The Antiviral Restriction Factors IFITM1, 2 and 3 Do Not Inhibit Infection of Human Papillomavirus, Cytomegalovirus and Adenovirus

Warren, Cody J.; Griffin, Laura; Little, Alexander S.; Huang, I‐Chueh; Farzan, Michael; Pyeon, Dohun

doi:10.1371/journal.pone.0096579

Cited by 68 publications

(71 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In fact, mA3 was also found to have no impact on murine gammaherpesvirus 68, another DNA virus (66). We speculate that other type I interferon-responsive proteins may further augment the antiviral effect in early MmuPV1 infection in mice (53,67,68).…”

Section: Discussionmentioning

confidence: 83%

APOBEC3A Functions as a Restriction Factor of Human Papillomavirus

Warren

Guo

et al. 2015

J Virol

Self Cite

169

203

View full text Add to dashboard Cite

Human papillomaviruses (HPVs) are small DNA viruses causally associated with benign warts and multiple cancers, including cervical and head-and-neck cancers. While the vast majority of people are exposed to HPV, most instances of infection are cleared naturally. However, the intrinsic host defense mechanisms that block the early establishment of HPV infections remain mysterious. Several antiviral cytidine deaminases of the human APOBEC3 (hA3) family have been identified as potent viral DNA mutators. While editing of HPV genomes in benign and premalignant cervical lesions has been demonstrated, it remains unclear whether hA3 proteins can directly inhibit HPV infection. Interestingly, recent studies revealed that HPV-positive cervical and head-and-neck cancers exhibited higher rates of hA3 mutation signatures than most HPV-negative cancers. Here, we report that hA3A and hA3B expression levels are highly upregulated in HPV-positive keratinocytes and cervical tissues in early stages of cancer progression, potentially through a mechanism involving the HPV E7 oncoprotein. HPV16 virions assembled in the presence of hA3A, but not in the presence of hA3B or hA3C, have significantly decreased infectivity compared to HPV virions assembled without hA3A or with a catalytically inactive mutant, hA3A/E72Q. Importantly, hA3A knockdown in human keratinocytes results in a significant increase in HPV infectivity. Collectively, our findings suggest that hA3A acts as a restriction factor against HPV infection, but the induction of this restriction mechanism by HPV may come at a cost to the host by promoting cancer mutagenesis. IMPORTANCEHuman papillomaviruses (HPVs) are highly prevalent and potent human pathogens that cause >5% of all human cancers, including cervical and head-and-neck cancers. While the majority of people become infected with HPV, only 10 to 20% of infections are established as persistent infections. This suggests the existence of intrinsic host defense mechanisms that inhibit viral persistence. Using a robust method to produce infectious HPV virions, we demonstrate that hA3A, but not hA3B or hA3C, can significantly inhibit HPV infectivity. Moreover, hA3A and hA3B were coordinately induced in HPV-positive clinical specimens during cancer progression, likely through an HPV E7 oncoprotein-dependent mechanism. Interestingly, HPV-positive cervical and head-and-neck cancer specimens were recently shown to harbor significant amounts of hA3 mutation signatures. Our findings raise the intriguing possibility that the induction of this host restriction mechanism by HPV may also trigger hA3A-and hA3B-induced cancer mutagenesis. Human papillomaviruses (HPVs) are small, nonenveloped DNA viruses known as one of the most prevalent sexually transmitted pathogens. Among almost 200 different genotypes, ϳ24 high-risk HPV genotypes are causally associated with multiple human cancers, including nearly all cervical cancers and a portion of head-and-neck squamous cell carcinomas (1). From 1988 to 2004, the incidence of HPV-associ...

show abstract

Section: Discussionmentioning

confidence: 83%

APOBEC3A Functions as a Restriction Factor of Human Papillomavirus

Warren

Guo

et al. 2015

J Virol

Self Cite

169

203

View full text Add to dashboard Cite

show abstract

“…Using a sensitive next-generation sequencing approach, however, hA3A mutational signatures were not detected above the background in the HPV16 LCR and E2 regions of the viral genome. These investigators found that IFN-b induced the expression of hA3A, and this correlated with the ability to inhibit HPV-16 replication (Warren et al, 2014(Warren et al, , 2015. Finally, these investigators showed that upregulation of hA3A in normal immortalized keratinocytes was dependent on the presence of the HPV oncoprotein E7, and that knockdown of hA3A in keratinocytes resulted in an increase in the infectivity of HPV (Warren et al, 2015).…”

