Michael Oldstone began his biomedical research career over three decades ago, showing contrary to established scientific dogma, the host was not tolerant but made a specific antiviral immune response during persistent virus infections. Further, the immune response to the virus actually caused tissue damage and disease, the first observation that several manifestations ordinarily accompanying infections were due to the host's antiviral immune response. These observations made originally with lymphocytic choriomeningitis virus (LCMV) and murine retroviruses were extended to other microbial infections including those in humans. Buildings on this work, he showed that antibodies to virus could recognize similar amino acid sequences or motifs found in host/cell proteins and cause disease. This cross-reactivity, referred to as molecular mimicry, has and is now been extensively studied by many laboratories. Another mechanism by which persistent virus infection produced disease was uncovered by cocumenting that viruses could alter the differentiation or "luxury" function of cells with causing cell destruction, thereby altering homeostasis. Finally, Oldstone was one of the first to show that viruses caused immunosuppression, abrogated immunologic surveillance resulting in viral persistence, work carried out long before HIV was discovered. He has also defined host-cell receptors for several viruses. In recent studies, host-cell receptor used by LCMV strains or variants that cause persistence have been identified. This led to observations that a single amino acid on the viral glycoprotein provides the infectious agent a selective ability ot displace extra-cellular matrix molecule, bind to and infect dendritic cells leading to their inability to act as antigen presenting cells thereby aborting the host's ability to generate the antiviral immune response required to clean the infection.