospitalized COVID-19 patients during acute infection and six months following diagnosis. Twenty four laboratory confirmed COVID-19 patients with mild/moderate and severe COVID-19 were included. Most were males (83%) with a median age of 61 years. Twenty one percent were admitted to the intensive care unit (ICU) and eight of them (33.3%) met the criteria for severe COVID-19 disease. A delay in SARS-CoV-2 levels’ decline during the first six days of follow up, and viral load persistence until month 3 were related to severe COVID-19, but not viral load levels at the diagnosis. Higher levels of anti-SARS-CoV-2 IgA, IgM, IgG and the cytokines IL-6, IL-8 and MIP-1β at the diagnosis time were related to the severe COVID-19 outcome. Higher levels of MIP-1β, IL-1β, MIP-1α and IFN-γ were observed at month 1 and 3 during mild/moderate disease, compared to severe COVID-19. IgG persisted at low levels after six months of diagnosis. In conclusion, higher concentrations of IgA, IgM, and IgG, and IL-6, IL-8 and MIP-1β are identified as early predictors of COVID-19 severity, whereas no significant association is found between baseline SARS-COV-2 viral load and COVID-19 severity., This work was supported by the Plan Estatal de I+D+I 2013-2016 and 2017–2020 and cofinanced by the Instituto de Salud Carlos III (ISCIII)—Subdirección General de Evaluación y Fomento de la investigación del Fondo Europeo de Desarrollo Regional (FEDER), Fondo COVID19 of Instituto de Salud Carlos III (COV20/00698), RETICS, Red de Investigación en SIDA [RD16/0025/0026]; and Fundación Biomédica Galicia Sur. E.R-M. was supported by the Spanish Research Council (CSIC) and by the research grant CV20-85418 from the Consejería de Transformación Económica, Industria, Conocimiento y Universidades (Junta de Andalucía). A.P. was supported by the Instituto de Salud Carlos III, Subprograma Rio Hortega (CM20/00243). A.G.-V. was supported by the Instituto de Salud Carlos III, cofinanced by the European Development Regional Fund (“A way to achieve Europe”), Subprograma Miguel Servet (CP19/00159). E.M.M. was supported by the Instituto de Salud Carlos III, cofinanced by the European Development Regional Fund (“A way to achieve Europe”), Subprogram PFIS (FI19/00304). C.K. was supported by Fondo COVID19 of Instituto de Salud Carlos III (COV20/00823).

This work was supported by Plan Nacional de I+D+i 2013

The activation phenotypes and functional changes in monocyte subsets during hepatitis C virus (HCV) elimination in HIV/HCV-coinfected patients were evaluated. Twenty-two HIV/HCV-coinfected patients on suppressive combination antiretroviral treatment (cART) achieving HCV elimination after direct-acting antiviral (DAA) therapy and 10 HIV-monoinfected patients were included. The activation phenotype (10 markers) and polyfunctionality (intracellular interleukin-1α [IL-1α], IL-1β, IL-6, IL-8, tumor necrosis factor alpha [TNF-α], and IL-10 production) in three monocyte subsets (classical, intermediate, and nonclassical) were evaluated by flow cytometry before and at the end of treatment. Cell-associated HIV DNA levels were assayed by droplet digital PCR. After HCV clearance, there was a significant increase in classical monocyte and decreases in intermediate and nonclassical monocyte levels. The levels of the activation markers CD49d, CD40, and CX3CR1 were decreased after treatment in the monocyte subsets, reaching the levels in HIV-monoinfected patients. After lipopolysaccharide (LPS) stimulation, although polyfunctionality significantly decreased in intermediate and nonclassical monocytes, some combinations, such as the IL-1α− (IL-1α-negative) IL-1β− IL-6+ (IL-6-producing) IL-8− TNF-α− IL-10− combination, were remarkably increased at the end of treatment compared to the control group. Cell-associated HIV DNA levels correlated with activation markers before but not after treatment. HCV clearance after DAA treatment in patients on cART exerts an anti-inflammatory profile on monocyte subsets, activation phenotypes, and polyfunctionality. However, there is not a complete normalization compared with HIV-monoinfected patients., This work was supported by the Instituto de Salud Carlos III (research contracts CPII014/00025 to E.R.-M., CP19/00159 to A.G.-V., FI17/00186 to M.R.J.-L., and FI14/00431 to L.T.-D. and research projects PI16/00684 and PI19/01127 to E.R.-M.) and the Red Temática de Investigación Cooperativa en SIDA (RD16/0025/0020 and RD16/0025/0019), which is included in the Acción Estratégica en Salud, Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica, 2008 to 2011 and 2013 to 2016, Instituto de Salud Carlos III, Fondos FEDER. E.R.-M. was supported by the Consejería de Salud y Bienestar Social of the Junta de Andalucía through the Nicolás Monardes program (C-0032/17).

