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 homolog 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 MHC class II, however they differ in a number of other immunomodulatory properties, such as the ability to bind the IL10 receptor and induce signaling 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. HCMV uses the viral IL-10 proteins to manipulate the immune system during lytic and latent phases of infection. In this review, we will discuss the literature on the viral IL-10 transcripts identified to date, their encoded proteins and the structures of these proteins as well as the functional properties of all the different isoforms of viral IL-10.
Highlights
Viruses have to face many challenges to become established in the host population
In this article we review and discuss the transcripts, protein structure and immune subversive mechanisms of the Human Cytomegalovirus (HCMV) viral interleukin 10 (IL10) isoforms during productive lytic and latent HCMV infections concentrating on its role in modulating infection in the myeloid lineage and comparing it to the structure and functions of human IL10 and other IL-10 homologs encoded by other herperviruses
The HCMV vIL10 proteins have a variety of immunosuppressive properties in different cell types
Summary
Viruses have to face many challenges to become established in the host population. Herpesviruses are extremely successful in overcoming such challenges as evidenced by their ability to establish lifelong infection (Sinclair and Poole, 2014; Collins-McMillen et al, 2018). With the expression of viral antigens during both lytic and latent infection, it is clear that the virus must have to continually evade host immune surveillance in vivo and, HCMV is able to perform this task very efficiently through multiple mechanisms (Jackson et al, 2011; Stack et al, 2012). One of the strategies used by HCMV to disable the immune system is to manipulate the immunoregulatory functions of cellular anti-inflammatory interleukin 10 (cIL-10) (Redpath et al, 2001) As part of this strategy, and similar to other herpesviruses, during coevolution with its host, HCMV has ‘captured’ a cIL-10 viral gene (UL111A) which expresses different IL-10 protein isoforms (Kotenko et al, 2000; Lockridge et al, 2000; Jenkins et al, 2004; Lin et al, 2008), which help manipulate the immune response to HCMV. In this article we review and discuss the transcripts, protein structure and immune subversive mechanisms of the HCMV viral IL10 (vIL-10) isoforms during productive lytic and latent HCMV infections concentrating on its role in modulating infection in the myeloid lineage and comparing it to the structure and functions of human IL10 and other IL-10 homologs encoded by other herperviruses
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