Herpes virus can modulate immune reactions

Virus proteins are able to modulate immune response

Kaposi's sarcoma-associated herpesvirus (KSHV) can modulate the innate immune response by producing various proteins. Damania Blossom, University of North Carolina, Chapel Hill, NC, USA presented experimental data at the CROI 2019 on 6 March 2019 in Seattle, Washington.

There are eight human herpes viruses that are widespread. They can be divided into 3 subgroups: Alpha, Beta, and Gamma. Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV 8), belongs to the gamma subgroup along with the Epstein-Barr virus (EBV). In humans, the virus is associated with Kaposi's sarcoma, primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). In these diseases, the virus can be detected in all tumor cells. In addition to endothelial cells and B cells, KHSV is found in monocytes, macrophages, and dendritic cells.

Like all herpes viruses, KHSV is a large double-stranded DNA virus that can dock to cell receptors with its receptors. After endocytosis, the virus enters the plasma and from there into the cell nucleus. Like all herpes viruses, the KSHV also has a pronounced virus latency. Sporadically, it can enter a replicative phase. An infection with this virus persists for life. The life cycle of the virus is controlled by the immune system.

The innate immune system has a series of Pattern Recognition Receptors (PRRs) as guardians in the cells, which are located on the cell surface, in the cytoplasm or in the cell nucleus. When a virus or bacterium enters the cell, it comes into contact with these PRRs. In the cell membrane area, the pathogen comes into contact with toll-like receptors such as TLR1,2,4-6 or 10. In the cytosol, it encounters RLRs and NLRs and in the nucleus, too, there are various recognition possibilities.

cGAS-STING way activates interferon production

The working group around Blossom found that the cGAS-STING metabolic pathway is important for the recognition of KSHV. Cyclic-GMP-AMP(cGAMP)-Synthase (cGAS) is a DNA sensor, it is activated by binding to DNA and converts ATP and GTP into cGAMP. This binds to STING (stimulator of interferon genes) and activates it, which in turn leads to activation of TBK-1 and IRF3/7 (interferon response factors). The IRF switch on type 1 interferon production in the nucleus. cGAS-STING detects a number of pathogens, including HI viruses. Blossom and her colleagues were able to show that cGAS and STING are involved in IFN response during KSHV reactivation and replication. Both proteins, therefore, have an antiviral effect. Further experiments showed that depletion of cGAS/STING increased the expression of the viral genes of KSV during reactivation from the latency phase.

Virus proteins modulate the immune response

The researchers explain the lifelong survival of the virus in the body by the fact that the virus produces proteins that inhibit cGAS/STING. A viral version of IRF1 (vIRF1), which occurs in the cytoplasm and cell nucleus, inhibits the cellular IRFs. vIRF1-expressing cells inhibit IFN-beta production after DNA stimulation by various pathogens, such as HSV or E. coli. It is known about the mechanism of action of vIRF1 that it induces its effects through interaction with STING: By binding to STING, vIRF1 inhibits interaction with TBK1.

The protein NLRX1 also has a proviral effect and can disrupt the STING-TBK1 axis. A lack of NLRX1 slows down viral replication. The interferon response is amplified.

Source:
Blossom D. Modulation of host innate immunity at KSHV. CROI 2019, Seattle, Washington, March 5, 209, Abstract 55. http://www.croiconference.org/sessions/modulation-host-innate-immunity-kshv

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