The Potency of Nef-Mediated SERINC5 Antagonism Correlates with the Prevalence of Primate Lentiviruses in the Wild

The cellular factor serine incorporator 5 (SERINC5)impairs HIV-1 infectivity but is antagonized by theviral Nef protein. We analyzed the anti-SERINC5 ac-tivity of Nef proteins across primate lentivirusesand examined whether SERINC5 represents a barrierto cross-species transmissions and/or within-spe-cies viral spread. HIV-1, HIV-2, and SIV Nefs coun-teract human, ape, monkey, and murine SERINC5 or-thologs with similar potency. However, HIV-1 Nefsare more active against SERINC5 than HIV-2 Nefs,and chimpanzee SIV (SIVcpz) Nefs are more potentthan those of their monkey precursors. Additionally,Nefs of HIV and most SIVs rely on the dileucine motifin the C-terminal loop for anti-SERINC5 activity, whilethe Nef from colobus SIV (SIVcol) evolved differentinhibitory mechanisms. We also found a significantcorrelation between anti-SERINC5 potency and theSIV prevalence in the respective ape and monkeyspecies. Thus, Nef-mediated SERINC5 antagonismmay determine the ability of primate lentiviruses tospread within natural hosts.