Dokument: HIV and SIV capsid: A determinant for host and pharmacological factors
| Titel: | HIV and SIV capsid: A determinant for host and pharmacological factors | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=62445 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20240503-091229-2 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Twizerimana, Augustin Penda [Autor] | |||||||
| Dateien: |
| |||||||
| Beitragende: | Prof. Dr. Münk, Carsten [Gutachter] Prof. Dr. med. Lang, Philipp [Gutachter] | |||||||
| Dewey Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit | |||||||
| Beschreibung: | Following the retroviral-cell membrane fusion, the viral core is released in the cytosol. This triggers mobilization of capsid interactors that either shield the core, mediate its transport, or prematurely disassemble it. The Human Immunodeficiency Virus 1 (HIV-1) and its simian relatives Simian Immunodeficiency viruses (SIV) have specific interactions with factors of infected cells. In case of HIV-1, these include host proteins such as cyclophilin A or B (CYPA or CYPB), Tripartite motif-containing proteins (TRIM5, TRIM34, TrimCYP) and Cleavage and Polyadenylation Specificity Factor 6 (CPSF6). The HIV capsid is also a binding site for many pharmacological factors such as PF74 and Lenacapavir, known to halt HIV replication cycle. Under this thesis are findings from three projects I worked on, to explore host or pharmacological interactions with viruses from the four groups of HIV-1, HIV-2, SIVgor and SIVcpz, in a way to decipher more on SIV molecular evolution towards HIVs as well as infection biology differences between HIVs.
In the first project, I focused on understanding molecular evolution of SIVcpz towards HIV-1. I investigated sensitivity of SIVcpzPtt (the origin of HIV-1 M and HIV-1 N) and SIVcpzPts (which did not spread to humans) to capsid inhibitors PF74, PF57 and GS-CA1 in human and non-human cells. I also explored their CYPA usage and sensitivity to truncated, cytoplasmic form of CPSF6, the CPSF6_358, which shares a binding site with PF74; all this in comparison with HIV-1 M. Findings show that SIVcpzPts can use CYPA to escape inhibition by capsid inhibitors and resisted inhibition by the antiviral CPSF6_358. The two SIVcpz differed in how they use CYPA as revealed by findings of CYPA blocking with CsA or CYPA depletion with CRISPR/Cas9 system. In this chapter I also present a review on post-entry restriction of SIVcpz. In my second project, I explored why group N, group O, group P HIV-1 and HIV-2 did not set pandemics as opposed to HIV-1 M. I found that one of the possible several answers to this question is the sensitivity of non-M group HIVs capsids to human TRIM5 and a different use of CYPA. While HIV-1 M capsid binds CYPA as a protection against TRIM5, HIV-1 N, HIV-1 O, HIV-1 P and HIV-2 can be inhibited by TRIM5 even when their cores bind CYPA. I also identified capsid residue 88 in the capsid CYPA binding loop, as an important regulator of CYPA activity for such differential sensitivity to TRIM5. In my last project, I present an anti-HIV role of CYPB, a CYPA closely related cyclophilin, which I found to use many residues in the capsid CYPA binding loop, to interact with viral Gag. I also used fusion proteins of CYPB and TRIM5 proteins (TrimCYPB) to make strong anti-HIV proteins which inhibited viruses from the four groups of HIV-1, as opposed to TrimCYP which is known to selectively inhibit these viruses. Finally, I used a range of assays to show that CYPB inhibits the early phase of HIV-1 infection. My findings on SIVcpzPts open a door towards understanding why only SIVcpzPtt but not SIVcpzPts, managed to adapt to human cellular environment, to evolve as HIV-1, but more is needed to fully answer such question. To fully understand why non-M HIVs did not spread in form of pandemics, more work on possible contribution of host factors but also viral determinants, will be needed. Further investigations on the role of CYPB are needed to see if binding of this isomerase to HIV capsid also impairs or help other host or pharmacological players. | |||||||
| Lizenz: |  Dieses Werk ist lizenziert unter einer Creative Commons Namensnennung 4.0 International Lizenz | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät | |||||||
| Dokument erstellt am: | 03.05.2024 | |||||||
| Dateien geändert am: | 03.05.2024 | |||||||
| Promotionsantrag am: | 27.02.2023 | |||||||
| Datum der Promotion: | 14.04.2023 |
