TASK DEFINITION: In this task, you're given a paragraph from the research paper and your task is to generate a suitable title for the research paper based on the given paper. Under 100 words is a good title length.
PROBLEM: Chronic infection and cancer are associated with suppressed T cell responses in the presence of cognate antigen. Recent work identified memory-like CXCR5 + TCF1 + CD8 + T cells that sustain T cell responses during persistent infection and proliferate upon anti-PD1 treatment. Approaches to expand these cells are sought. We show that blockade of interferon type 1 (IFN-I) receptor leads to CXCR5 + CD8 + T cell expansion in an IL-27-and STAT1-dependent manner. IFNAR1 blockade promoted accelerated cell division and retention of TCF1 in virus-specific CD8 + T cells. We found that CD8 + T cell-intrinsic IL-27 signaling safeguards the ability of TCF1 hi cells to maintain proliferation and avoid terminal differentiation or programmed cell death. Mechanistically, IL-27 endowed rapidly dividing cells with IRF1, a transcription factor that was required for sustained division in a cell-intrinsic manner. These findings reveal that IL-27 opposes IFN-I to uncouple effector differentiation from cell division and suggest that IL-27 signaling could be exploited to augment self-renewing T cells in chronic infections and cancer.

SOLUTION: IL-27 promotes the expansion of self-renewing CD8 + T cells in persistent viral infection

PROBLEM: Background: The HIV-1 RNA genome has a biased nucleotide composition with a surplus of As. Several hypotheses have been put forward to explain this striking phenomenon, but the A-count of the HIV-1 genome has thus far not been systematically manipulated. The reason for this reservation is the likelihood that known and unknown sequence motifs will be affected by such a massive mutational approach, thus resulting in replication-impaired virus mutants. We present the first attempt to increase and decrease the A-count in a relatively small polymerase (pol) gene segment of HIV-1 RNA. To minimize the mutational impact, a new mutational approach was developed that is inspired by natural sequence variation as present in HIV-1 isolates. This phylogeny-instructed mutagenesis allowed us to create replication-competent HIV-1 mutants with a significantly increased or decreased local A-count. The local A-count of the wild-type (wt) virus (40.2%) was further increased to 46.9% or reduced to 31.7 and 26.3%. These HIV-1 variants replicate efficiently in vitro, despite the fact that the pol changes cause a quite profound move in HIV-SIV sequence space. Extrapolating these results to the complete 9 kb RNA genome, we may cautiously suggest that the A-rich signature does not have to be maintained. This survey also provided clues that silent codon changes, in particular from G-to-A, determine the subtype-specific sequence signatures.

SOLUTION: HIV-1 tolerates changes in A-count in a small segment of the pol gene

PROBLEM: A new coronavirus (CoV) identified as COVID-19 virus is the etiological agent responsible 31 for the 2019-2020 viral pneumonia outbreak that commenced in Wuhan 1-4 . Currently there 32 is no targeted therapeutics and effective treatment options remain very limited. In order to 33 rapidly discover lead compounds for clinical use, we initiated a program of combined 34 structure-assisted drug design, virtual drug screening and high-throughput screening to 35 identify new drug leads that target the COVID-19 virus main protease (M pro ). M pro is a key 36 CoV enzyme, which plays a pivotal role in mediating viral replication and transcription, 37 making it an attractive drug target for this virus 5,6 . Here, we identified a mechanism-based 38 inhibitor, N3, by computer-aided drug design and subsequently determined the crystal 39 structure of COVID-19 virus M pro in complex with this compound. Next, through a 40 combination of structure-based virtual and high-throughput screening, we assayed over 41 10,000 compounds including approved drugs, drug candidates in clinical trials, and other 42 pharmacologically active compounds as inhibitors of M pro . Six of these inhibit M pro with 43 IC50 values ranging from 0.67 to 21.4 μM. Ebselen also exhibited promising antiviral 44 activity in cell-based assays. Our results demonstrate the efficacy of this screening strategy, 45 which can lead to the rapid discovery of drug leads with clinical potential in response to 46 new infectious diseases where no specific drugs or vaccines are available. 47 48 author/funder. All rights reserved. No reuse allowed without permission. : bioRxiv preprint CoVs infect humans and other animal species, causing a variety of highly prevalent and 49 severe diseases, including Severe Acute Respiratory Syndrome (SARS) and Middle East 50 Respiratory Syndrome (MERS) 7 . The COVID-19 virus genome is comprised of ~30,000 51 nucleotides; its replicase gene encodes two overlapping polyproteins, pp1a and pp1ab, 52 required for viral replication and transcription 3,4 . The functional polypeptides are released 53 from the polyproteins by extensive proteolytic processing, predominantly by a 33.8-kDa 54 main protease (M pro ), also referred to as the 3C-like protease. M pro digests the polyprotein 55 at no less than 11 conserved sites, starting with the autolytic cleavage of this enzyme itself 56 from pp1a and pp1ab 8 . The functional importance of M pro in the viral life cycle, together 57 with the absence of closely related homologues in humans, identify the M pro as an attractive 58 target for antiviral drug design 9 . 59 To facilitate the rapid discovery of antiviral compounds with clinical potential, we 60 developed a strategy combining structure-assisted drug design, virtual drug screening and 61 high-throughput screening to repurpose existing drugs to target COVID-19 virus M pro . 62 Establishing a high-throughput activity assay 63 Recombinant COVID-19 virus M pro with native N and C termini was expressed in 64 Escherichia coli and subsequently purified (Extended Data Fig. 1a, b). The molecular 65 weight of COVID-19 virus M pro as determined by mass spectroscopy is 33797.0 Da, 66 consistent with its theoretical molecular weight 33796.8 Da. In order to characterize its 67 enzymatic activity and to carry out high-throughput screening of inhibitors, we developed 68 a fluorescence resonance energy transfer (FRET) assay. To do this, a fluorescently labeled 69 substrate, MCA-AVLQ↓SGFR-Lys(Dnp)-Lys-NH2, derived from the N-terminal auto-70 cleavage sequence of the viral protease was designed and synthesized for time-dependent

SOLUTION:
Structure of M pro from COVID-19 virus and discovery of its inhibitors