Cytomegalovirus induced up-regulation of LFA-3 (CD58) and ICAM-1 (CD54) is a direct viral effect that is not prevented by ganciclovir or foscarnet treatment.
Cytomegalovirus (CMV) is a major pathogen in transplant recipients and AIDS patients, and the virus may also play a role in allograft rejection. Previous work from this laboratory demonstrated increased cell surface expression of the adhesion molecules ICAM-1 (CD54) and LFA-3 (CD58) following CMV infection in vitro. We investigated whether the induction of adhesion molecules by CMV was a direct viral effect or secondary to cytokine induction. Cytokines known to up-regulate ICAM-1, such as TNFalpha or IL-1beta, were not detected in the supernatants of infected fibroblasts, and neutralizing antibodies against these cytokines did not abrogate the induction of either ICAM-1 or LFA-3 by CMV. Infected cell supernatants had increased levels of IL-6, IL-8 and IFNbeta however, the addition of recombinant forms of these cytokines did not affect adhesion molecule expression. Neither virus-free infected cell supernatants nor UV-inactivated virus up-regulated adhesion molecules, demonstrating that the induction of ICAM-1 and LFA-3 by CMV was a direct effect requiring infectious virus. Effective antiviral treatment with ganciclovir or foscarnet accentuated rather than abrogated the up-regulation of adhesion molecules, suggesting that CMV immediate early/early gene expression, which is not blocked by such treatment, was responsible for the adhesion molecule induction. Thus, despite effective antiviral therapy in the transplant recipient, CMV infected cells may continue to provide a focus of proinflammatory activity, which could contribute to immunopathology and/or accentuate graft rejection or graft-versus-host disease in vivo.
Department of Clinical Immunology, Royal Free Hospital School of Medicine, London, United Kingdom.
J L
JL
Craigen
J E
JE
Grundy
D000998:Antiviral Agents / Q000494:pharmacology; D016026:Bone Marrow Transplantation / Q000276:immunology; D018968:CD58 Antigens / Q000502:physiology*; D003587:Cytomegalovirus / Q000737:chemistry / Q000502:physiology*; D003586:Cytomegalovirus Infections / Q000150:complications; D005347:Fibroblasts / Q000821:virology; D017245:Foscarnet / Q000627:therapeutic use*; D015774:Ganciclovir / Q000627:therapeutic use*; D006084:Graft Rejection / Q000517:prevention & control; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology*; D016377:Organ Transplantation / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology*; D014764:Viral Proteins / Q000096:biosynthesis
D000998:Antiviral Agents; D018968:CD58 Antigens; D014764:Viral Proteins; D018799:Intercellular Adhesion Molecule-1; D017245:Foscarnet; D015774:Ganciclovir