Understanding the Interplay Between Viral and Host Dynamics

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The evolution of antigenically variable viruses cannot be understood without studying the interaction between viruses and the host immune system. Viral evolution is driven by their fast acquisition of genetic variation as well as by the strong selection imposed by the host immune response. Moreover, understanding viral evolution dynamics and its interplay on the host immune response can provide essential information for vaccine development. In this dissertation, I use an integrative approach to study various aspects of this interplay in two viral systems: influenza A (IAV) and cytomegalovirus (CMV), both ubiquitous in humans and significant public health threats.

Congenital cytomegalovirus infection is the leading infectious cause of congenital defects. As such, the study of viral dynamics is essential to develop better treatment and prevention procedures. In a monkey challenge study for congenital cytomegalovirus infection, I investigated viral transmission between maternal and fetal compartments. Using high-coverage sequencing data, I examined viral evolutionary dynamics in time and space. I found evidence of large transmission bottleneck sizes between maternal compartments and in congenital transmission. I also inquire about the role of preexistent CMV-specific antibodies in the virus population, finding no apparent effect in the viral genetic make-up but reduced viral load and also reduced congenital transmission.

One of the more promising vaccine formulation for CMV until now is the gB-MF59 vaccine, which is based on a soluble version of the immunodominant gB protein. To understand immune and viral factors contributing to vaccine efficacy for this formulation, I examined immunoglobulin G binding to a gB-specific peptide microarray from seropositive individuals and vaccinees prior to and after vaccination. The antibody profile observed from binding clustered by individual immune exposure history. While the antibody profile elicited by vaccination show high agreement with the one from seropositive individuals, I also identified regions in gB preferentially targeted in vaccinees. Moreover, I observe no difference between the antibody profiles of vaccinees with different clinical outcomes and instead found further evidence for reduced cross-immunity between divergent genotypes.

Original antigenic sin (OAS) refers to the tendency of the host immune system to focus on previously recognized viral epitopes during secondary challenges with related viral strains. This preference is sustained by antibody memory and can result in suboptimal immune protection. Mounting evidence highlights the importance of the initial viral strain encountered during childhood, which primes the antibody repertoire to contend against further infections. Here, the goal was to identify OAS-driven cohort effects in IAV driven by at least one antigenic mutation. Using sequence data and host's age information from individuals infected with H1N1 in the U.S. from 2009 to the present, we searched for potential signatures of birth year cohort changes driven by new variants with nonsynonymous mutations. We identified multiple variants with such properties and studied the age groups with differential abundance after such variant arose.





Vera Cruz, Diana (2020). Understanding the Interplay Between Viral and Host Dynamics. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/20923.


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