Biochemical Characterization of Two Cytomegalovirus MHC Class I Homologs

Author: Chapman, Tara Lynn

Year: 2000

Degree: Dissertation (Ph.D.)

Advisor: Bjorkman, Pamela J.

Committee Members: Rees, Douglas C.; Bjorkman, Pamela J.; Rothenberg, Ellen V.; Strauss, James H.

Option: Biochemistry

DOI: 10.7907/1jbr-8b50

Abstract

Cytomegaloviruses are ubiquitous host-specific pathogens that are capable of causing life-long persistent infections in immunocompetent hosts. To maintain this persistence in the presence of a functional immune system, both human and murine cytomegaloviruses (HCMV and MCMV, respectively) encode genes that modulate the host immune response. These genes include the MHC class I homologs UL18 from HCMV and m144 from MCMV. The host receptor for UL18 has been identified as LIR-1, a B cell, monocyte and dendritic cell inhibitory receptor related to natural killer cell inhibitory receptors, whereas the receptor for m144 remains unknown. In order to facilitate understanding of the functions of UL18 and m144 in viral pathogenesis and immune evasion, we have initiated structure/function analyses of ml 44, UL18 and LIR-1. We show that soluble m144 associates with the MHC class I light chain, B2-microglobulin, but unlike UL18 and class I MHC proteins, m144 does not associate with endogenous peptides, presumably due to a large deletion in the peptide binding platform. Using soluble versions of UL18, class I MHC molecules and LIR-1, we find that LIR-1 interacts with the relatively non-polymorphic a3 domain of class I proteins and the analogous region of ULI 8 using its N-terminal immunoglobulin-like domain. Recognition of the a3 domain, which is relatively non-polymorphic in class I MHC molecules, predicts that LIR-1 can interact with most or all class I MHC molecules, consistent with previous observations that LIR-1 binds a wide range of class I proteins. We also find that LIR-1 binds UL18 with a > 1000-fold higher affinity than it binds classical and non-classical class I MHC proteins, illustrating how a viral protein can effectively compete with host proteins to subvert the host immune response.

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