ABSTRACTHIV-2 is the second causative agent of AIDS and is commonly considered as an attenuated form of retroviral infection. Most of HIV-2-infected individuals display a slow-progressing disease, lower viral loads and a stronger immunological control of viral infection as compared with HIV-1-infected patients. The main hypothesis that could explain the difference of disease progression between HIV-1 and HIV-2 implies a more efficient T cell–mediated immunity in the control of HIV-2 infection. Herein, we investigate the effects of the HIV-2 envelope glycoprotein (Env) and its antitetherin function in the NF-κB signaling pathway during single-round infection of CD4+ T cells. First, we report an essential role of the Env cytoplasmic tail (CT) in the activation of this signaling pathway and we also demonstrate that the HIV-2 Env CT activates NF-κB in a TRAF6-dependent but TAK1-independent manner. Further, we show that HIV-2 reference strains and clinical isolates are unable to completely inhibit NF-κB mainly via the Env-mediated BST-2/tetherin antagonism in the late stages of the viral replication cycle in CD4+ T cells, in striking contrast to the HIV-1 Vpu-mediated counteraction of tetherin. We observe that this inability of HIV-2 to suppress NF-κB signaling pathway promotes stimulation of numerous genes involved in the antiviral immune response, such as il-6, il-21 and ifn-β genes. Therefore, HIV-1 and HIV-2 differentially regulate the NF-κB-induced antiviral immune response mainly through the BST-2/tetherin antagonism. These new insights highlight molecular mechanisms determining, at least partly, the distinct immune control and disease outcomes of HIV-1 and HIV-2 infections.IMPORTANCEThis study explores how HIV-1 and HIV-2 diverge in their regulation of the NF-κB signaling pathway. We revealed that HIV-2 fails to completely inhibit NF-κB activity, thereby inducing a stronger antiviral response than HIV-1. We demonstrated that the ability to antagonize the cellular restriction factor BST-2/tetherin largely governs the regulation of the NF-κB pathway: at the late stages of the viral replication cycle, HIV-1 Vpu blocks this pathway whereas HIV-2 Env does not. We also demonstrated that several NF-κB-targeted genes are upregulated in CD4+ T cells infected with HIV-2, but not with HIV-1. This stronger NF-κB-induced antiviral response may explain the better immune control of HIV-2 infection and the differences between HIV-1 and HIV-2 pathogenesis. Moreover, we observed in this study that non-pathogenic isolates of HIV-2 have an impaired NF-κB inhibitory capacity compared to pathogenic ones.
Neuroblastoma-targeted Anticancer Drug Delivery