The human gamma-herpesviruses, Epstein–Barr virus and Kaposi's sarcoma-associated herpesvirus, establish lifelong latency in B cells and are associated with multiple malignancies. Virus-host coevolution often drive changes in both host immunity and in the viral genome. We consider one host immune mechanism, the activation-induced deaminase (AID)/APOBEC family of cytidine deaminases, that induces mutations in viral DNA. AID, the ancestral gene in the family has a conserved role in somatic hypermutation, a key step in antibody affinity maturation. The APOBEC3 subfamily, of which there are seven genes in human, have evolved antiviral functions and have diversified in terms of their expression pattern, subcellular localization, and DNA mutation motifs (hotspots). In this study, we investigated how the human gamma-herpesviruses have evolved to avoid the action of the AID/APOBEC enzymes and determine if these enzymes are contributing to the ongoing evolution of the viruses. We used computational methods to evaluate observed versus expected frequency of AID/APOBEC hotspots in viral genomes and found that the viruses have evolved to limit the representation of AID and certain APOBEC3 motifs. At the same time, the remaining hotspots were highly likely to cause amino acid changes, suggesting prolonged evolutionary pressure of the enzymes on the viruses. To study current hypermutation, as opposed to historical mutation processes, we also analyzed putative mutations derived from alignments of published viral genomes and found again that AID and APOBEC3 appear to target the genome most frequently. New protein variants resulting from AID/APOBEC activity may have important consequences in health, including vaccine development (epitope evolution) and host immune evasion.
Objectives: Hypothermia is associated with increased morbidity and mortality in trauma victims. The prognostic value of hypothermia on emergency department (ED) presentation in burn victims is not well known. The objective of this study was to determine the incidence of hypothermia in burn victims and its association with mortality and hospital length of stay (LOS). The study also examined the potential causative role of prehospital cooling in hypothermic burn patients.Methods: This was a retrospective review of a county trauma registry. The county was both suburban and rural, with a population of 1.5 million and with one burn center. Burn patients between 1994 and 2007 who met trauma registry criteria were included. Demographic and clinical data including prehospital cooling, burn size and depth, and presence of inhalation injury were collected. Hypothermia was defined as a core body temperature of less than or equal to 35°C. Data analysis consisted of univariate associations between patient characteristics and hypothermia.Results: There were 1,215 burn patients from 1994 to 2007. Mean age (±standard deviation [±SD]) was 29 (±24) years, 67% were male, 248 (26.7%) had full-thickness burns, and 24 (2.6%) had inhalation injury. Only 17 (1.8%) had a burn larger than 70% total body surface area (TBSA). A total of 929 (76%) patients had an initial ED temperature recorded. Only 15 ⁄ 929 (1.6%) burn patients had hypothermia on arrival, and all were mild (lowest temperature was 32.6°C). There was no association between sex, year, and presence of inhalation injury with hypothermia. Hypothermic patients were older (44 years vs. 29 years, p = 0.01), and median Injury Severity Score (ISS) was higher (25 vs. 4, p = 0.002) than for nonhypothermic patients. Hypothermia was present in 6 ⁄ 17 (35%) patients with a TBSA of 70% or greater and in 8 ⁄ 869 (0.9%) patients with a TBSA of <70% (p < 0.001). Mortality was higher in hypothermic patients (60% vs. 3%, p < 0.001). None of the hypothermic patients received prehospital cooling.Conclusions: Hypothermia on presentation to the ED was noted in 1.6% of all burn victims in this trauma registry. Hypothermia was more common in very large burns and was associated with high mortality. In this series, prehospital cooling did not appear to contribute to hypothermia.ACADEMIC EMERGENCY MEDICINE 2010; 17:456-459 ª
Unrepaired uracils in DNA can lead to mutations and compromise genomic stability. Herpesviruses have hijacked host processes of DNA repair and nucleotide metabolism by encoding a viral UNG that excises uracils and a viral dUTPase that initiates conversion of dUTP to dTTP. To better understand the impact of these processes on gammaherpesvirus pathogenesis, we examined the separate and collaborative roles of vUNG and vDUT upon MHV68 infection of mice. Simultaneous disruption of the enzymatic activities of both vUNG and vDUT led to a severe defect in acute replication and establishment of latency, while also revealing a novel, combinatorial function in promoting viral genomic stability. We propose that herpesviruses require these enzymatic processes to protect the viral genome from damage, possibly triggered by misincorporated uracil. This reveals a novel point of therapeutic intervention to potentially block viral replication and reduce the fitness of multiple herpesviruses.
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