Étude mécanistique et fonctionnelle de l'acquisition des molécules HLA-DR et CD40L par le virus de l'immunodéficience humaine de type 1
|Advisor:||Tremblay, Michel J.|
|Abstract:||Ever since mankind faced human immunodeficiency virus (HIV), advances in research have been compromised by many difficulties, some of them being related to the complexity of the virus. Because HIV causes 14 000 new infections and 8 000 deaths daily (1), we must work intensely to fight this pathogen. Although antiretroviral drugs help the immune system of HIV-infected individuals to contain the virus, these drugs are ineffective to cure the infection, considering that the viral genome is integrated within the host genome. Thus, the best way to fight HIV infection at this point is to prevent it. The design of new therapies and prevention tools rely on our knowledge of the replication cycle of HIV. Therefore, we study steps of the viral cycle that are less defined, such as budding, and particularly the incorporation of molecules of cellular origin in the viral envelope. The results we present in this thesis show that host-derived HLA-DR, ICAM-1, CD40, CD86 and CD40L molecules are acquired by clinical isolates of HIV-1 produced in the most natural culture models, such as pieces of palatine tonsils cultured ex vivo. Moreover, we are the first to report the CD40L molecule as being part of HIV-1’s envelope. Also, our results indicate that incorporation of host HLA-DR and CD40L is independent of viral envelope glycoproteins. Furthermore, our results show that B lymphocytes from tonsils are activated following the binding of their CD40 receptor by the CD40L molecule inserted in the envelope of HIV-1. The translocation of NF-κB to the nucleus of cells is then induced, as for the secretion of IgG antibodies, production of IL-6 and homotypic cell-to-cell adhesion. The CD40L protein facilitates binding of virions to B lymphocytes which transfer them to T CD4+ lymphocytes. In the future, further investigation of the mechanism of HIV-1 host molecule incorporation and its impact on HIV-1 pathogenesis may help in the identification of new molecules being able to be targeted by a new therapy or immunization.|
|Document Type:||Thèse de doctorat|
|Open Access Date:||13 April 2018|
|Collection:||Thèses et mémoires|
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