Peer-review started: March 21, 2016
First decision: April 19, 2016
Revised: May 3, 2016
Accepted: July 11, 2016
Article in press: July 13, 2016
Published online: August 12, 2016
Before a pathogen even enters a cell, intrinsic immune defenses are active. This first-line defense is mediated by a variety of constitutively expressed cell proteins collectively termed “restriction factors” (RFs), and they form a vital element of the immune response to virus infections. Over time, however, viruses have evolved in a variety ways so that they are able to overcome these RF defenses via mechanisms that are specific for each virus. This review provides a summary of the universal characteristics of RFs, and goes on to focus on the strategies employed by some of the most important RFs in their attempt to control human cytomegalovirus (HCMV) infection. This is followed by a discussion of the counter-restriction mechanisms evolved by viruses to circumvent the host cell’s intrinsic immune defenses. RFs include nuclear proteins IFN-γ inducible protein 16 (IFI16) (a Pyrin/HIN domain protein), Sp100, promyelocytic leukemia, and hDaxx; the latter three being the keys elements of nuclear domain 10 (ND10). IFI16 inhibits the synthesis of virus DNA by down-regulating UL54 transcription - a gene encoding a CMV DNA polymerase; in response, the virus antagonizes IFI16 via a process involving viral proteins UL97 and pp65 (pUL83), which results in the mislocalizing of IFI16 into the cytoplasm. In contrast, viral regulatory proteins, including pp71 and IE1, seek to modify or disrupt the ND10 proteins and thus block or reverse their inhibitory effects upon virus replication. All in all, detailed knowledge of these HCMV counter-restriction mechanisms will be fundamental for the future development of new strategies for combating HCMV infection and for identifying novel therapeutic agents.
Core tip: Cellular “restriction factors”, active before human cytomegalovirus (HCMV) enters the cells, form a component of the intrinsic resistance to virus infection. Examples of such factors are hDaxx, promyelocytic leukemia, Sp100 - components of ND10 - and IFN-γ inducible protein 16 (IFI16), an Interferon-inducible protein of the Pyrin/HIN domain protein family. Over time, viruses have developed mechanisms to counteract ND10 and IFI16 through viral proteins, such as IE1 and pp71, or UL97 and pp65, respectively. Detailed knowledge of these mechanisms will provide new competencies useful to control HCMV infection and, in turn, contribute to the development of novel therapeutic approaches.