Class I HLA molecules sample the proteome of the virus-infected cell.  While reverse-immunologic methods are designed to identify virus-derived epitopes presented during infection, we have developed a direct ligand-scanning method in order to identify host-encoded epitopes unique to the class I of virus infected cells.  Application of this method to human immunodeficiency virus (HIV)-infected cells demonstrates that numerous host-derived peptide ligands are present on the infected cell.  These host-derived epitopes fall into specific biologic categories and serve as indicators for viral points of interaction within the host cell. The presentation of host-derived epitopes during viral infection indicates new targets on infected cells and represents a novel mechanism for the generation of autoreactive T cells. The direct characterization of class I HLA presented viral-associated antigens (VAAs) therefore provides (1) unrealized points of host-pathogen interaction,  (2) new insights for how the immune response can distinguish virally infected cells, and (3) mechanisms whereby infection might initiate autoimmune disease.