Cell Activation Signals and the Pathogenesis of Human Cytomegalovirus

Abstract

Cytomegalovirus (CMV) infection induces a series of cellular responses that resemble those observed in cells activated by growth factors or hormones including: hydrolysis of phosphatidylinositol-4,5-bisphosphate; Ca²⁺ influx and an increase in the cytosolic free [Ca²⁺]; an increase in Na⁺ entry; and, increases in cellular levels of cyclic AMP and cyclic GMP. The time courses for some of these responses appear to be markedly protracted relative to those observed for growth factors. The prolonged physiologic responses in CMV-infected cells appear to be related to modifications in the intracellular environment that are associated with the development of cytomegaly and with the phasing of CMV-directed macromolecular synthesis. For example, as the infected cell enlarges, the rate of CMV DNA synthesis increases by about 4-fold, late nuclear inclusions develop and progeny viruses are formed. When the CMV-induced activation signals are inhibited or their physiologic responses are blocked, then the yields of infectious CMV are substantially reduced. Furthermore, perturbation of the cell cycle resulting from induction of the cell activation process by CMV may be causally related to the induction of cellular damage by CMV, even in the absence of productive infection. Accordingly, the CMV-induced pathophysiologic cell activation responses represent potential targets for novel antiviral therapy.

Constitutive Signaling of the Human Cytomegalovirus-encoded Receptor UL33 Differs from That of Its Rat Cytomegalovirus Homolog R33 by Promiscuous Activation of G Proteins of the Gq, Gi, and Gs Classes

“…It is known that, following CMV infection, effector responses such as inositol lipid hydrolysis, kinase activation, and arachidonic acid metabolism are increased within the host cell and are required to direct and control early viral gene expression and DNA replication (47). Here we show that HCMV also induces a strong activation of CRE, at early and late times post infection.…”

The Human Cytomegalovirus US28 Protein Is Located in Endocytic Vesicles and Undergoes Constitutive Endocytosis and Recycling

“…This viral US28 may have some propensity to bind fractalkine on target cells (Kledal et al, 1998) and would be inserted into the plasma membrane of the target cell after fusion. Whether this protein is responsible for cellular changes associated with G protein signaling (Albrecht et al, 1990) remains to be established. The possibility that other proteins, including the viral glycoproteins involved in fusion and entry, are located on endocytic membranes also remains to be established.…”

“…This protein binds with high affinity to several CC-chemokines such as macrophage inflammatory polypeptide (MIP)-1␣, MIP-1␤, monocyte chemotactic protein (MCP)-1, and regulated on activation normal T cell expressed and secreted (RANTES) (Neote et al, 1993;Gao and Murphy, 1994;Kuhn et al, 1995) as well as the CX 3 C-chemokine fractalkine (Kledal et al, 1998). At the cellular level, HCMV infection induces cellular changes, some of which are associated with G-protein signaling (Albrecht et al, 1990). Signal transduction through US28 has been observed as a transient increase in intracellular calcium in response to high CC-chemokine concentrations (Gao and Murphy, 1994;Vieira et al, 1998) and as an activation of the mitogen-activated protein kinase pathway in response to RANTES (Billstrom et al, 1998).…”

Human cytomegalovirus-induced immunosuppression. Relationship to tumor necrosis factor-dependent release of arachidonic acid and prostaglandin E2 in human monocytes.

“…CMV was shown to affect transmembrane signaling pathways (12)(13)(14) including the cAMP-dependent protein kinase A pathway (15,31). cAMP serves as a multifunctional relay for mitogenic stimuli acting as an intracellular signal for activation of eukaryotic cells.…”

“…CMV infection in vitro has been shown to affect cellular activation pathways of human fibroblasts. CMV was reported to induce the hydrolysis of phosphatidyl inositol 4,5 biphosphate (PIP 2 ), Ca 2 ϩ influx, and an increase in intracellular free Ca 2 ϩ , as well as increased cellular levels of cAMP and cGMP (12), and arachidonic acid (AA) metabolism (13,14). More recently, it has been reported that CMV affects transmembrane signaling pathways in CD4-positive T-lymphocytes.…”