In recent years, human adenovirus (HAdV) infections have shown a high clinical impact in both immunosuppressed and immunocompetent patients. The research into specific antiviral drugs for the treatment of HAdV infections in immunocompromised patients constitutes a principal objective for medicinal chemistry due to the lack of any specific secure drug to treat these infections. In this study, we report a small-molecule library (67 compounds) designed from an optimization process of piperazine-derived urea privileged structures and their biological evaluation: antiviral activity and cytotoxicity. The active compounds selected were further evaluated to gain mechanistic understanding for their inhibition. Twelve derivatives were identified that inhibited HAdV infections at nanomolar and low micromolar concentrations (IC50 from 0.6 to 5.1 μM) with low cytotoxicity. In addition, our mechanistic assays suggested differences in the way the derivatives exert their anti-HAdV activity targeting transcription, DNA replication and later steps in the HAdV replication cycle. Furthermore, eight of the 12 studied derivatives blocked human cytomegalovirus (HCMV) DNA replication at low micromolar concentrations. The data provided herein indicates that the 12 thiourea/urea piperazine derivatives studied may represent potential lead compounds for clinical evaluation and development of new anti-HAdV drugs., This work has been supported by Ministerio de Economía y Competitividad, Plan Estatal 2013–2016 Retos-Proyectos I + D + i (CTQ2016-78580-C2-2-R) and by Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0009) – co-financed by European Development Regional Fund “A way to achieve Europe”, Operative program Intelligent Growth 2014–2020, the Instituto de Salud Carlos III(DTS17/00130) and the Spanish Adenovirus Network (AdenoNet, BIO2015/68990-REDT) grants. MVH also thanks Ministerio de Economía y Competitividad, Plan Estatal 2013–2016 Excelencia I + D + i (CTQ2016-78703-P). JSC is a researcher belonging to the program “Nicolás Monardes” (C-0059-2018), Servicio Andaluz de Salud, Junta de Andalucía, Spain. FA thanks Dipartimento di Farmacia e Scienze della Salute e della Nutrizione-Dipartimento di Eccellenza MIUR L 232/2016". JAV thanks Junta de Andalucia (Contrato de Garantías Juveniles).

