A viral kinase mimics S6 kinase to enhance cell proliferation

Viruses usurp the host cell machinery to replicate, disseminate, and propagate themselves. Kaposi’s sarcoma-associated herpesvirus (KSHV) encodes a viral protein kinase (vPK) also known as ORF36. Using in silico modeling and biochemistry, we report that vPK/ORF36 displays limited homology to cellular S6 kinase B1 (S6KB1). Both kinases share overlapping substrates and can phosphorylate S6. However, unlike S6KB1, vPK augments S6 phosphorylation under conditions where mammalian target of rapamycin (mTOR) is inhibited. vPK modulates cellular proliferation and protein synthesis, augments anchorage independence, and enhances angiogenesis. Depletion of vPK/ORF36 during lytic replication inhibits the production of infectious virions, thereby underscoring the importance of this kinase during the KSHV life cycle. Our collective observations suggest that vPK may function as a constitutively active mimic of S6KB1

Ancient Plasmodium genomes shed light on the history of human malaria

Malaria-causing protozoa of the genus Plasmodium have exerted one of the strongest selective pressures on the human genome, and resistance alleles provide biomolecular footprints that outline the historical reach of these species1. Nevertheless, debate persists over when and how malaria parasites emerged as human pathogens and spread around the globe1,2. To address these questions, we generated high-coverage ancient mitochondrial and nuclear genome-wide data from P. falciparum, P. vivax and P. malariae from 16 countries spanning around 5,500 years of human history. We identified P. vivax and P. falciparum across geographically disparate regions of Eurasia from as early as the fourth and first millennia bce, respectively; for P. vivax, this evidence pre-dates textual references by several millennia3. Genomic analysis supports distinct disease histories for P. falciparum and P. vivax in the Americas: similarities between now-eliminated European and peri-contact South American strains indicate that European colonizers were the source of American P. vivax, whereas the trans-Atlantic slave trade probably introduced P. falciparum into the Americas. Our data underscore the role of cross-cultural contacts in the dissemination of malaria, laying the biomolecular foundation for future palaeo-epidemiological research into the impact of Plasmodium parasites on human history. Finally, our unexpected discovery of P. falciparum in the high-altitude Himalayas provides a rare case study in which individual mobility can be inferred from infection status, adding to our knowledge of cross-cultural connectivity in the region nearly three millennia ago.This project was funded by the National Science Foundation, grants BCS-2141896 and BCS-1528698; the European Research Council (ERC) under the European Union’s Horizon 2020 programme, grants 851511-MICROSCOPE (to S. Schiffels), 771234-PALEoRIDER (to W.H.) and starting grant 805268-CoDisEASe (to K.I.B.); and the ERC starting grant Waves ERC758967 (supporting K. Nägele and S.C.). We thank the Max Planck-Harvard Research Center for the Archaeoscience of the Ancient Mediterranean for supporting M. Michel, E. Skourtanioti, A.M., R.A.B., L.C.B., G.U.N., N.S., V.V.-M., M. McCormick, P.W.S., C.W. and J.K.; the Kone Foundation for supporting E.K.G. and A.S.; and the Faculty of Medicine and the Faculty of Biological and Environmental Sciences at the University of Helsinki for grants to E.K.G. A.S. thanks the Magnus Ehrnrooth Foundation, the Sigrid Jusélius Foundation, the Finnish Cultural Foundation, the Academy of Finland, the Life and Health Medical Foundation and the Finnish Society of Sciences and Letters. M.C.B. acknowledges funding from: research project PID2020-116196GB-I00 funded by MCIN/AEI/10.13039/501100011033; the Spanish Ministry of Culture; the Chiang Ching Kuo Foundation; Fundación Palarq; the EU FP7 Marie Curie Zukunftskolleg Incoming Fellowship Programme, University of Konstanz (grant 291784); STAR2-Santander Universidades and Ministry of Education, Culture and Sports; and CEI 2015 project Cantabria Campus Internacional. M.E. received support from the Czech Academy of Sciences award Praemium Academiae and project RVO 67985912 of the Institute of Archaeology of the Czech Academy of Sciences, Prague. This work has been funded within project PID2020-115956GB-I00 ‘Origen y conformación del Bronce Valenciano’, granted by the Ministry of Science and Innovation of the Government of Spain, and grants from the Canadian Institutes for Health Research (MZI187236), Research Nova Scotia (RNS 2023-2565) and The Center for Health Research in Developing Countries. D.K. is the Canada research chair in translational vaccinology and inflammation. R.L.K. acknowledges support from a 2019 University of Otago research grant (Human health and adaptation along Silk Roads, a bioarchaeological investigation of a medieval Uzbek cemetery). P.O. thanks the Jane and Aatos Erkko Foundation, the Finnish Cultural Foundation and the Academy of Finland. S. Peltola received support from the Emil Aaltonen Foundation and the Ella and Georg Ehrnrooth Foundation. D.C.S.-G. thanks the Generalitat Valenciana (CIDEGENT/2019/061). E.W.K. acknowledges support from the DEEPDEAD project, HERA-UP, CRP (15.055) and the Horizon 2020 programme (grant 649307). M. Spyrou thanks the Elite program for postdocs of the Baden-Württemberg Stiftung. Open access funding provided by Max Planck Society

Ten millennia of hepatitis B virus evolution

Hepatitis B virus (HBV) has been infecting humans for millennia and remains a global health problem, but its past diversity and dispersal routes are largely unknown. We generated HBV genomic data from 137 Eurasians and Native Americans dated between ~10,500 and ~400 years ago. We date the most recent common ancestor of all HBV lineages to between ~20,000 and 12,000 years ago, with the virus present in European and South American hunter-gatherers during the early Holocene. After the European Neolithic transition, Mesolithic HBV strains were replaced by a lineage likely disseminated by early farmers that prevailed throughout western Eurasia for ~4000 years, declining around the end of the 2nd millennium BCE. The only remnant of this prehistoric HBV diversity is the rare genotype G, which appears to have reemerged during the HIV pandemic

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

A viral kinase mimics S6 kinase to enhance cell proliferation

Viruses depend upon the host cell for manufacturing components of progeny virions. To mitigate the inextricable dependence on host cell protein synthesis, viruses can modulate protein synthesis through a variety of mechanisms. We report that the viral protein kinase (vPK) encoded by open reading frame 36 (ORF36) of Kaposi’s sarcoma-associated herpesvirus (KSHV) enhances protein synthesis by mimicking the function of the cellular protein S6 kinase (S6KB1). Similar to S6KB1, vPK phosphorylates the ribosomal S6 protein and up-regulates global protein synthesis. vPK also augments cellular proliferation and anchorage-independent growth. Furthermore, we report that both vPK and S6KB1 phosphorylate the enzyme 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase 2 (PFKFB2) and that both kinases promote endothelial capillary tubule formation