CD4 and HIV-1 infection: Indeed, CARD8, which is expressed and functional in naïve and memory CD4+ and CD8+ T cells (Linder et al., 2020), was recently shown to be required for pyroptosis in primary human blood- and lymphoid-derived CD4+ T cells and humanized mouse models (Wang et al., 2024), implicating CARD8 as a major driver of CD4+ T cell depletion during HIV-1 infection.