Bedeutung zellulärer Anheftungsfaktoren für die Ausbreitung des humanen Immundefizienz-Virus
Year: 2008
Type: dissertation
Abstract: The envelope protein (Env) of human immunodeficiency virus (HIV) mediates infectious entry into target cells. The interaction of Env with the CD4 receptor and a chemokine receptor is essential for infection, while binding to so-called attachment factors is dispensable. However, attachment factor engagement can profoundly augment infection efficiency. The attachment factor DC-SIGN is expressed on submucosal dendritic cells and it has been postulated that binding of HIV to DC-SIGN on dendritic cells might promote sexual transmission of HIV. However, more recent work suggests that dendritic cells can also bind to HIV in a DC-SIGN-independent manner and that DC-SIGN-negative cells can promote HIV infection of adjacent cells (trans-infection). Furthermore, it has been shown that polymorphisms in the DC-SIGN gene influence the risk of HIV infection upon parenteral, but not mucosal HIV transmission. This observation indicates that DC-SIGN on mucosal dendritic cells might not be involved in sexual transmission of HIV, whereas hitherto unknown DC-SIGN-positive cells might augment dissemination of the virus after its entry into the bloodstream. Therefore, the objective of this work was to identify new DC-SIGN-positive cells and new HIV attachment factors, and to determine their impact on HIV dissemination. In the present study the cellular surface protein CLEC-2 could be identified as a new HIV attachment factor. It could be shown that CLEC-2 is expressed on platelets and megakaryocytes, and that platelets mediate HIV trans-infection of T-cells in a partly CLEC-2-dependent manner. Furthermore, it could be demonstrated that platelets also express DC-SIGN and that this lectin is mainly responsible for HIV binding to platelets. Evidence was obtained that CLEC-2, in contrast to DC-SIGN, does not interact with the HIV Env protein but with a cellular factor incorporated into the viral membrane upon virus release. Expression analysis and siRNA-mediated knock-down demonstrated that this cellular factor is podoplanin, a mucin-type protein found to be expressed on 293T cells, which were routinely used for virus production. However, the observation that viruses generated in podoplanin-negative cells still interacted with CLEC-2 suggested that either endogenous podoplanin expression is induced during HIV infection or additional CLEC-2 ligands are expressed on HIV target cells. In summary, it could be demonstrated that platelets bind and transmit HIV to T-cells via DC-SIGN and CLEC-2, a process that might aid HIV dissemination in infected individuals.
Author: Chawaree Chaipan
Language: German
Topic: HIV Research and Treatment
Subfield: Virology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W3144468916