Viral Inhibition of PRR-Mediated Innate Immune Response: Learning from KSHV Evasion Strategies

Abstract

The innate immune system has evolved to detect and destroy invading pathogens before they can establish systemic infection. To successfully eradicate pathogens, including viruses, host innate immunity is activated through diverse pattern recognition receptors (PRRs) which detect conserved viral signatures and trigger the production of type I interferon (IFN) and pro-inflammatory cytokines to mediate viral clearance. Viral persistence requires that viruses co-opt cellular pathways and activities for their benefit. In particular, due to the potent antiviral activities of IFN and cytokines, viruses have developed various strategies to meticulously modulate intracellular innate immune sensing mechanisms to facilitate efficient viral replication and persistence. In this review, we highlight recent advances in the study of viral immune evasion strategies with a specific focus on how Kaposi’s sarcoma-associated herpesvirus (KSHV) effectively targets host PRR signaling pathways.

Differential Effects of Autophagy-Related 10 Protein on HCV Replication and Autophagy Flux Are Mediated by Its Cysteine44 and Cysteine135

“…In this study, it was verified that the ATG10 mutants without Cys 44 and Cys 135 also elevated the levels of il28a /IL28a, ifr-3 /IRF-3, and irf-7 /IRF-7. IRF-3 and IRF-7 could induce IFNs expression as interferon regulatory factors ( 46 , 47 ) by nuclear-translocation upon virus infection ( 48 ). In this study, the nuclear translocation and nuclear–cytoplasmic fractionation assays indicated that the ATG10 mutant proteins surprisingly translocated into the nucleus much like the ATG10S protein, but ATG10 and ATG10 ΔM43 did not.…”

KSHV-encoded viral interferon regulatory factor 4 (vIRF4) interacts with IRF7 and inhibits interferon alpha production

“…Hence, there exists a need for the viruses to manipulate the host immune surveillance mechanism to facilitate their propagation efficiently [1,8]. Because of this, KSHV encodes for various immunomodulatory proteins, including four vIRFs (vIRF1 to 4) that are homologous to cellular IRFs [17].…”

“…These IFNs are upregulated by interferon regulatory factors (IRFs), which serve as transcriptional factors [1]. Among them, IRF3 and IRF7 especially act as direct transducers of viral-mediated type I IFN gene induction.…”

Deregulation of HDAC5 by Viral Interferon Regulatory Factor 3 Plays an Essential Role in Kaposi's Sarcoma-Associated Herpesvirus-Induced Lymphangiogenesis

“…The KSHV genome encodes four types of viral interferon regulatory factors (vIRFs), vIRF1 to vIRF4, which are homologous to cellular IRFs, which are clustered within one genomic locus ( 18 – 20 ). Although all vIRFs inhibit both host interferon response and control cellular growth, differences in their activation characteristics result in distinct immune evasion strategies.…”

“…This enables efficient lifelong persistence and facilitates the development of KSHV-associated malignancy. Expression of vIRF3 is required for continuous proliferation of PEL cells ( 21 ) and causes dramatic changes in critical host pathways such as apoptosis, cell cycle, antiviral immune response, and tumorigenesis ( 9 , 18 – 20 ). It was previously shown that vIRF3 (also referred to as LANA-2) is constitutively expressed in B cell lymphotropic diseases, PEL, and MCD but not in KS tumors ( 22 ).…”