A Novel Human Cytomegalovirus Locus Modulates Cell Type-Specific Outcomes of Infection

PLoS Pathogens

Louis Cicchini¹  Michael Rak¹  Mahadevaiah Umashankar¹  Felicia Goodrum¹  Farah Bughio¹  Alex Petrucelli²  Kimberly L. Hamlin³  Devorah C. Goldman³  William H. Fleming³  Craig N. Kreklywich⁴  Daniel N. Streblow⁴  Patrizia Caposio⁴  Jay A. Nelson⁴ 

[1] BIO5 Institute, The University of Arizona, Tucson, Arizona, United States of America;Department of Immunobiology, The University of Arizona, Tucson, Arizona, United States of America;Oregon Stem Cell Center, Papé Family Pediatric Research Institute, Department of Pediatrics, and Center for Hematologic Malignancies Knight Cancer Institute, Oregon Health and Sciences University, Portland, Oregon, United States of America;Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, Oregon, United States of America

关键词: Viral replication;    Integral membrane proteins;    Fibroblasts;    Viral persistence;    latency;    Endothelial cells;    Immunoblotting;    Antibodies;    Mouse models;   

DOI  :  10.1371/journal.ppat.1002444

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Clinical strains of HCMV encode 20 putative ORFs within a region of the genome termed ULb′ that are postulated to encode functions related to persistence or immune evasion. We have previously identified ULb′-encoded pUL138 as necessary, but not sufficient, for HCMV latency in CD34+ hematopoietic progenitor cells (HPCs) infected in vitro. pUL138 is encoded on polycistronic transcripts that also encode 3 additional proteins, pUL133, pUL135, and pUL136, collectively comprising the UL133-UL138 locus. This work represents the first characterization of these proteins and identifies a role for this locus in infection. Similar to pUL138, pUL133, pUL135, and pUL136 are integral membrane proteins that partially co-localized with pUL138 in the Golgi during productive infection in fibroblasts. As expected of ULb′ sequences, the UL133-UL138 locus was dispensable for replication in cultured fibroblasts. In CD34+ HPCs, this locus suppressed viral replication in HPCs, an activity attributable to both pUL133 and pUL138. Strikingly, the UL133-UL138 locus was required for efficient replication in endothelial cells. The association of this locus with three context-dependent phenotypes suggests an exciting role for the UL133-UL138 locus in modulating the outcome of viral infection in different contexts of infection. Differential profiles of protein expression from the UL133-UL138 locus correlated with the cell-type dependent phenotypes associated with this locus. We extended our in vitro findings to analyze viral replication and dissemination in a NOD-scid IL2Rγcnull-humanized mouse model. The UL133-UL138NULL virus exhibited an increased capacity for replication and/or dissemination following stem cell mobilization relative to the wild-type virus, suggesting an important role in viral persistence and spread in the host. As pUL133, pUL135, pUL136, and pUL138 are conserved in virus strains infecting higher order primates, but not lower order mammals, the functions encoded likely represent host-specific viral adaptations.

【 授权许可】

CC BY