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THE CYTOPLASMIC TAIL IS REQUIRED FOR DOWN-REGULATION OF MICA BY HUMAN CYTOMEGALOVIRUS.
Yizhou Zou, MD, Wade Bresnahan, PhD, R. Travis Taylor and Peter Stastny, MD. Dallas TX, UT Southwestern Med Cntr, Internal Medicine and Dallas TX, UT Southwestern Med Cntr, Microbiology.

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HCMV evades the host immune response by down-regulation of MHC antigens. The MHC-encoded MICA glycoproteins enhance killing by NK cells and T cells by binding to NKG2D. After HCMV infection, expression of surface MICA was decreased in the microglial cell line U373 which is MICA*001 homozygous, but was not changed in a line of primary human fibroblasts that express only MICA*008. This allele of MICA is known to have a mutation with an insertion of a guanine at position 952 in the transmembrane region, resulting in a truncated cytoplasmic tail. In primary fibroblasts with MICA*027, which is identical to MICA*008 but without the truncated cytoplasmic tail, MICA was down-regulated by HCMV, while MICA*008 was not. Fibroblasts were transduced with retrovirus to express MICA*001, MICA*002, MICA*004, MICA*027 or MICA*008 and 72 hours after infection with HCMV, 73-80% of fibroblasts expressing MICA alleles with full cytoplasmic tail lost surface expression of MICA while MICA*008 was lost from only 4%. We modified the MICA*001 allele, by site-directed mutagenesis, by inserting a guanine at position 952 resulting in a shortened cytoplasmic tail. This mutated MICA allele was resistant to down-regulation by HCMV. Cells with decreased MICA expression due to HCMV were found to be protected from killing by the NK cell line NKL. The finding that MICA*008 is resistant to down-regulation by HCMV provides a possible mechanism for its high prevalence, especially if similar interactions exist also for other pathogens. It appears that the strategy utilized by HCMV to evade the immune response of the host is countered in the host by a mutation in MICA encoding a molecule that is resistant to modulation by the virus.