Regain of Nef-mediated tetherin antagonism in a chimpanzee experimentally infected with HIV-1

Abstract

The interferon-inducible host restriction factor tetherin poses a barrier for SIV transmission from apes to humans. After cross-species transmission, the chimpanzee precursor of pandemic HIV-1 M had to switch from the Nef protein to Vpu to efficiently counteract human tetherin due to a deletion of five amino acids in its cytoplasmic tail, which governed susceptibility of Nef in the primate tetherin ortholog. In this thesis, it has been revealed that the experimental reintroduction of HIV-1 M into its original chimpanzee host resulted in a virus that utilizes both Vpu and Nef to antagonize chimpanzee tetherin. Functional analyses identified amino acid changes in and around the highly conserved ExxxLL adaptor protein binding motif within the C-terminal loop of Nef to be critical for the reacquisition of antitetherin activity. Strikingly, just two amino acid changes allowed a HIV-1 M Nef to antagonize chimpanzee tetherin and rescue virus release by enhanced endocytosis of the restriction factor from the cell surface and subsequent sequestration into perinuclear compartments. These data illustrate that primate lentiviruses can regain lost gene functions within a single in vivo passage and suggest that multifunctionality of Nef and the redundant requirement of functional motifs may be beneficial to reacquire antitetherin activity.