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Prolonged exposure of CD8 + T cells to antigenic stimulation, as in chronic viral infections, leads to a state of diminished function termed exhaustion. We now demonstrate that even during exhaustion there is a subset of functional CD8 + T cells defined by surface expression of SIRPα, a protein not previously reported on lymphocytes. On SIRPα + CD8 + T cells, expression of co-inhibitory receptors is counterbalanced by expression of co-stimulatory receptors and it is only SIRPα + cells that actively proliferate, transcribe IFNγ and show cytolytic activity. Furthermore, target cells that express the ligand for SIRPα, CD47, are more susceptible to CD8 + T cell-killing in vivo. SIRPα + CD8 + T cells are evident in mice infected with Friend retrovirus, LCMV Clone 13, and in patients with chronic HCV infections. Furthermore, therapeutic blockade of PD-L1 to reinvigorate CD8 + T cells during chronic infection expands the cytotoxic subset of SIRPα + CD8 + T cells. SIRPa is most commonly known as a phagocytosis inhibitory receptor expressed by myeloid cells. Here the authors show SIRPa is expressed on a subset of CD8+ T cells with higher proliferative and effector activity during the chronic phase of the immune response to viral infection.

Development of cancer therapeutics requires a thorough evaluation of drug efficacy in vitro before animal testing and subsequent clinical trials. Three‐dimensional (3‐D) in vitro models have therefore been investigated for drug screening. In this study, we have developed a novel in vitro model in which multicellular aggregates, or spheroids, were incorporated into 3‐D porous scaffolds. Drug resistance assays showed that spheroid‐seeded scaffolds have much higher drug resistance than monolayer cultures, spheroids on flat substrates, or scaffolds seeded with dispersed cells. Furthermore, spheroid‐seeded scaffolds demonstrated higher lactate production leading to acidosis, and higher expression of angiogenic factors. These data suggest that the spheroid‐seeded 3‐D scaffolds might serve as a useful in vitro system for screening cancer therapeutics. (Cancer Sci 2010; 101: 2637–2643)

Chronic liver disease is a major cause of morbidity and mortality worldwide. Even though effective treatments are now available for most chronic viral hepatitis, treatment options for other causes of chronic liver disease remain inadequate. Recent research has revealed a previously unappreciated role that the human intestinal microbiome plays in mediating the development and progression of chronic liver diseases. The recent remarkable success of fecal microbiota transplantation (FMT) in treating Clostridioides difficile demonstrates that the intestinal microbiota can be manipulated to obtain favorable therapeutic benefits and that FMT may become an important component of a total therapeutic approach to effectively treat hepatic disorders.

Drug discovery campaigns against COVID-19 are beginning to target the SARS-CoV-2 RNA genome. The highly conserved frameshift stimulation element (FSE), required for balanced expression of viral proteins, is a particularly attractive SARS-CoV-2 RNA target. Here we present a 6.9 Å resolution cryo-EM structure of the FSE (88 nucleotides, ~28 kDa), validated through an RNA nanostructure tagging method. The tertiary structure presents a topologically complex fold in which the 5′ end is threaded through a ring formed inside a three-stem pseudoknot. Guided by this structure, we develop antisense oligonucleotides that impair FSE function in frameshifting assays and knock down SARS-CoV-2 virus replication in A549-ACE2 cells at 100 nM concentration. The frameshift stimulation element (FSE) of coronaviruses is an RNA structure that is required for balanced expression of viral proteins and is thus a promising drug target. A structure of the SARS-CoV-2 FSE serves as a guide for the development of antisense oligonucleotides that impair virus replication.

High rates of concurrent gastrointestinal manifestations have been noted in patients with corona virus disease 2019 (COVID-19); however, the association between these digestive manifestations and need for hospitalization has not been established. This is a retrospective review of consecutive patients diagnosed with COVID-19. A total of 207 patients were identified; 34.5% of patients noted concurrent gastrointestinal symptoms, with 90% of gastrointestinal symptoms being mild. In a multivariate regression model controlled for demographics and disease severity, an increased risk of hospitalization was noted in patients with any digestive symptom (adjusted odds ratio 4.84, 95% confidence interval: 1.68-13.94). The presence of digestive symptoms in COVID-19 is associated with a need for hospitalization.

