Human cytomegalovirus (HCMV) : detection and elimination of infected blood cells in vitro, immune reactivity and complications following HCMV infection

Abstract

Human cytomegalovirus (HCMV) belongs to the herpes virus family and establishes life-long persistence in a latent state following a primary infection. HCMV disease causes high morbidity in immunosuppressed individuals, such as bone marrow and organ transplant patients. In these patients, HCMV can be reactivated either from the patient's own latent infection or from latent HCMV which may be transmitted by blood products or solid organ transplants.

In this study, HCMV was demonstrated to infect monocytes and a small subpopulation of T cells among peripheral blood mononuclear cells (PBMCs) in vitro. The CD13 molecule was found to be a common denominator for HCMV infected PBMCs, and was shown to be important for the early events of HCMV infection of cells in vitro. In addition, latent and productive HCMV infection was demonstrated to be exclusively present in CD13 positive PBMCs both in in vitro infected PBMCs and in PBMCs from acutely infected patients. These observations imply that there may be a possibility to specifically eliminate cells carrying latent HCMV before blood component transfusion or BMT. Due to frequent reports of transmission of HCMV infection by blood products from seronegative individuals, an analysis was performed to examine the presence of HCMV DNA in PBMCs from seropositive and seronegative healthy blood donors. Virus DNA was demonstrated in PBMCs from all seropositive and a majority of seronegative donors when analyzing samples over time. In addition, a specific cellular proliferative response against HCMV was demonstrated in PBMC samples from most seropositive and few seronegative individuals.

These results indicate the presence of a specific cellular immune response against HCMV in seronegative individuals and supports the findings of virus DNA in a substantial number of seronegative individuals. Thus, the serological testing of blood donors may not be an accurate method for identification of HCMV negative blood donors. Chronic graft-versus-host disease (GVHD) is an immunological complication following BMT, which is clinically associated with HCMV infection. Chronic GVHD has been suggested to be an autoimmune disease, but the specific target antigen as well as the mechanism for induction of this disease is unknown. Autoimmune diseases have been suggested to be associated with virus infection.

Since an infection may precipitate the development of autoimmune disease and HCMV particles have been shown to incorporate host cell-derived CD 13 in their envelope, an analysis of production of autoantibodies directed against CD13 was performed. CD13-specific autoantibodies were demonstrated in bone marrow transplant (BMT) patients who had experienced HCMV infection or disease. Furthermore, a clinical association was demonstrated between the presence of CD13-specific autoantibodies and the development of chronic GVHD in BMT patients. In addition, in vitro and in vivo binding of antibodies suggested a direct role of CD13-specific antibodies in the development of chronic GVHD. Several hypotheses for antibody-mediated tissue damage are discussed in relation to the known cellular localization and biological functions of CD13. Thus, our results imply a causative link between two of the major complications which occurs following BMT; HCMV infection and chronic GVHD. These findings further stresses the importance of prevention of HCMV transmission and early treatment of infection to avoid long term complications in BMT patients.