Dokument: APOBEC3-mediated hypermutation of retroviruses:A defensive tool of the innate immune system

Titel:	APOBEC3-mediated hypermutation of retroviruses:A defensive tool of the innate immune system
URL für Lesezeichen:	https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=29196
URN (NBN):	urn:nbn:de:hbz:061-20140411-114509-6
Kollektion:	Dissertationen
Sprache:	Englisch
Dokumententyp:	Wissenschaftliche Abschlussarbeiten » Dissertation
Medientyp:	Text
Autor:	Dr. Krikoni, Aikaterini [Autor]
Dateien:	[Dateien anzeigen] Adobe PDF [Details] 4,31 MB in einer Datei [ZIP-Datei erzeugen] Dateien vom 11.04.2014 / geändert 11.04.2014
Beitragende:	Prof. Münk, Carsten [Gutachter] Prof. Dr. Willbold, Dieter [Gutachter]
Dewey Dezimal-Klassifikation:	500 Naturwissenschaften und Mathematik » 570 Biowissenschaften; Biologie
Beschreibung:	The APOBEC3 family of cytidine deaminases (A3-A, -B, -C, -D, -F, -G, and –H) has been identified to restrict the replication and spread of retroviruses, hepadnaviruses, and retroelements. In the infected cells, the A3 proteins act as sensors that recognize and bind to the retroviral Gag polyprotein of the assembling viral particles. During the next round of infection, the encapsidated A3s attack and mutate heavily the viral cDNAs synthesised in the reverse transcription step leading to non-functional viral genomes and reduced number of integrated proviruses. This work focuses on the broad understanding of the A3 inhibition of two human pathogens: HIV-1 (Human Immunodeficiency Virus type-1) and HTLV-1 (Human T cell Lymphotropic Virus type-1). Both viruses target CD4+ T cells and macrophages. Nevertheless, these viruses evolved independently mechanisms to defeat the A3 immunity barrier. On one side, HIV-1 can escape from the A3 inhibition by its Vif accessory protein, known for promoting A3 proteasomal degradation, and on the other side, HTLV-1 is characterized by the presence of a C-terminal nucleocapsid area that excludes incorporation of A3s from nascent viral particles. Here, I present that A3A, A3B and A3H haplotype 2 act as potent inhibitors of HTLV-1, while wild-type HIV-1 can be restricted by A3B and A3H haplotype 2, but not by A3A. A3A and A3B exhibit a deaminase-dependent inhibition of HTLV-1, whereas A3H haplotype 2 acts with a deaminase-idependent mechanism of restriction. Analysis of the A3 editing profile of HTLV-1 sequences recovered from T cell lines, which established from HTLV-1 infected patients, shows an extensive hypermuation of the viral genome. The dinucleotide context of substitutions reveals that HTLV-1 may be in vivo a target of several A3s, such as A3A, A3B, or A3G. To further investigate the A3A anti-retroviral activity, I compared the A3A-mediated restriction of a gamma-retrovirus; MLV (Murine Leukemia Virus) and HIV-1. My results demonstrate that MLV tropism is associated with the A3A inhibitory capacity. In particular, A3A can be fully incorporated into the Moloney MLV, but not into the AKV-derived N and B tropic MLV viral particles. These data might indicate that variability of the viral Gag protein determines the viral sensitivity to the A3 molecules. On the other hand, A3A fails to achieve restriction of HIV-1 through incorporation into the produced viral particles. In addition, I present that A3A, but also other A3s expressed in viral target cells; A3B, A3C, A3G, and A3H haplotype 2, can inhibit HIV-1 expressing an inactive integrase (D64V). This finding might suggest that A3 molecules can mediate clearance of the un-integrated HIV-1 genomes in the target cells. To sum up, my work contributes on the better understanding of the molecular function of the A3 enzymes. A3s can be considered as a potent defensive tool of the innate immunity network against retroviral spread and infection. Strategies to inhibit the viral counteracting mechanisms will allow us to sufficiently control retroviral infections.
Lizenz:	Urheberrechtsschutz
Fachbereich / Einrichtung:	Mathematisch- Naturwissenschaftliche Fakultät
Dokument erstellt am:	11.04.2014
Dateien geändert am:	11.04.2014
Promotionsantrag am:	16.09.0013
Datum der Promotion:	10.12.0013