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.