Our analysis of 339 diverse Nef clones from these four major HIV subtypes demonstrates that subtype A and C clones displayed lower ability to internalize SERINC5 compared to those from subtypes B and D. This raises the intriguing possibility that an attenuated capacity to counteract SERINC5 may contribute to decreased pathogenesis in the context of subtype A or C infection, which has been seen in regions where these strains co-circulate with subtype D [24]. This evidence concerns the gene SERINC5 and infection.