Although little is known about Vpu-induced host protein cleavage, the cleavage and pathological aggregation of TDP-43 in neurodegenerative diseases are attributed mainly to caspase activation (Rohn, 2008; Yin et al, 2019; Zhang et al, 2007), which inspired us to explore the potential pathways involved in HIV-1 Vpu-mediated TDP-43 cleavage. Here, TARDBP is linked to neurodegenerative disease.