To establish a persistent infection HIV must counteract numerous antiviral defenses. The HIV-1 accessory protein, Vpr, facilitates the spread of HIV-1 infection in monocyte-derived macrophages (MDMs) by counteracting an intrinsic antiviral response that limits viral particle production and spread of infection from macrophages to T lymphocytes.1 The HIV Nef protein functions to protect infected cells from cytotoxic T lymphocyte (CTL) lysis by disrupting the expression of host MHC-I, which is required for CTL recognition. Nef misdirects MHC-I into a naturally existing cellular pathway normally used by antigen presenting cells to cross-prime naïve T cell responses.2 This is an interesting example of a virus inappropriately activating a natural pathway to disarm the host immune response. By studying the celluar targets of viral factors much can be learned about the host immune response that will aid our ability to develop antiviral therapies and vaccines.