Cytomegalovirus (CMV) infection has been the most frequent infectious cause of death following bone marrow transplantation (BMT). Prevention of the disease caused by this infection requires understanding of how CMV is acquired, since some patients reactivate latent infection while others acquire the infection from exogenous sources, in particular blood products or bone marrow from donors previously exposed to CMV. The long-term objectives of the current proposal are to clarify the methods by which CMV infection occurs, to seek laboratory markers which can distinguish current (or predict development of CMV disease) from asymptomatic infection, and finally to improve prophylaxis and treatment of CMV disease and infections for patients following BMT. To this end, the following specific aims and studies are proposed: 1) To define the role of viremia in predicting CMV disease. Techniques will be used to allow rapid detection (by CMV antigenemia test) and characterization of viral interaction with blood cells of patients following BMT. Specific blood cells infected will be identified, the expression of specific viral mRNAs and proteins identified, and these observations correlated with clinical outcomes. These studies may identify characteristics which will predict which patients will remain asymptomatic and which will develop tissue damage from CMV. 2) To characterize the interaction of virus with lung cells obtained (by bronchoalveolar lavage (BAL), Patterns of viral mRNAs and protein expression in BAL cells will be compared with clinical courses of patients following BMT in an effort to identify indicators of current or predictors of future development of CMV interstitial pneumonitis, the most devastating complication of this infection. 3) To determine the role of bone marrow donor in transmitting CMV. Individual.strains of CMV from donor marrow will be identified using molecular techniques and compared to strains causing post-BMT infections in marrow recipients. These studies should clarify the role of the marrow donor, but may also shed light on the relative importance of blood products, marrow donor, and reactivation of endogenous virus from the recipient in causing CMV infection and disease. These studies may predict the success of prophylactic measures (e.g., giving seronegative blood products to seropositive recipients) for future studies. 4) To study the effect of prophylactic measures and early intervention in preventing CMV disease. Randomized studies of chemo-immunoprophylaxis (for seropositive individuals) and blood product manipulation (for seronegative individuals) are proposed. For all such studies laboratory investigations from the first 3 Aims will be correlated with outcomes. Rapid detection of viremia (Aim 1) will be used as a means of identifying early viremia which will then be treated to try to prevent the development of CMV disease. These studies represent a comprehensive approach to defining effective prophylaxis, for defining predictors of CMV disease, and for clarifying the methods of virus transmission. This should lead to improved understanding of virus interaction with the host and to better methods of prevention and early therapy of viral infection.
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