Manipulation of the innate immune response by human papillomaviruses

Hong, Siqi; Laimins, Laimonis A.

doi:10.1016/j.virusres.2016.11.004

Cited by 46 publications

(43 citation statements)

References 58 publications

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“…Escape from innate immune surveillance appears to be the hallmark of HPV infections (6,7,60). Although some mechanisms of immune evasion by HPVs, especially HPV16, have been characterized, they were mostly based on results obtained from KCs overexpressing only E6 and E7 or nonepithelial cells, thereby hampering data interpretation (17)(18)(19)(20)(21).…”

Section: Discussionmentioning

confidence: 99%

“…niaid.nih.gov/]. Although it has been known for quite some time that HPVs are able to evade the innate immune response and persist in the host, the molecular mechanisms regulating these critical events have only recently begun to emerge and still remain largely uncharacterized (5)(6)(7). Thus, gaining mechanistic insights into the immune escape by HPVs would allow us to better understand how these viruses can favor cancer progression.…”

mentioning

confidence: 99%

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HPV18 Persistence Impairs Basal and DNA Ligand–Mediated IFN-β and IFN-λ1 Production through Transcriptional Repression of Multiple Downstream Effectors of Pattern Recognition Receptor Signaling

Albertini

Cigno

Calati

et al. 2018

The Journal of Immunology

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Although it is clear that high-risk human papillomaviruses (HPVs) can selectively infect keratinocytes and persist in the host, it still remains to be unequivocally determined whether they can escape antiviral innate immunity by interfering with pattern recognition receptor (PRR) signaling. In this study, we have assessed the innate immune response in monolayer and organotypic raft cultures of NIKS cells harboring multiple copies of episomal HPV18 (NIKSmcHPV18), which fully recapitulates the persistent state of infection. We show for the first time, to our knowledge, that NIKSmcHPV18, as well as HeLa cells (a cervical carcinoma-derived cell line harboring integrated HPV18 DNA), display marked downregulation of several PRRs, as well as other PRR downstream effectors, such as the adaptor protein stimulator of IFN genes and the transcription factors IRF1 and 7. Importantly, we provide evidence that downregulation of stimulator of IFN genes, cyclic GMP-AMP synthase, and retinoic acid-inducible gene I mRNA levels occurs at the transcriptional level through a novel epigenetic silencing mechanism, as documented by the accumulation of repressive heterochromatin markers seen at the promoter region of these genes. Furthermore, stimulation of NIKSmcHPV18 cells with salmon sperm DNA or poly(deoxyadenylic-deoxythymidylic) acid, two potent inducers of PRR signaling, only partially restored PRR protein expression. Accordingly, the production of IFN-β and IFN-λ was significantly reduced in comparison with the parental NIKS cells, indicating that HPV18 exerts its immunosuppressive activity through downregulation of PRR signaling. Altogether, our findings indicate that high-risk human papillomaviruses have evolved broad-spectrum mechanisms that allow simultaneous depletion of multiple effectors of the innate immunity network, thereby creating an unreactive cellular milieu suitable for viral persistence.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

HPV18 Persistence Impairs Basal and DNA Ligand–Mediated IFN-β and IFN-λ1 Production through Transcriptional Repression of Multiple Downstream Effectors of Pattern Recognition Receptor Signaling

Albertini

Cigno

Calati

et al. 2018

The Journal of Immunology

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“…There is accumulating evidence that the HPV E6 and E7 oncoproteins also have important roles in the modulation of innate immune responses, a prerequisite for persistent infection and ultimately tumorigenesis (34)(35)(36). While a role for E6 and E7 in inhibiting the signal transduction by TLRs and the cGAS-STING pathway has been reported (37)(38)(39), it is unknown whether either of the two proteins plays a role in HPV evasion of other innate immune sensing pathways, in particular the RIG-I signaling pathway.…”

mentioning

confidence: 99%

The Human Papillomavirus E6 Oncoprotein Targets USP15 and TRIM25 To Suppress RIG-I-Mediated Innate Immune Signaling

