Date of Award

1-1-2010

Document Type

Campus Access Dissertation

Department

Biological Sciences

First Advisor

Austin L Hughes

Abstract

Viruses, such as Hepatitis and HIV, are able to evade the host immune responses they provoke and often lead to chronic infections and even death. Global estimates reveal that 130 million people are infected with Hepatitis C, while the number of people living with HIV/AIDS is 33.4 million. The extensive genetic diversity, characteristic of both Hepatitis C and HIV, has undoubtedly made vaccine development difficult and has prompted several to carefully study the relationship between virus and host.

Analysis of complete polyprotein-encoding sequences of the two most prevalent genotypes of Hepatitis C (HCV-1a and HCV-1b) showed evidence, not only of past purifying selection, but also of abundant slightly deleterious nonsynonymous variants subject to ongoing purifying selection. In the case of both HCV-1a and HCV-1b, the NS3 protein (with protease and NTPase/helicase activity) demonstrated a high incidence of forward-and-backward or parallel nonsynonymous changes in CTL epitopes. This pattern is best explained by the frequent re-occurrence of the same set of escape mutations in CTL epitopes of NS3, which are selectively favored within hosts presenting the class I major histocompatability complex molecule, but subject to purifying selection in the population at large. This pattern was more pronounced in HCV-1b than in HCV-1a, suggesting that there may be differences between the two genotypes with respect to NS3's interaction with host immune recognition.

Analysis of population-level polymorphism in eight coding genes of human immunodeficiency virus type 1 (HIV-1) subtype B revealed evidence not only of past purifying selection, but also of abundant slightly deleterious nonsynonymous variants subject to ongoing purifying selection. Both CD4 and CTL epitopes showed an excess of nonsynonymous variants that were singletons (occurring in just one sequence) in our dataset. Overall, median gene diversities at polymorphic nonsynonymous sites were highest at sites located in neither CD4 or CTL epitopes, while polymorphic nonsynonymous sites in CD4 epitopes revealed the lowest median gene diversity. Our results support the hypothesis that there is an evolutionary conflict between immune escape and functional constraint on epitopes recognized by host T-cells, and suggest that amino acid sequences of CD4 epitopes are subject to particularly strong functional constraint.

Rights

© 2010, Stephanie Jimenez Irausquin

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