Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2016 Aug 12;5(3):87-96.
doi: 10.5501/wjv.v5.i3.87.

Intrinsic host restriction factors of human cytomegalovirus replication and mechanisms of viral escape

Santo Landolfo  1 , Marco De Andrea  1 , Valentina Dell'Oste  1 , Francesca Gugliesi  1
Affiliations
Review

Intrinsic host restriction factors of human cytomegalovirus replication and mechanisms of viral escape

Santo Landolfo et al. World J Virol. .

Abstract

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.

Keywords: DNA sensors; Human cytomegalovirus; Intrinsic immunity; Restriction factors; Viral escape mechanisms.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Simplified model of host restrictions against human cytomegalovirus and mechanisms of viral escape. IFI16 recognizes HCMV-DNA in the nucleus. In the early phases of infection, HCMV-pp65 hijacks IFI16 to activate MIEP expression; later on the complex IFI16-pp65 blocks HCMV replication by inhibiting the action of Sp1 on UL54 promoter. IFI16 is not degraded, but it was stabilized by its interaction with pp65. To evade IFI16 antiviral activity, HCMV induces nuclear translocation of IFI16 upon recruitment of HCMV kinase UL97 to IFI16. In the cytoplasm, IFI16 activates STING-mediated antiviral cytokine expression. ND10 components (hDaxx, Sp100, PML) limit viral replication by silencing viral IE genes, inducing a transcriptionally inactive chromatin state of the MIEP via recruitment of ATRX or HDACs to the viral DNA. The viral pp71 binds to hDaxx for proteasome degradation and relieves MIEP repression. Degradation of hDaxx is preceded by the release of ATRX from ND10. IE1 promotes the dispersion of the ND10, by de-SUMOylation, with the consequent inhibition of PML oligomerization. HCMV: Human cytomegalovirus; IFI16: IFN-γ inducible protein 16; PYHIN: Pyrin/HIN domain; AIM2: Absent in melanoma 2; MIEP: Major immediate early promoter; ND10: Nuclear domain 10; ATRX: Alpha thalassemia and mental retardation syndrome X-linked; PML: Promyelocytic leukemia.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. McCormick AL, Mocarski ES. Viral modulation of the host response to infection. Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis. Cambridge: Cambridge University Press. [accessed 2016 Apr 19] In: Arvin A, Campadelli-Fiume G, Mocarski E, Moore PS, Roizman B, et al., editors. Available from: http://www.ncbi.nlm.nih.gov/books/NBK47417.
    1. Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell. 2010;140:805–820. - PubMed
    1. Bieniasz PD. Intrinsic immunity: a front-line defense against viral attack. Nat Immunol. 2004;5:1109–1115. - PubMed
    1. Bieniasz PD. Restriction factors: a defense against retroviral infection. Trends Microbiol. 2003;11:286–291. - PubMed
    1. Johnson WE. Rapid adversarial co-evolution of viruses and cellular restriction factors. Curr Top Microbiol Immunol. 2013;371:123–151. - PubMed