The virally encoded chemokine receptors US28 from human cytomegalovirus and ORF74 from human herpesvirus 8 are both constitutively active. We show that both receptors constitutively activate the transcription factors nuclear factor of activated T cells (NFAT) and cAMP response element binding protein (CREB) and that both pathways are modulated by their respective endogenous receptor ligands. By addition of specific pathway modulators against the G protein subunit Galphai, phospholipase C, protein kinase C, calcineurin, p38 MAP kinase, and MEK1, we find that the constitutive and ligand-dependent inductions are mediated by multiple yet similar pathways in both receptors. The NFAT and CREB transcription factors and their upstream activators are known inducers of host and virally encoded genes. We propose that the activity of these virally encoded chemokine receptors coordinates host and potentially viral gene expression similarly. As ORF74 is a known inducer of neoplasia, these findings may have important implications for cytomegalovirus-associated pathogenicity.

Open reading frame 74 (ORF74) of many ␥ 2 -herpesviruses encodes a CXC chemokine receptor. The molecular pharmacological profile of ORF74 from herpesvirus saimiri, ECRF3, is characterized here and compared with that of the well known ORF74 from human herpesvirus 8 (HHV8). The ECRF3 receptor bound the so-called ELR (Glu-Leu-Arg) CXC chemokines 125 I-CXCL1/GRO␣, 125 I-CXCL6/GCP-2, and 125 I-CXCL8/interleukin-8 with high affinity; but in contrast to ORF74 from HHV8, it did not bind the non-ELR CXC chemokine 125 I-CXCL10/IP10. Interestingly, the B max value for CXCL6/GCP-2 was 3-fold higher than the capacity for maximal binding of CXCL1/GRO␣ to ECRF3 and 85-fold higher than that of CXCL8/interleukin-8, despite similar affinities. Like ORF74 from HHV8, ECRF3 activated a broad range of pathways (G q , G i , and G 12/13 as well as the cAMP response element-binding protein, NF-B, NFAT, and serum response element transcription factors) in a ligandregulated manner, with CXCL6/GCP-2 being the most potent and efficacious agonist. ECRF3 signaled constitutively through G i and G 12/13 , but surprisingly not through G q . At the level of transcription factor activation, the serum response element was activated constitutively by ECRF3, whereas cAMP response element-binding protein, NFAT, and NF-B were only ligand-regulated. The maximal signaling capacities were similar for the two receptors; however, the ligand-regulated signaling was responsible for the major part of the total ECRF3 signaling and only for a minor part of the total HHV8 ORF74 signaling. The activation pattern of ECRF3 with constitutive activation of some (but not all) of the employed pathways has not been seen before in endogenous or virus-encoded chemokine receptors. The results suggest that the unique ligand selectivity of ECRF3 among ORF74 receptors could reflect differences in the cellular tropism of the ␥ 2 -herpesviruses.Chemokine receptors belong to the family of rhodopsin-like seven-transmembrane (7TM)

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The results reported here are from a 2-year follow-up study of 58 elderly patients in a continuing-care unit. Most of these patients were in a hyperosmolar state at the time of entry (mean plasma osmolality 304 +/- 8 mOsmol/kg). The survival of those patients with the highest osmolality (greater than 308 mOsmol/kg) was significantly reduced (p = 0.025), with an increased mortality at 2 years (15/20 patients, p = 0.053). There was no correlation between age and plasma osmolality (r = 0.02) and the effect of osmolality on survival was independent of age. Hyperosmolality was either a marker for, or a cause of, increased mortality in this group of frail elderly patients.