In this study, we used the humanized NOD-scid IL2Rγnull (NSG) mouse model of acute HIV infection as well as CCR5-tropic HIV-1 virus that lack Vpu or encode WT Vpu or Vpu with mutations in the β-TrCP-binding site to assess the role of Vpu-mediated BST2 antagonism in establishing efficient plasma viremia and viral dissemination in lymphoid tissues during infection in vivo. Here, BST2 is linked to infection.