Monajemi, Mahdis (2012) Novel role of APOBEC3G/F enzymes in adaptive immunity. Masters thesis, Memorial University of Newfoundland.
- Accepted Version
Available under License - The author retains copyright ownership and moral rights in this thesis. Neither the thesis nor substantial extracts from it may be printed or otherwise reproduced without the author's permission.
Human immunodeficiency virus (HIV) utilizes our immune system to replicate in the body while having developed ways to evade it. However, immune cells have intrinsic barriers against HIV. Apolipoprotein B mRNA editing enzyme, catalytic polypeptide (APOBEC), most notably APOBEC3G (A3G) and APOBEC3F (A3F) are cytidine deaminases that act by mutating deoxycytidine (dC) to deoxyuridine (dU) in the(-) strand DNA that is generated upon reverse transcription of the viral genome. A3G/F are constitutively expressed pre-infection with HIV and act non-specifically throughout the viral DNA. For these reasons, they are considered anti-viral host restriction agents that participate in the initial innate immune response against HIV. Adaptive immunity is a more specific immune response that carries an immunological memory, and in the case of HIV, consists of anti-viral antibodies as well as cytotoxic CDS+ T cells (CTL). Here, we hypothesize that beyond A3G/F role in innate immunity within infected cells, mutations by A3G/F modulate HIV recognition by the adaptive immune system through modifying peptide epitopes recognized by CTL. To test our hypothesis, we I) identified all CTL epitopes restricted to each human leukocyte antigen (HLA) in silica, 2) identified the CTL epitopes and A3G/F hotspots therein that are mutable by A3G/F and simulated mutations in them, 3) measured the CTL responses of HLA-matched, HIV-infected individuals to peptides containing A3G/F mutations ex vivo, and 4) analyzed the frequencies of A3G/F hotspot motifs inside and outside of the CTL epitopes in silica. Our results reveal for the first time that rather than being beneficial for the adaptive immune system, mutations of the HIV genome by A3G/F may have the opposite effect by assisting HIV to escape from CTL responses. Furthermore, we show that the HIV genome has adapted to position A3G/F hotspot motifs selectively in CTL epitopes to maximally subvert the action of A3G/F towards immune escape.
|Item Type:||Thesis (Masters)|
|Additional Information:||Includes bibliographical references (leaves 76-95).|
|Department(s):||Medicine, Faculty of|
|Library of Congress Subject Heading:||HIV (Viruses)--Enzymes; HIV infections--Genetic aspects; Immunogenetics|
|Medical Subject Heading:||HIV Infections--genetics; Immunogenetics|
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