Human immunodeficiency virus (HIV) is a major global health concern with more than 30 million individuals currently infected worldwide. To date, attempts to stimulate protective immunity to viral components of HIV have been unsuccessful in preventing or clearing infection. Lymphocytic choriomeningitis virus (LCMV) is an established murine model of persistent viral infection that has been instrumental in illuminating several critical aspects of antiviral immunity. Although virologically the course of LCMV infection differs significantly from HIV, the immune responses and regulatory mechanisms elicited by these two viruses are markedly similar. In this review we discuss important recent findings in the LCMV model, highlighting the role of host-derived proteins in shaping immune responses to persistent infections, and explore the therapeutic potential of manipulating these pathways to enhance HIV vaccination strategies.