The Latency-Associated UL138 Gene Product of Human Cytomegalovirus Sensitizes Cells to Tumor Necrosis Factor Alpha (TNF-α) Signaling by Upregulating TNF-α Receptor 1 Cell Surface Expression

Abstract

Many viruses antagonize tumor necrosis factor alpha (TNF-␣) signaling in order to counteract its antiviral properties. One way viruses achieve this goal is to reduce TNF-␣ receptor 1 (TNFR1) on the surface of infected cells. Such a mechanism is also employed by human cytomegalovirus (HCMV), as recently reported by others and us. On the other hand, TNF-␣ has also been shown to foster reactivation of HCMV from latency. By characterizing a new variant of HCMV AD169, we show here that TNFR1 downregulation by HCMV only becomes apparent upon infection of cells with HCMV strains lacking the so-called ULb region. This region contains genes involved in regulating viral immune escape, cell tropism, or latency and is typically lost from laboratory strains but present in low-passage strains and clinical isolates. We further show that although ULb-positive viruses also contain the TNFR1-antagonizing function, this activity is masked by a dominant TNFR1 upregulation mediated by the ULb gene product UL138. Isolated expression of UL138 in the absence of viral infection upregulates TNFR1 surface expression and can rescue both TNFR1 reexpression and TNF-␣ responsiveness of cells infected with an HCMV mutant lacking the UL138-containing transcription unit. Given that the UL138 gene product is one of the few genes recognized to be expressed during HCMV latency and the known positive effects of TNF-␣ on viral reactivation, we suggest that via upregulating TNFR1 surface expression UL138 may sensitize latently infected cells to TNF-␣-mediated reactivation of HCMV.

Antagonistic Determinants Controlling Replicative and Latent States of Human Cytomegalovirus Infection

“…It is intriguing to speculate how these proteins may indirectly target one another through their interaction with cellular factors. While pUL138 has been shown to increase the levels of surface TNFR (31,32) and decrease the levels of surface MRP-1 (33), pUL135 has not been implicated in the counterregulation of these proteins. Our data suggest an elegant mechanism by which the virus coordinately regulates the expression of two determinants from a single genetic locus which oppose one another with respect to their effects on viral replication.…”

“…The pUL133-pUL138 complex appears to cooperatively function in promoting a latent infection, as viruses containing disruptions in pUL133, pUL138, or both replicate with increased efficiency in CD34 ϩ cells (27,30). pUL138 has been shown to increase cell surface levels of TNFR (31,32) and decrease surface levels of MRP-1 (33), although the significance of these surface alterations to viral infection is not completely understood. The roles of pUL135 and pUL136 have not yet been described.…”

Identification of immediate early gene X-1 as a cellular target gene of hcmv-mir-UL148D

“…Compared with the genome of the prototype laboratory strain, AD169, genomes of low-passage HCMV clinical isolates contain the UL/b' region, including ORFs UL133-UL151, considered as a critical candidate cluster to clinical pathogenesis (3). Although the UL/b' region is not essential to viral growth or replication (4), products of this region, including UL141, UL142 and UL144 have been experimentally identified to aid in viral escape from immune surveillance through interactions with cellular molecules (5)(6)(7)(8)(9)(10).…”

The Myeloid Transcription Factor GATA-2 Regulates the Viral UL144 Gene during Human Cytomegalovirus Latency in an Isolate-Specific Manner

“…The latency-expressed UL138 ORF has recently been shown to modulate cell surface expression of TNF receptor 1 (26,27), suggesting that TNF signaling may impact HCMV latency, as has been shown for mouse CMV (36). A second connection between the TNF family and UL/b= region proteins is highlighted by the UL144 ORF, which shows high homology to the herpesvirus entry mediator (HVEM/TNFRSF14) (37,38).…”

“…Several proteins encoded in this region have been established to perform immune-modulatory functions (26)(27)(28)(29)(30)(31)(32). Recently, this genomic locus has also been implicated in the regulation of experimental latency (18,33).…”