Browsing by Subject "viral evolution"
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Item Open Access Understanding the Interplay Between Viral and Host Dynamics(2020) Vera Cruz, DianaThe 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.
Item Open Access Viral evolution in a pediatric rhesus macaque model of HIV therapy and rebound(2019-04) Mangold, JesseIn 2017, approximately 180,000 infants were infected with HIV and 1.8 million children were living with HIV globally. While lifelong combination antiretroviral therapy (ART) can effectively suppress virus replication, ART is not curative due to the establishment of stable latent viral reservoirs immediately after infection. A functional cure able to achieve sustained viral remission will be required to attain an ART-free life. Our study goal was to characterize the kinetics of Simian-Human Immunodeficiency Virus (SHIV) evolution and viral rebound in infant and adult preclinical models of HIV reservoir on ART. In this study, 6 infant and adult rhesus macaques (RMs) were infected with Simian-Human Immunodeficiency Virus (SHIV).C.CH0505.375H.dCT virus via oral and intravenous challenge, respectively. Twelve weeks post infection (wpi), infant and adult RMs were placed on ART for 8 and 12 weeks, respectively. ART was then interrupted and kinetics of viral rebound was measured using qRT-PCR. Viral diversity was measured pre- and post-ART using single genome amplification and sequencing of the HIV env gene. Plasma viral RNA (vRNA) in infants and adults displayed similar kinetics until ART initiation, peaking at 2 wpi. Upon ART initiation, plasma vRNA load was suppressed in infants and adults to undetectable levels within 2-4 weeks. Post-ART, 5/6 infant and 3/6 adult RMs rebounded to >150 vRNA copies/ml of plasma within 1-3 weeks. Pre-ART and post-ART, HIV env sequence diversity was greater in adult plasma viruses than in infant plasma viruses, with average pairwise distance values of 0.007 and 0.005, respectively. Post-ART, infant plasma viruses are more closely related to pre-ART viruses than are adult plasma viruses, perhaps due to less immune pressure in infants. These findings further delineate the clinically relevant differences in HIV env genetic diversity between infants and adults and emphasize the clear need for highly relevant, preclinical models for the development of pediatric-specific therapeutic and curative strategies to achieve an HIV-free generation.