Investigation of genetic variability, expression in vitro and in vivo, and functional properties of the human cytomegalovirus IL10 proteins

Abstract

Human Cytomegalovirus (HCMV) can cause a variety of health disorders that can lead to death in immunocompromised individuals and neonates. The HCMV lifecycle comprises both a lytic (productive) and a latent (non-productive) phase. HCMV lytic infection occurs in a wide range of terminally differentiated cell types. HCMV latency has been less well studied, but one characterized site of latency is in precursor cells of the myeloid lineage. All known viral genes are expressed during a lytic infection and a subset of these are also transcribed during latency. The UL111A gene which encodes the viral IL-10, a homologue of the human IL-10, is one of these genes. During infection, different transcript isoforms of UL111A are generated by alternative splicing. The most studied of the UL111A isoforms are cmvIL-10 (also termed the 'A' transcript) and LAcmvIL-10 (also termed the 'B' transcript), the latter being a well characterized latency associated transcript. Both isoforms can downregulate class II, however they differ in a number of other immunomodulatory properties, such as the ability to bind the IL10 receptor and induce signalling through STAT3. There are also a number of other isoforms which have been identified which are expressed by differential splicing during lytic infection termed C, D, E, F and G, although these have been less extensively studied. This project aims to study the functional properties of the HCMV IL10 isoforms, in special the isoforms C, D, E, F, G and H, the last identified in our laboratory. In addition, we propose to investigate the expression and relative levels the HCMV IL10 transcripts samples from HCMV positive healthy and immunosupressed individuals and analyze presence of variability in the UL111A gene and their correlation with HCMV disease. (AU)