Influenza A virus’s (IAV’s) frequent genetic changes challenge vaccine strategies and engender resistance to current drugs. We sought to identify conserved and essential RNA secondary structures within IAV’s genome that are predicted to have greater constraints on mutation in response to therapeutic targeting. We identified and genetically validated an RNA structure (packaging stem–loop 2 (PSL2)) that mediates in vitro packaging and in vivo disease and is conserved across all known IAV isolates. A PSL2-targeting locked nucleic acid (LNA), administered 3 d after, or 14 d before, a lethal IAV inoculum provided 100% survival in mice, led to the development of strong immunity to rechallenge with a tenfold lethal inoculum, evaded attempts to select for resistance and retained full potency against neuraminidase inhibitor-resistant virus. Use of an analogous approach to target SARS-CoV-2, prophylactic administration of LNAs specific for highly conserved RNA structures in the viral genome, protected hamsters from efficient transmission of the SARS-CoV-2 USA_WA1/2020 variant. These findings highlight the potential applicability of this approach to any virus of interest via a process we term ‘programmable antivirals’, with implications for antiviral prophylaxis and post-exposure therapy. Targeting conserved secondary structure of RNA viruses offers the potential for a customizable therapeutic approach to viral variants.

Chronic inflammation is thought to be a major cause of morbidity and mortality in aging, but whether similar mechanisms underlie dysfunction in infection-associated chronic inflammation is unclear. Here, we profiled the immune proteome, and cellular composition and signaling states in a cohort of aging individuals versus a set of HIV patients on long-term antiretroviral therapy therapy or hepatitis C virus (HCV) patients before and after sofosbuvir treatment. We found shared alterations in aging-associated and infection-associated chronic inflammation including T cell memory inflation, up-regulation of intracellular signaling pathways of inflammation, and diminished sensitivity to cytokines in lymphocytes and myeloid cells. In the HIV cohort, these dysregulations were evident despite viral suppression for over 10 y. Viral clearance in the HCV cohort partially restored cellular sensitivity to interferon-α, but many immune system alterations persisted for at least 1 y posttreatment. Our findings indicate that in the HIV and HCV cohorts, a broad remodeling and degradation of the immune system can persist for a year or more, even after the removal or drastic reduction of the pathogen load and that this shares some features of chronic inflammation in aging.

Background Despite the availability of safe and effective direct-acting antiviral drugs (DAAs), the vast majority of patients with chronic hepatitis C (HCV) in the USA remain untreated, in part due to lack of access to specialist providers. Aims To determine the effectiveness of DAA-based treatment in medically underserved areas in California, in a healthcare model dependent on task-shifting—wherein a visiting hepatologist assesses patients for treatment eligibility, but subsequent routine follow-up evaluation of patients prescribed treatment is devolved to a part-time licensed vocational nurse under remote supervision of the hepatologist. Methods We retrospectively determined rates of sustained virologic response 12 weeks after treatment completion (SVR-12), adverse events, and treatment discontinuations in patients who received sofosbuvir-based DAA regimens between December 2013 and November 2014. Results Despite limited specialist provider involvement in medically underserved areas, all but two of 58 patients completed treatment, and 88 % of patients achieved the curative endpoint of undetectable HCV RNA 12 weeks after completing treatment (sustained virologic response, SVR-12). Almost 80 % of patients with cirrhosis and 85 % of patients with prior treatment experience achieved SVR-12. Conclusions Treatment effectiveness with sofosbuvir-based regimens in medically underserved areas utilizing task-shifting from a specialist to a mid-level provider is comparable to those achieved in pivotal clinical trials for these regimens, and to “real-world” experiences of tertiary care centers in the USA.

Although currently available therapies for chronic hepatitis B virus infection can suppress viremia and provide long-term benefits for patients, they do not lead to a functional cure for most patients. Advances in our understanding of the virus-host interaction and the recent remarkable success of immunotherapy in cancer offer new and promising strategies for developing immune modulators that may become important components of a total therapeutic approach to hepatitis B, some of which are now in clinical development. Among the immunomodulatory agents currently being investigated to combat chronic HBV are toll-like receptor agonists, immune checkpoint inhibitors, therapeutic vaccines, and engineered T cells. The efficacy of some immune modulatory therapies is compromised by high viral antigen levels. Cutting edge strategies, including RNA interference and CRISPR/Cas9, are now being studied that may ultimately be shown to have the capacity to lower viral antigen levels sufficiently to substantially increase the efficacy of these agents. The current advances in therapies for chronic hepatitis B are leading us toward the possibility of a functional cure.