ADP-ribosylation is a ubiquitous post-translational addition of either monomers or polymers of ADP-ribose to target proteins by ADP-ribosyltransferases, usually by interferon-inducible diphtheria toxin-like enzymes known as PARPs. While several PARPs have known antiviral activities, these activities are mostly independent of ADP-ribosylation. Consequently, less is known about the antiviral effects of ADP-ribosylation. Several viral families, including Coronaviridae, Togaviridae, and Hepeviridae, encode for macrodomain proteins that bind to and hydrolyze ADP-ribose from proteins and are critical for optimal replication and virulence. These results suggest that macrodomains counter cellular ADP-ribosylation, but whether PARPs or, alternatively, other ADP-ribosyltransferases cause this modification is not clear. Here we show that pan-PARP inhibition enhanced replication and inhibited interferon production in primary macrophages infected with macrodomain-mutant but not wild-type coronavirus. Specifically, knockdown of two abundantly expressed PARPs, PARP12 and PARP14, led to increased replication of mutant but did not significantly affect wild-type virus. PARP14 was also important for the induction of interferon in mouse and human cells, indicating a critical role for this PARP in the regulation of innate immunity. In summary, these data demonstrate that the macrodomain is required to prevent PARP-mediated inhibition of coronavirus replication and enhancement of interferon production.

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MicroRNAs (miRNAs) play regulatory roles in diverse processes in both eukaryotic hosts and their viruses, yet fundamental questions remain about which viruses code for miRNAs and the functions that they serve. Simian foamy viruses (SFVs) of Old World monkeys and apes can zoonotically infect humans and, by ill-defined mechanisms, take up lifelong infections in their hosts. Here, we report that SFVs encode multiple miRNAs via a noncanonical mode of biogenesis. The primary SFV miRNA transcripts (pri-miRNAs) are transcribed by RNA polymerase III (RNAP III) and take multiple forms, including some that are cleaved by Drosha. However, these miRNAs are generated in a context-dependent fashion, as longer RNAP II transcripts spanning this region are resistant to Drosha cleavage. This suggests that the virus may avoid any fitness penalty that could be associated with viral genome/transcript cleavage. Two SFV miRNAs share sequence similarity and functionality with notable host miRNAs, the lymphoproliferative miRNA miR-155 and the innate immunity suppressor miR-132. These results have important implications regarding foamy virus biology, viral miRNAs, and the development of retroviral-based vectors.

Background-Interest in the reporting of risk-adjusted outcomes for patients with acute myocardial infarction is growing.A useful risk-adjustment model must balance parsimony and ease of data collection with predictive ability. Methods and Results-From our analysis of 82 359 patients Ն65 years of age admitted with acute myocardial infarction to 2401 hospitals, we derived a parsimonious model that predicts 30-day mortality. The model was validated on a similar group of 78 699 patients from 2386 hospitals. Of the 73 candidate predictor variables examined, 7 variables describing patient characteristics on arrival were selected for inclusion in the final model: age, cardiac arrest, anterior or lateral location of myocardial infarction, systolic blood pressure, white blood cell count, serum creatinine, and congestive heart failure. The area under the receiver-operating characteristic curve for the final model was 0.77 in the derivation cohort and 0.77 in the validation cohort. The rankings of hospitals by performance (in deciles) with this model were most similar to a comprehensive 27-variable model based on medical chart review and least similar to models based on administrative billing codes. Conclusions-A simple 7-variable risk model performs as well as more complex models in comparing hospital outcomes for acute myocardial infarction. Although there is a continuing need to improve methods of risk adjustment, our results provide a basis for hospitals to develop a simple approach to compare outcomes. (Circulation. 1999;99:2986-2992.)