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Both proteins are needed to efficiently establish lytic infection, and nascent expression of IE1 and IE2 is critical for reactivation from latency. The regulation of IE1 and IE2 protein expression is thus a central event in the outcome of HCMV infection. Transcription of the primary transcript encoding both IE1 and IE2 is well studied, but relatively little is known about the posttranscriptional mechanisms that control IE1 and IE2 protein synthesis. The mRNA 5\u2032 untranslated region (5\u2032 UTR) plays an important role in regulating mRNA translation. Therefore, to better understand the control of IE1 and IE2 mRNA translation, we examined the role of the shared 5\u2032 UTR of the IE1 and IE2 mRNAs (MIE 5\u2032 UTR) in regulating translation. In a cell-free system, the MIE 5\u2032 UTR repressed translation, as predicted based on its length and sequence composition. However, in transfected cells we found that the MIE 5\u2032 UTR increased the expression of a reporter gene and enhanced its association with polysomes, demonstrating that the MIE 5\u2032 UTR has a positive role in translation control. We also found that the MIE 5\u2032 UTR was necessary for efficient IE1 and IE2 translation during infection. Replacing the MIE 5\u2032 UTR with an unstructured sequence of the same length decreased IE1 and IE2 protein expression despite similar levels of IE1 and IE2 mRNA and reduced the association of the IE1 and IE2 mRNAs with polysomes. The wild-type MIE 5\u2032-UTR sequence was also necessary for efficient HCMV replication. Together these data identify the shared 5\u2032 UTR of the IE1 and IE2 mRNAs as an important regulator of HCMV lytic replication.<\/jats:p><jats:p><jats:bold>IMPORTANCE<\/jats:bold>The HCMV IE1 and IE2 proteins are critical regulators of HCMV replication, both during primary infection and during reactivation from viral latency. Thus, defining factors that regulate IE1 and IE2 expression is important for understanding the molecular events controlling the HCMV replicative cycle. Here we identify a positive role for the MIE 5\u2032 UTR in mediating the efficient translation of the IE1 and IE2 mRNAs. This result is an important advance for several reasons. To date, most studies of IE1 and IE2 regulation have focused on defining events that regulate IE1 and IE2 transcription. Our work reveals that in addition to the regulation of transcription, IE1 and IE2 are also regulated at the level of translation. Therefore, this study is important in that it identifies an additional layer of regulation controlling IE1 and IE2 expression and thus HCMV pathogenesis. These translational regulatory events could potentially be targeted by novel antiviral therapeutics that limit IE1 and IE2 mRNA translation and thus inhibit lytic replication or prevent HCMV reactivation.<\/jats:p>","DOI":"10.1128\/jvi.02128-17","type":"journal-article","created":{"date-parts":[[2018,1,18]],"date-time":"2018-01-18T11:24:25Z","timestamp":1516274665000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":15,"title":["The 5\u2032 Untranslated Region of the Major Immediate Early mRNA Is Necessary for Efficient Human Cytomegalovirus Replication"],"prefix":"10.1128","volume":"92","author":[{"given":"Kyle C.","family":"Arend","sequence":"first","affiliation":[{"name":"Department of Microbiology &amp; Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik M.","family":"Lenarcic","sequence":"additional","affiliation":[{"name":"Department of Microbiology &amp; Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathaniel J.","family":"Moorman","sequence":"additional","affiliation":[{"name":"Department of Microbiology &amp; Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.46.1.1-14.1983"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0407933101"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1305548110"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00348-10"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.70.6.4028-4037.1996"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1099\/0022-1317-74-12-2691"},{"key":"e_1_3_2_8_2","first-page":"81","article-title":"Identification of human cytomegalovirus target sequences in the human immunodeficiency virus long terminal repeat. 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