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Blood, 1 August 2007, Vol. 110, No. 3, pp. 937-945.
Prepublished online as a Blood First Edition Paper on April 17, 2007; DOI 10.1182/blood-2007-01-070078.
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IMMUNOBIOLOGY
Human cytomegalovirus sequences expressed in latently infected individuals promote a latent infection in vitro
Felicia Goodrum1,
Matthew Reeves2,
John Sinclair2,
Kevin High3, and
Thomas Shenk4
1 Department of Immunobiology, University of Arizona, Tucson;
2 Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridgeshire, United Kingdom;
3 Department of Infectious Diseases, Wake Forest University School of Medicine, Winston-Salem, NC; and
4 Department of Molecular Biology, Princeton University, NJ
Latency enables human cytomegalovirus (HCMV) to persist in the hematopoietic cells of infected individuals indefinitely and prevents clearance of the pathogen. Despite its critical importance to the viral infectious cycle, viral mechanisms that contribute to latency have not been identified. We compared the ability of low-passage clinical and laboratory-adapted strains of HCMV to establish a latent infection in primary human CD34+ cells. The low-passage strains, Toledo and FIX, established an infection with the hallmarks of latency, whereas the laboratory strains, AD169 and Towne, replicated producing progeny virus. We hypothesized that ULb' region of the genome, which is unique to low-passage strains, may encode a latency-promoting activity. We created and analyzed recombinant viruses lacking segments or individual open reading frames (ORFs) in the ULb' region. One 5-kb segment, and more specifically the UL138 ORF, was required for HCMV to establish and/or maintain a latent infection in hematopoietic progenitor cells infected in vitro. This is the first functional demonstration of a virus-coded sequence required for HCMV latency. Importantly, UL138 RNA was expressed in CD34+ cells and monocytes from HCMV-seropositive, healthy individuals. UL138 might be a target for antivirals against latent virus.
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