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9/26/2014  |   9:30 AM - 10:00 AM   |  Topical Session 1   |  Arizona

CMV genomics in congenital infections: relevance to therapeutic and vaccine design

Diseases associated with viral infections reflect complex and dynamic processes. For congenital CMV (cCMV), the virus must not only survive but also thrive in the presence of maternal immunity and the variable physiologic systems of the pregnant woman, placenta, and developing fetus. We have developed a viral genomics program to determine how CMV responds to selective pressures and physiological constraints on replication encountered in these host settings. The goal is to identify therapeutically tractable “weak” points during CMV evolution in congenital infections. The 15 infants in this study are located in the US, Brazil, and Europe. We have analyzed ~21 billion bases of viral deep sequencing data from 26 specimens including urine, plasma, saliva, cord blood, and amniotic fluid. We have found that CMV exists as complex populations having ~20,000 single nucleotide polymorphisms (SNPs)/sample. Most SNPs are at <20% frequency and ~70% are stable in longitudinal sampling. Dramatic changes in viral populations emerge when comparing SNPs from different compartments. By using the viral population data to model historical events, we infer that positive selection and bottlenecks/expansions contribute to the evolution of cCMV populations. Positive selection is likely associated with tissue tropism and the developing fetal immune system. Bottlenecks coincide temporally with biological events including maternal-fetal transmission. They reduce viral population complexity by >90%, with subsequent replication expanding the population and introducing new mutations. Importantly, the models make biological sense and are backed by robust statistics. These observations have significant public health relevance because both positive selection and bottlenecks define quantifiable targets for the development of interventions that prevent viral transmission and can serve as monitors during treatment regimens. Lastly, the results show that disease-associated, intrahost viral populations differ from virus that evolved for host-to-host spread (i.e., secreted virus), which raise questions regarding which population should be targeted during vaccine design.

Timothy Kowalik (POC,Primary Presenter,Author), timothy.kowalik@umassmed.edu;
Timothy Kowalik, Ph.D. has been studying CMV since 1990. Prior to CMV research, he studied the genetics of bluetongue virus, a pathogen of ruminants including cattle, during his graduate training at Utah State University. Upon obtaining his PhD, he moved to North Carolina for postdoctoral studies at the University of North Carolina School of Medicine and then at Duke University Medical School. In 1996, he joined the faculty at the University of Massachusetts Medical, where is currently an Associate Professor of Microbiology and Physiological Systems.


Financial - Receives Consulting fee for Consulting from GlaxoSmithKline.   Receives Intellectual property rights,Ownership interest for Ownership from TaTT, LLC.   Receives Ownership interest for Other activities from Cytrx, Inc.   Receives Ownership interest for Other activities from RXi Pharmaceuticals Corp..   Receives Ownership interest for Other activities from Galena Biopharma, Inc..   Receives Consulting fee for Consulting from Merck & Co., Inc..  

Nonfinancial - No relevant nonfinancial relationship exist.

Nicholas Renzette (Author), nicholas.renzette@umassmed.edu;

Laura Gibson (Author), laura.gibson@umassmed.edu;

William Britt (Author), WBritt@peds.uab.edu;

Marisa Mussi-Pinhata (Author), mmussi50@gmail.com;

Aparecida Yamamoto (Author), yulie@fmrp.usp.br;

Klaus Hamprecht (Author), Klaus.Hamprecht@med.uni-tuebingen.de;

Mark Schleiss (Co-Author), schleiss@umn.edu;

Jeffrey Jensen (Author), jeffrey.jensen@epfl.ch;


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