Abstract
Human cytomegalovirus (CMV) is beta-herpesvirus that infects the majority of the population worldwide and establishes a lifelong relationship with its host by way of a latent infection. Although, CMV is of little consequence to healthy individuals, reactivation of CMV from latency can cause life-threatening disease in immunocompromised individuals such as bone marrow transplant recipients and AIDS patients. CMV establishes a latent infection in cells of the hematopoietic system. The focus of our work is to elucidate the mechanisms governing a latent infection and reactivation from latency. It is likely that both viral and cellular mechanisms govern the latent program. We have developed a novel in vitro model for CMV latency using primary human hematopoietic progenitors. Using this model to compare CMV infection in CD34+ hematopoietic subpopulations, the outcome of CMV infection was found to depend on the nature of the subpopulation of cells infected. Only primitive CD34+/CD38− progenitor cells harboured an infection with the hallmarks of latency. This subpopulation transiently expressed a unique subset of CMV genes in the absence of viral replication. Importantly, viral replication could be reactivated from this subpopulation. Other primitive (CD34+/c-kit+) and more mature (CD34+/CD38+ and CD34+/c-kit−) subpopulations resulted in an apparently abortive infection. Strikingly, a CD34+ subpopulation expressing a stem cell phenotype supported a productive infection. These results indicate that cellular determinants contribute to the outcome of HCMV infection in hematopoietic cells. Further, we have also demonstrated that viral determinants play a role in establishing a latent infection using our in vitro model. Comparing the clinical Toledo and FIX strains and the laboratory-adapted AD169 strain of CMV, only the clinical strains were able to establish an infection consistent with latency. AD169, by contrast, replicated productively. Genetic sequences unique to clinical strains have been identified and may contribute to its ability to establish a latent infection in vitro. These studies indicate that both viral and cellular determinants contribute to the establishment of CMV latency. Furthermore, these determinants may serve as targets for CMV disease prophylaxis following bone marrow transplantation or in AIDS patients.
In Vitro Model for the Study of the Dissociation of Increasing Antigenemia and Decreasing DNAemia and Viremia during Treatment of Human Cytomegalovirus Infection with Ganciclovir in Transplant Recipients
