Following acute infection, herpes simplex virus (HSV) establishes latency in sensory neurons, from which it can reactivate and cause recurrent disease. Available antiviral therapies do not affect latent viral genomes; therefore, they do not prevent reactivation following therapy cessation. One possible curative approach involves the introduction of DNA double strand breaks in latent HSV genomes by rare-cutting endonucleases, leading to mutagenesis of essential viral genes. We tested this approach in an in vitro HSV latency model using the engineered homing endonuclease (HE) HSV1m5, which recognizes a sequence in the HSV-1 gene UL19, encoding the virion protein VP5. Coexpression of the 3′-exonuclease Trex2 with HEs increased HE-mediated mutagenesis frequencies up to sixfold. Following HSV1m5/Trex2 delivery with adeno-associated viral (AAV) vectors, the target site was mutated in latent HSV genomes with no detectable cell toxicity. Importantly, HSV production by latently infected cells after reactivation was decreased after HSV1m5/Trex2 exposure. Exposure to histone deacetylase inhibitors prior to HSV1m5/Trex2 treatment increased mutagenesis frequencies of latent HSV genomes another two- to fivefold, suggesting that chromatin modification may be a useful adjunct to gene-targeting approaches. These results support the continuing development of HEs and other nucleases (ZFNs, TALENs, CRISPRs) for cure of chronic viral infections.
BackgroundAlthough hematopoietic cell transplant (HCT) recipients are routinely exposed to classic risk factors for Clostridium difficile infection (CDI), few studies have assessed CDI risk in these high-risk patients, and data are especially lacking for pediatric HCT recipients. We aimed to determine incidence and risk factors for CDI in adult and pediatric allogeneic HCT recipients.MethodsCDI was defined as having diarrhea that tested positive for C. difficile via PCR, cytotoxin assay, or dual enzyme immunoassays. We included all patients who received an allogeneic HCT from 2008 to 2012 at the Fred Hutchinson Cancer Research Center; those <1 year old or with CDI within 8 weeks pre-HCT were excluded. Patients were categorized by transplanting hospital (“adult” or “pediatric”) and followed for 100 days post-HCT.ResultsOf 1182 HCT recipients, CDI was diagnosed in 17 % (33/192) of pediatric recipients for an incidence of 20 per 10,000 patient-days, and 11 % (107/990) of adult recipients for an incidence of 12 per 10,000. Pediatric recipients were diagnosed a median of 51 days (interquartile range [IQR]: 5, 72) after HCT and adults at 16 days (IQR = 5, 49). Compared with calendar year 2008, pediatric recipients transplanted in 2012 were at increased risk for CDI (hazard ratio [HR] = 3.99, p =.02). Myeloablative conditioning increased CDI risk in adult recipients (HR = 1.81, p =.005).ConclusionsPediatric and adult allogeneic recipients are at high risk of CDI post-HCT, particularly adult recipients of myeloablative conditioning. Differences in CDI incidence between children and adults may have resulted from exposure differences related to age; therefore, separately evaluating these groups should be considered in future CDI studies.
Background Diarrhea, abdominal pain and fever are common among patients undergoing hematopoietic cell transplant (HCT), but such symptoms are also typical with foodborne infections. The burden of disease caused by foodborne infections in patients undergoing HCT is unknown. We sought to describe bacterial foodborne infection incidence post-transplant within a single-center population of HCT recipients. Methods All HCT recipients transplanted from 2001 through 2011 at the Fred Hutchinson Cancer Research Center in Seattle, WA were followed for one year post-transplant. Data were collected retrospectively using center databases, which include information from transplant, on-site examinations, outside records, and collected laboratory data. Patients were considered to have a bacterial foodborne infection if Campylobacter jejuni/coli, Listeria monocytogenes, E. coli 0157:H7, Salmonella species, Shigella species, Vibrio species or Yersinia species were isolated in culture within one-year post-transplant. Non-foodborne infections with these agents and patients with preexisting bacterial foodborne infection (within 30 days of transplant) were excluded from analyses. Results A total of 12/4069 (0.3%) patients developed a bacterial foodborne infection within one year post-transplant. Patients with infections had a median age at transplant of 50.5 years (interquartile range [IQR]: 35–57), and the majority were adults ≥18 years of age (9/12 [75%]), male gender (8/12 [67%]) and post-allogeneic transplant (8/12 [67%]). Infectious episodes occurred at an incidence rate of 1.0 per 100,000 patient-days (95% CI: 0.5–1.7) and at a median of 50.5 days after transplant (IQR: 26–58.5). The most frequent pathogen detected was Campylobacter jejuni/coli (5/12 [42%]) followed by Yersinia (3/12 [25%]), while Salmonella (2/12 [17%]) and Listeria (2/12 [17%]) showed equal frequencies; no cases of Shigella, Vibrio, or E. coli 0157:H7 were detected. Most patients were diagnosed via stool (8/12 [67%]), fewer through blood (2/12 [17%]), one via both stool and blood simultaneously, and one through urine. Mortality due to bacterial foodborne infection was not observed during follow-up. Conclusions Our large single-center study indicates that common bacterial foodborne infections were a rare complication following HCT, and the few cases that did occur resolved without complications. These data provide important baseline incidence for future studies evaluating dietary interventions for HCT patients.
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