The repositioning of drugs already approved by regulatory agencies for other indications is an emerging alternative for the development of new antimicrobial therapies. The repositioning process involves lower risks and costs than the de novo development of novel antimicrobial drugs. Currently, infections by adenovirus show a steady increment with a high clinical impact in immunosuppressed and immunocompetent patients. The lack of a safe and efficacious drug to treat these infections supports the search for new antiviral drugs. Here we evaluated the anti-adenovirus activity of niclosanide, oxyclozanide, and rafoxanide, three salicylanilide anthelmintic drugs. Also, we carried out the cytotoxicity evaluation and partial characterization of the mechanism of action of these drugs. The salicylanilide anthelmintic drugs showed significant anti-adenovirus activity at low micromolar concentrations with little cytotoxicity. Moreover, our mechanistic assays suggest differences in the way the drugs exert anti-adenovirus activity. Niclosamide and rafoxanide target transport of the HAdV particle from the endosome to the nuclear envelope, whilst oxyclozanide specifically targets adenovirus immediately early gene E1A transcription. Data suggests that the studied salicylanilide anthelmintic drugs could be suitable for further clinical evaluation for the development of new antiviral drugs to treat infections by adenovirus in immunosuppressed patients and in immunocompetent individuals with community-acquired pneumonia., Supported by Plan Nacional de I + D + i 2013–2016 and Instituto de Salud Carlos III, Ministerio de Economía, Industria y Competitividad, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0009) – co-financed by “A way to achieve Europe” ERDF, the Instituto de Salud Carlos III, Proyectos de Investigación en Salud (PI15/00489) and Proyectos de Desarrollo Tecnológico en Salud (DTS17/00130), and the Spanish Adenovirus Network (AdenoNet, BIO2015/68990-REDT). J.S.C. is supported by the “Contract to Access to the Spanish System of Research and Innovation of the Program of R + D + i of the University of Seville” (USE-13901-D) grant.

The repurposing of drugs approved by the regulatory agencies for other indications is emerging as a valuable alternative for the development of new antimicrobial therapies, involving lower risks and costs than the de novo development of novel antimicrobial drugs. Adenovirus infections have showed a steady increment in recent years, with a high clinical impact in both immunosuppressed and immunocompetent patients. In this context, the lack of a specific drug to treat these infections supports the search for new therapeutic alternatives. In this study, we examined the anti-HAdV properties of mifepristone, a commercially available synthetic steroid drug. Mifepristone showed significant in vitro anti-HAdV activity at low micromolar concentrations with little cytotoxicity. Our mechanistic assays suggest that this drug could affect the microtubule transport, interfering with the entry of the virus into the nucleus and therefore inhibiting HAdV infection.

Multiple multicomponent reactions rapidly assemble complex structures. Despite being very productive, the lack of selectivity and the reduced number of viable transformations restrict their general application in synthesis. Hereby, we describe a rationale for a selective version of these processes based in the preferential generation of intermediates which are less reactive than the initial substrates. In this way, applying the Groebke–Blackburn–Bienaymé reaction on a range of α-polyamino-polyazines, we prepared a family compact heterocyclic scaffolds with relevant applications in medicinal and biological chemistry (live cell imaging probes, selective binders for DNA quadruplexes, and antiviral agents against human adenoviruses). The approach has general character and yields complex molecular targets in a selective, tunable and direct manner. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, We thank the funding of DGICYT-Spain (CTQ2015-67870-P, CTQ2014-52588-R, SAF2017-88107-R, ERA-NET PCIN-2015-224), and Generalitat de Catalunya (SGR 2014-137, 187, 1189 and 2017-1439), Instituto de Salud Carlos III, MINECO, the Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0009)- cofinanced by "A way to achieve Europe" ERDF. S.C., on leave from the University of Genoa, thanks a U. Genoa scholarship to support her stage. F.J.L. thanks the Consorci de Serveis Universitaris de Catalunya (Molecular Recognition) and the ICREA Academia. M. V. acknowledges funding from the Biotechnology and Biological Sciences Research Council (BB/M025160/1). We thank Prof. Juan C. de la Torre (Scripps Research Institute, San Diego), Dr. Antonio L. Llamas-Saiz (U. Santiago de Compostela), Prof. Carmen Escolano (University of Barcelona) and Dr. Shoaleh Ghashghaie for useful contributions.

Human adenoviruses (HAdV) are the cause of many acute infections, mostly in the respiratory and gastrointestinal (GI) tracts, as well as conjunctivitis. HAdV diseases in immunocompetent individuals are mostly self-limiting; however, in immunocompromised individuals, especially in pediatric units, HAdV infections are the cause of high morbidity and mortality. Despite the significant clinical impact, there are currently no approved antiviral therapies for HAdV infections. Here, we provide an overview of the different targets that could be considered for the design of specific drugs against HAdV, as well as the available in vitro and in vivo tools for the screening and evaluation of candidate molecules.