Abstract
Persistent infection with high-risk human papillomaviruses (HPVs) is the major risk factor associated with development of anogenital and oropharyngeal cancers. Initial infection by HPVs occurs into basal epithelial cells where viral genomes are established as nuclear episomes and persist until cleared by the immune response. Productive replication or amplification occurs upon differentiation and is dependent upon activation of the ataxia-telangiectasia mutated (ATM), ataxia telangiectasia and RAD3-related (ATR) DNA damage repair (DDR) pathways. In addition to activating DDR pathways, HPVs must escape innate immune surveillance mechanisms by antagonizing sensors, adaptors, interferons and antiviral gene expression. Both DDR and innate immune pathways are key host mechanisms that crosstalk with each other to maintain homeostasis of cells persistently infected with HPVs. Interestingly, it is still not fully understood why some HPV infections get cleared while others do not. Targeting of these two processes with antiviral therapies may provide opportunities for treatment of cancers caused by high-risk HPVs.
Highlights
Human papillomaviruses (HPVs) are important pathogens that are the causative agents of many anogenital as well as oral cancers [1]
The innate immune response consists of a variety of sensors, referred to as pattern recognition receptors (PRRs), that detect the presence of foreign components such as bacterial lipopolysaccharides or viral nucleic acids such as cyclic nucleotides, ssRNA or dsRNA, cytosolic dsDNA and RNA-DNA hybrids [83]
E6 binding to the GADD34/PP1 phosphatase complex directly inhibits phosphorylation of eIF2α [100], while HPV16 E6 relocates it to cytoplasmic clusters that phosphorylation of eIF2α [100], while HPV16 E6 relocates it to cytoplasmic clusters that co-localize with P-bodies [99]
Summary
Human papillomaviruses (HPVs) are important pathogens that are the causative agents of many anogenital as well as oral cancers [1]. HPV type 1 infects epithelia in the soles of feet and causes plantar or palmar warts, while cutaneous HPVs (e.g., HPV 5) are responsible for warts on hands. About one-third of HPV types infect the genital epithelia and are classified as high and low risk according to their propensity to be associated with human cancers. At least 10 types are designated high risk and are the causative agents of over 98% of cervical cancers as well as those of the anus and vulva [2]. Low-risk HPVs infect the genital epithelia (e.g., HPV 6, 11) but are rarely associated with cancer [4]. A need, exists to develop antivirals to treat cancers that develop in individuals, who are persistently infected.
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