Efficient class I major histocompatibility complex down-regulation by simian immunodeficiency virus Nef is associated with a strong selective advantage in infected rhesus macaques

Substitution of Y223F disrupts the ability of simian immunodeficiency virus (SIV) Nef to down-modulate major histocompatibility complex (MHC) class I from the cell surface but has no effect on other Nef functions, such as dow n-regulation of CD4, CD28, and CD3 cell surface expression or stimulation o f viral replication and enhancement of virion infectivity. Inoculation of t hree rhesus macaques with the SIVmac239 Y223F-Nef variant revealed that thi s point mutation consistently reverts and that Nef activity in MHC class I down-modulation is fully restored within 4 weeks after infection. Our resul ts demonstrate a strong selective pressure for a tyrosine at amino acid pos ition 223 in SIV Nef, and they constitute evidence that Nef-mediated MHC cl ass I down-regulation provides a selective advantage for viral replication in vivo.