Bioinformatics Insights on Viral Gene Expression Transactivation: From HIV-1 to SARS-CoV-2.

Viruses provide vital insights into gene expression control. Viral transactivators, with other viral and cellular proteins, regulate expression of self, other viruses, and host genes with profound effects on infected cells, underlying inflammation, control of immune responses, and pathogenesis. The multifunctional Tat proteins of lentiviruses (HIV-1, HIV-2, and SIV) transactivate gene expression by recruiting host proteins and binding to transacting responsive regions (TARs) in viral and host RNAs. SARS-CoV-2 nucleocapsid participates in early viral transcription, recruits similar cellular proteins, and shares intracellular, surface, and extracellular distribution with Tat. SARS-CoV-2 nucleocapsid interacting with the replication-transcription complex might, therefore, transactivate viral and cellular RNAs in the transcription and reactivation of self and other viruses, acute and chronic pathogenesis, immune evasion, and viral evolution. Here, we show, by using primary and secondary structural comparisons, that the leaders of SARS-CoV-2 and other coronaviruses contain TAR-like sequences in stem-loops 2 and 3. The coronaviral nucleocapsid C-terminal domains harbor a region of similarity to TAR-binding regions of lentiviral Tat proteins, and coronaviral nonstructural protein 12 has a cysteine-rich metal binding, dimerization domain, as do lentiviral Tat proteins. Although SARS-CoV-1 nucleocapsid transactivated gene expression in a replicon-based study, further experimental evidence for coronaviral transactivation and its possible implications is warranted.

Intragenomic rearrangements involving 5'-untranslated region segments in SARS-CoV-2, other betacoronaviruses, and alphacoronaviruses.

BACKGROUND: Variation of the betacoronavirus SARS-CoV-2 has been the bane of COVID-19 control. Documented variation includes point mutations, deletions, insertions, and recombination among closely or distantly related coronaviruses. Here, we describe yet another aspect of genome variation by beta- and alphacoronaviruses that was first documented in an infectious isolate of the betacoronavirus SARS-CoV-2, obtained from 3 patients in Hong Kong that had a 5'-untranslated region segment at the end of the ORF6 gene that in its new location translated into an ORF6 protein with a predicted modified carboxyl terminus. While comparing the amino acid sequences of translated ORF8 genes in the GenBank database, we found a subsegment of the same 5'-UTR-derived amino acid sequence modifying the distal end of ORF8 of an isolate from the United States and decided to carry out a systematic search. METHODS: Using the nucleotide and in the case of SARS-CoV-2 also the translated amino acid sequence in three reading frames of the genomic termini of coronaviruses as query sequences, we searched for 5'-UTR sequences in regions other than the 5'-UTR in SARS-CoV-2 and reference strains of alpha-, beta-, gamma-, and delta-coronaviruses. RESULTS: We here report numerous genomic insertions of 5'-untranslated region sequences into coding regions of SARS-CoV-2, other betacoronaviruses, and alphacoronaviruses, but not delta- or gammacoronaviruses. To our knowledge this is the first systematic description of such insertions. In many cases, these insertions would change viral protein sequences and further foster genomic flexibility and viral adaptability through insertion of transcription regulatory sequences in novel positions within the genome. Among human Embecorivus betacoronaviruses, for instance, from 65% to all of the surveyed sequences in publicly available databases contain inserted 5'-UTR sequences. CONCLUSION: The intragenomic rearrangements involving 5'-untranslated region sequences described here, which in several cases affect highly conserved genes with a low propensity for recombination, may underlie the generation of variants homotypic with those of concern or interest and with potentially differing pathogenic profiles. Intragenomic rearrangements thus add to our appreciation of how variants of SARS-CoV-2 and other beta- and alphacoronaviruses may arise.

Interview: commercial translation of cell-based therapies and regenerative medicine: learning by experience. Interview by Emily Culme-Seymour.

Dr Haseltine speaks to Emily Culme-Seymour, Assistant Commissioning Editor William A Haseltine, PhD has an active career in both Science and Business. He was a professor at Harvard Medical School and Harvard School of Public Health (MA, USA) from 1976 to 1993, where he was Founder and Chair of two academic research departments. He is well known for his pioneering work on cancer, HIV/AIDS and genomics. He has authored more than 200 manuscripts in peer-reviewed journals and is the author of several books. He is the founder of Human Genome Sciences, Inc. and served as the Chairman and CEO of the company until 2004. He is also the founder of several other successful biotechnology companies. William Haseltine is currently Chairman and President of ACCESS Health International, Inc., which supports access to affordable, high-quality health services in low, middle and high income countries, and Chairman of the Haseltine Foundation for Science and the Arts, which fosters a dialog between sciences and the arts. He is an Adjunct Professor at the Scripps Institute for Medical Research and the Institute of Chemical Engineering, the University of Mumbai, India. He is a member of the Advisory Board of the IE University, Madrid, the President's Council of the Cold Spring Harbor Laboratory, the Advisory Council for the Koch Institute of MIT, a member of the University Council Committee on technology transfer, Yale University, and is a Lifetime Governor of the New York Academy of Science (NY, USA). He is an honorary member of the Board of Trustees of the Brookings Institution, a member of the Board of Trustees of the Center for Emerging Markets of the Indian School of Business, a member of the Council on Foreign Relations, a member of the Board of AID for AIDS International, and a member of the Chairman's Circle of the Asia Society. He is a member of the Advisory Board of the Metropolitan Opera (NY, USA), the Chairman's Council of the Metropolitan Museum (NY, USA), the International Council of the Guggenheim Museum, the International Council of the Tate Modern, the Board of Directors of the Young Concert Artists, Inc. and the Youth Orchestra of the Americas.