Chiang

Pauli

Biryukov

et al. 2018

J Virol

107

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Retinoic acid-inducible gene I (RIG-I) is a key pattern recognition receptor that senses viral RNA and interacts with the mitochondrial adaptor MAVS, triggering a signaling cascade that results in the production of type I interferons (IFNs). This signaling axis is initiated by K63-linked ubiquitination of RIG-I mediated by the E3 ubiquitin ligase TRIM25, which promotes the interaction of RIG-I with MAVS. USP15 was recently identified as an upstream regulator of TRIM25, stabilizing the enzyme through removal of degradative K48-linked polyubiquitin, ultimately promoting RIG-I-dependent cytokine responses. Here, we show that the E6 oncoprotein of human papillomavirus type 16 (HPV16) as well as of other HPV types form a complex with TRIM25 and USP15 in human cells. In the presence of E6, the K48-linked ubiquitination of TRIM25 was markedly increased, and in line with this, TRIM25 degradation was enhanced. Our results further showed that E6 inhibited the TRIM25-mediated K63-linked ubiquitination of RIG-I and its CARD-dependent interaction with MAVS. HPV16 E6, but not E7, suppressed the RIG-I-mediated induction of IFN-β, chemokines, and IFN-stimulated genes (ISGs). Finally, CRISPR-Cas9 gene targeting in human keratinocytes showed that the TRIM25-RIG-I-MAVS triad is important for eliciting an antiviral immune response to HPV16 infection. Our study thus identifies a novel immune escape mechanism that is conserved among different HPV strains and further indicates that the RIG-I signaling pathway plays an important role in the innate immune response to HPV infection. Persistent infection and tumorigenesis by HPVs are known to require viral manipulation of a variety of cellular processes, including those involved in innate immune responses. Here, we show that the HPV E6 oncoprotein antagonizes the activation of the cytoplasmic innate immune sensor RIG-I by targeting its upstream regulatory enzymes TRIM25 and USP15. We further show that the RIG-I signaling cascade is important for an antiviral innate immune response to HPV16 infection, providing evidence that RIG-I, whose role in sensing RNA virus infections has been well characterized, also plays a crucial role in the antiviral host response to small DNA viruses of the family.

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“…Innate immunity is the first line of defense against extra- and intracellular pathogens, and detects the various pathogens invading the body and activates the cells of the adaptive immunity. The epithelium is the outermost physical and chemical shield against infections and the innate immune system is the protector in tissues and the circulation [13]. The main cellular players of innate immunity against viruses like HPV are macrophages, Langerhans cells (LCs), and the natural killer (NK) cells in concert with interferons, defenses, and the complement system.…”

Section: Introductionmentioning

confidence: 99%

From HPV Infection to Lesion Progression: The Role of HLA Alleles and Host Immunity

et al. 2019

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Persistent high-risk human papillomavirus (HPV) infection has been associated with increased risk for cervical precancerous lesions and cancer. The host’s genetic variability is known to play a role in the development of cervical cancer. The human leukocyte antigen (HLA) genes are highly polymorphic and have shown to be important risk determinants of HPV infection persistence and disease progression. HLA class I and II cell surface molecules regulate the host’s immune system by presenting HPV-derived peptides to T-cells. The activation of T-cell response may vary depending on the HLA allele polymorphism. The engagement of the T-cell receptor with the HPV peptide-HLA complex to create an active costimulatory signal is essential for the activation of the T-cell response. Functional peptide presentation by both HLA class I and II molecules is needed to activate efficient helper and effector T-cell responses in HPV infection recognition and clearance. Some of these HLA risk alleles could also be used as preventive tools in the detection of HPV-induced cervical lesions and cancer. These HLA alleles, together with HPV vaccines, could potentially offer possible solutions for reducing HPV-induced cervical cancer as well as other HPV-related cancers.

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Manipulation of the innate immune response by human papillomaviruses

Cited by 46 publications

References 58 publications

HPV18 Persistence Impairs Basal and DNA Ligand–Mediated IFN-β and IFN-λ1 Production through Transcriptional Repression of Multiple Downstream Effectors of Pattern Recognition Receptor Signaling

HPV18 Persistence Impairs Basal and DNA Ligand–Mediated IFN-β and IFN-λ1 Production through Transcriptional Repression of Multiple Downstream Effectors of Pattern Recognition Receptor Signaling

The Human Papillomavirus E6 Oncoprotein Targets USP15 and TRIM25 To Suppress RIG-I-Mediated Innate Immune Signaling

From HPV Infection to Lesion Progression: The Role of HLA Alleles and Host Immunity

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