Abstract: HIV-1 Nef protein has multifunctions which can keep high viral load in patients' plasma, accelerate AIDS progression, down-regulate crucial cell surface molecules, such as CD4, major histocompatibility complex (MHC) molecules, and enhance viral growth and infectivity. However, during the past two decades, the mechanism underlying the enhancement of viral growth and infectivity by Nef protein was unknown. Recently, host transmembrane proteins SERINC3 and SERINC5 (serine incorporator 3 and 5) were identified to be important host restriction factors against HIV-1. On the contrary, HIV-1 Nef protein antagonizes SERINC3 and SERINC5.