Viruses are adept at immune evasion. These strategies illuminate particularly important hot-pathogen relationships as well as individual immune components that are significant in host defense. The large DNA viruses are especially amenable for analysis because a large proportion of their genomes are devoted to host interactions. For example, herpesviruses encode several small molecules that target distinct steps of the major histocompatibility complex class I (MHC-I) biosynthesis pathways in order to thwart cytotoxic T lymphocytes (CTLs). On the other hand, according to the “missing-self” hypothesis, when MHC-I is downregulated, the target becomes more susceptible to natural killer (NK) cells, providing a host fail-safe mechanisms to thwart immune evasion. Our project will 1) study the viral mechanisms of MHC-I downregulation, 2) test the “missing-self” hypothesis by ascertaining the effect of MHC-I downregulation and/or NKG2D inhibition on innate and adaptive immune responses during in vivo infections, and 3) explore other viral strategies to evade innate immune responses.