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cellular repressor proteins vary among the different cell types infected by HCMV, then expression kinetics of US3 will be altered concominantly, with effects of gpUS3 on class I heavy chains not limited to the first few hours after infection.

One may speculate that class I heavy chains that are retained in the ER by gpUS3 are subsequently attacked by either gpUS11 or gpUS2. Although not formally tested, this may not be the case. gpUS2 and gpUS11 readily exert their effect on free heavy chains (T.R.J. and L.S., unpublished results), and their attack on β2-microglobulin-associated heavy chains is detected shortly after this association (21). Furthermore, gpUS11 has been shown to cause destabilization of newly synthesized heavy chains upon completion of polypeptide synthesis by dislocating them from the ER to the cytosol, probably by reverse transport through the ER translocation complex (21). gpUS2 acts in a similar fashion (E.J.H.J.W., H.L.P., and T.R.J., unpublished results). Therefore, the mechanism of action of these proteins may require class I heavy chains that remain in close association with, or in the proximity of, the translocation complex. In the presence of gpUS3, there are no apparent defects in a very early step of class I biosynthesis, namely, association with β2-microglobulin (Fig. 3). The apparent half-time for this association can vary widely, from less than 5 min to 4 hr for some heavy chain alleles (41, 42). Thus, it is unlikely that heavy chains retained by gpUS3 would still be in the proximity of the translocation complex. Further experiments are required to determine the susceptibility of gpUS3-retained class I heavy chains to gpUS2 or gpUS11 function to properly assess the role of US3 in HCMV infection.

This manuscript is dedicated to the memory of Yakov (Yasha) Gluzman, a mentor and colleague. We thank S.Ferrone for the generous gift of TP25.99 monoclonal antibody. H.L.P. and J.A.N. are supported by funding from the National Institutes of Health (Grants NIH-AI-33456 and NIH-AI-21640, respectively). E.J.H.J.W. is on leave from the National Institute of Public Health and Environmental Protection (Bilthoven, The Netherlands) and further supported by a Talent Stipendium of The Netherlands Organization for Scientific Research and a long-term fellowship from the European Molecular Biology Organization.

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