Section: A3a Restriction Of Dna Virusesmentioning

confidence: 92%

Role of the single deaminase domain APOBEC3A in virus restriction, retrotransposition, DNA damage and cancer

Wang

Schmitt

Guo

et al. 2016

Journal of General Virology

View full text Add to dashboard Cite

“…It is, therefore, of interest to determine if antiviral molecules that are known components of the innate or adaptive immune response to other infections could inhibit PV infection. In this regard, there has been a single report of type I interferons inhibiting in vitro HPV16 infection (6).…”

Section: Hpv Papillomavirus Interferon Ifn-␥ L2mentioning

confidence: 99%

Interferon Gamma Prevents Infectious Entry of Human Papillomavirus 16 via an L2-Dependent Mechanism

Day¹,

Thompson²,

Lowy³

et al. 2017

J Virol

View full text Add to dashboard Cite

In this study, we report that gamma interferon (IFN-␥) treatment, but not IFN-␣, -␤, or -treatment, dramatically decreased infection of human papillomavirus 16 (HPV16) pseudovirus (PsV). In a survey of 20 additional HPV and animal papillomavirus types, we found that many, but not all, PsV types were also inhibited by IFN-␥. Microscopic and biochemical analyses of HPV16 PsV determined that the antiviral effect was exerted at the level of endosomal processing of the incoming capsid and depended on the JAK2/STAT1 pathway. In contrast to infection in the absence of IFN-␥, where L1 proteolytic products are produced during endosomal capsid processing and L2/DNA complexes segregate from L1 in the late endosome and travel to the nucleus, IFN-␥ treatment led to decreased L1 proteolysis and retention of L2 and the viral genome in the late endosome/lysosome. PsV sensitivity or resistance to IFN-␥ treatment was mapped to the L2 protein, as determined with infectious hybrid PsV, in which the L1 protein was derived from an IFN-␥-sensitive HPV type and the L2 protein from an IFN-␥-insensitive type or vice versa.IMPORTANCE A subset of HPV are the causative agents of many human cancers, most notably cervical cancer. This work describes the inhibition of infection of multiple HPV types, including oncogenic types, by treatment with IFN-␥, an antiviral cytokine that is released from stimulated immune cells. Exposure of cells to IFN-␥ has been shown to trigger the expression of proteins with broad antiviral effector functions, most of which act to prevent viral transcription or translation. Interestingly, in this study, we show that infection is blocked at the early step of virus entry into the host cell by retention of the minor capsid protein, L2, and the viral genome instead of trafficking into the nucleus. Thus, a novel antiviral mechanism for IFN-␥ has been revealed. KEYWORDS HPV, papillomavirus, interferon, IFN-␥, L2P apillomaviruses (PV) are members of a large group of nonenveloped DNA tumor viruses that infect epithelial tissues of a wide range of vertebrate species. A subset of oncogenic mucosal human PV (HPV) types are the causal agents of cervical cancer. These high-risk types, especially HPV16, are also linked to vulvar, vaginal, anal, and oropharyngeal cancers (1). The cascade of viral protein expression is integrally tied to epithelial differentiation, with virion production only occurring in the terminally differentiated upper layers (2). These features combine to allow circumvention of host innate and adaptive immune responses, as few proinflammatory signals are elicited during these early stages (3). However, most PV infections that induce overt hyperproliferation are eventually cleared with the apparent involvement of lymphocytic infiltrates (reviewed in reference 4). Also, HPV infections are often superimposed on colonization with other microbial agents, e.g., in the female reproductive tract (reviewed in reference 5). It is, therefore, of interest to determine if antiviral molecules that are known compon...

show abstract

The Antiviral Restriction Factors IFITM1, 2 and 3 Do Not Inhibit Infection of Human Papillomavirus, Cytomegalovirus and Adenovirus

Cited by 68 publications

References 53 publications

APOBEC3A Functions as a Restriction Factor of Human Papillomavirus

APOBEC3A Functions as a Restriction Factor of Human Papillomavirus

Role of the single deaminase domain APOBEC3A in virus restriction, retrotransposition, DNA damage and cancer

Interferon Gamma Prevents Infectious Entry of Human Papillomavirus 16 via an L2-Dependent Mechanism

Contact Info

Product

Resources

About