HIV-1, the causative agent of the AIDS pandemic, is a complex retrovirus that thwarts innate antiviral immune mechanisms through auxiliary viral proteins. The Gottlinger laboratory has recently identified novel antiviral human cell surface proteins that are counteracted by the auxiliary HIV-1 protein Nef. In the absence of Nef, these antiviral membrane proteins are taken up into nascent HIV-1 virus particles and dramatically reduce their ability to infect new target cells. These findings suggest potential new strategies to combat HIV-1 that are currently being explored by the Gottlinger laboratory.