Multilayered and versatile functions of the HIV-2 envelope glycoprotein in the viral replication cycle
(2019)
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- The Human Immunodeficiency Virus type 2 (HIV-2) is the second etiologic agent causing AIDS (acquired immune deficiency syndrome) in the human host. However, this retrovirus may be considered as an attenuated model of retroviral infection since the HIV-2-infected individuals show a longer asymptomatic phase, lower plasmatic viral loads without antiviral therapy, and do not experience AIDS-like symptoms in 60-70% of cases, in striking contrast with HIV-1-infected patients. HIV-2-positive individuals appear to control the virus replication and the main hypothesis that could explain this phenotype is a strong T cell-mediated immunity and a robust early innate immune response against HIV-2. In this thesis research project, we focus on a host restriction factor involved in the antiviral immune response: BST-2/Tetherin. This interferon (IFN)-inducible protein is able to retain the budding virions at the plasma membrane of the infected cells, and promotes the endocytosis and degradation of the “tethered” viral particle. HIVs have evolved means to counteract BST-2/Tetherin in order to ensure the viral dissemination in the human host. HIV-1 uses the accessory Vpu protein to bind and degrade BST-2/Tetherin, whereas HIV-2 - that lacks Vpu - relies on its envelope (Env) glycoprotein. It has been reported that the HIV-2 envelope glycoproteins bind and remove BST-2 from the cell membrane, but this countermeasure does not result in the degradation of BST-2. HIV-2 Env and BST-2 interact mainly through their ectodomain. However, little was known concerning the domain in the Env protein that can exert this function. During this research project, we first revealed the precise motif within the ectodomain of HIV-2 Env protein involved in the anti-tetherin function. Indeed, we demonstrated that the N659 residue is clearly involved in the antagonism of BST-2/Tetherin. We also showed that the cytoplasmic tail (CT) of the HIV-2 Env protein cooperates in this anti-tetherin function. BST-2/Tetherin can also prime the expression of numerous antiviral genes via the activation of the NF-κB signaling pathway - a key regulator of the innate and adaptive immune response toward viral pathogens. The activation of the NF-κB transcription factor results in the expression of numerous genes involved in the antiviral response. Interestingly, we demonstrated that the HIV-2 Env glycoprotein, like HIV-1 Env, acts as a potent activator of the NF-κB signaling pathway and that the HIV-2 Env CT is involved in this activation. However, while HIV-1 Vpu completely abolishes the activation of NF-κB at the late stages of infection mainly through the potent antagonism of BST-2, we revealed that HIV-2 is unable to inhibit NF-κB primarily due to the inefficient Env-mediated BST-2 antagonism. As a consequence, numerous antiviral genes are upregulated during the late stages of the HIV-2 viral cycle, as compared with HIV-1. Thus, we may conclude that the differential regulation of the NF-κB-mediated antiviral response - through the viral countermeasure of the BST-2 restriction - is a major determinant of the differences between HIV-1 and HIV-2 pathogenesis, and may explain at least partly the stronger immunological control of the HIV-2 infection commonly seen in the majority of HIV-2-infected individuals.
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Dufrasne, F. E. (2019). Multilayered and versatile functions of the HIV-2 envelope glycoprotein in the viral replication cycle. https://hdl.handle.net/2078.5/96342