Dokument: The battle of human restriction factor APOBEC3 with SIV and HIV Vifs
| Titel: | The battle of human restriction factor APOBEC3 with SIV and HIV Vifs | |||||||
| Weiterer Titel: | Der Kampf des menschlichen Restriktionsfaktors APOBEC3 mit SIV und HIV Vifs | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=46042 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20180530-105722-2 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Mr. Zhang, Zeli [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Münk, Carsten [Betreuer/Doktorvater] Prof. Dr. Gohlke, Holger [Betreuer/Doktorvater] | |||||||
| Stichwörter: | APOBEC3, SIVcpz, HIV, Cross-species transmission, Vif | |||||||
| Dewey Dezimal-Klassifikation: | 500 Naturwissenschaften und Mathematik » 570 Biowissenschaften; Biologie | |||||||
| Beschreibung: | Apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3s (APOBEC3s, A3s) are potent restriction factors of human immunodeficiency virus type 1/simian immunodeficiency viruses (HIV-1/SIV). The family of human (h) APOBEC3 restriction factors is formed by seven different proteins, hA3A–D and hA3F–H. To overcome the restriction of A3s, lentiviruses encode Vif proteins that directly bind A3s and induce them for proteasomal degradation. However, the molecular interaction of diverse lentiviral Vif proteins with A3 proteins of distinct species is poorly understood. The Vif interaction with A3s is likely of unique importance for the capacity of lentiviruses to infect new host species.
In current study, HIV-1 Vif was identified to be resistant to simian A3C, such as rhesus monkey (rh) A3C and sooty-mangabey monkey (smm) A3C. The simian A3Cs prevented the functional interaction with HIV-1 Vif due to presence of specific residues (N/H130 and Q133). In addition, a natural HIV-1 Vif (F-1 Vif) was characterized that failed to induce the degradation of hA3C and hA3F. The results were instrumental to describe in F-1 Vif an internal salt bridge of E171-K167-D101 that influences the Vif-mediated degradation of hA3C and hA3F. This finding indicates a novel mechanism, demonstrating that internal interactions outside the A3 binding region in HIV-1 Vif are able to influence the capacity to induce degradation of A3s. Additionally, in current study, I also identified that HIV-2, SIVmac and SIVagm Vif could target the so-called linker domain of feline A3Z2Z3 for degradation, which provides a fundamental basis for developing HIV or SIV animal model in felines. To understand a role of human A3s during the zoonotic transmission of SIV of chimpanzee (SIVcpz) to humans, I investigated the impact of human A3s on the replication of SIVcpz. The hA3B and hA3H haplotype II strongly reduced the infectivity of SIVcpz, because both of them are resistant to SIVcpz Vifs. Human A3H haplotype II inhibited SIVcpz by deaminase dependent as well independent mechanisms. Moreover, most SIV and HIV lineage Vif proteins could degrade chimpanzee A3H, but no Vifs from SIVcpz and SIV of gorilla (SIVgor) lineages antagonized hA3H haplotype II. Expression of hA3H hapII in human T cells efficiently blocked the spreading replication of SIVcpz. The spreading replication of SIVcpz was also restricted by high levels of A3H protein in human PBMCs. Thus, the data suggest that stably expressed hA3H protects humans against the cross-species transmission of SIVcpz and that SIVcpz spillover to humans may have started in individuals that harbor haplotypes of unstable A3H proteins. Taken together, these findings indicate that A3s are able to form a barrier to prevent the spread of lentiviruses between different species. Further studies are required to develop strategies to overcome the species-specific antagonism of Vifs to develop new animal model for HIV-1. | |||||||
| Lizenz: |  Urheberrechtsschutz | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät » WE Biologie | |||||||
| Dokument erstellt am: | 30.05.2018 | |||||||
| Dateien geändert am: | 30.05.2018 | |||||||
| Promotionsantrag am: | 20.02.2018 | |||||||
| Datum der Promotion: | 28.05.2018 |
