Reassessment of the capacity of the HIV-1 Env cytoplasmic domain to trigger NF-κB activation

The cytoplasmic domain of lentiviral Envelopes (EnvCD) ensures Env incorporation into nascent virions and regulatesEnv trafficking to and from the plasma membrane. It has also been reported to promote transcription from the viralLTR both directly and indirectly. Noticeably, the HIV-1 and SIVmac239EnvCDs were described to trigger nucleartranslocation of NF-κB (Postler, Cell Host Microbes 2012). Given the paramount importance of identifying viral and host factors regulating HIV transcription, cellular signaling pathways and latency, and given that viral replicationcapacity is dependent on Env, we asked whether HIV EnvCDs from different HIV-1 subtypes differently modulatedNF-κB. To that aim, we evaluated the ability of primaryHIV-1 Envs from subtypes B and C to activate the NF-κB pathway.Primary subtype B and C Envs all failed to activate the NF-κB pathway. In contrast, when the EnvCD of HIV-1 Envs wasfused to the the CD8-αchain, it induced ~ 10-fold increase in NF-κB induction, and this increase was much stronger witha truncated form of the HIV EnvCD lacking the 76 C-terminal residues and containing the proposed TAK-1 bindingdomain. Our results indicate that the HIV-1 EnvCD is unlikely to trigger the NF-κB pathway in its native trimeric form.