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HPV

The human papillomavirus (HPV) is one of the most common causes of sexually transmitted disease in both men and women around the world. Today, more than 150 different HPV types have been cataloged and about 40 can infect the epithelial lining of the anogenital tract and other mucosal areas of the human body. Based on their association with cervical cancer and precursor lesions, HPVs can also be classified as high-risk (HR-HPV) and low-risk (LR-HPV) oncogenic types. LR-HPV types, such as HPV 6 and 11, can cause common genital warts or benign hyperproliferative lesions with very limited tendency to malignant progression, while infection with HR-HPV types, highlighting HPV 16 and 18, is associated with the occurrence of pre-malignant and malignant cervical lesions. HR-HPV types are also associated with many penile, vulvar, anal, and head and neck carcinomas, and contribute to over 40% of oral cancers.

The human papillomavirus (HPV) is a relatively small non-enveloped virus (approximately 50 to 60 nm in diameter) that contains a double-stranded closed circular DNA genome, associated with histone-like proteins and protected by a capsid formed by two late proteins, L1 and L2. The viral genome of the HPV consists of a single molecule of double-stranded and circular DNA, containing approximately 8000 base pairs and harboring an average of 8 open reading frames (ORFs).

Major capsid protein L1(P03101)

Function

Forms an icosahedral capsid with a T=7 symmetry and a 50 nm diameter. The capsid is composed of 72 pentamers linked to each other by disulfide bonds and associated with L2 proteins. Binds to heparan sulfate proteoglycans on cell surface of basal layer keratinocytes to provide initial virion attachment. This binding mediates a conformational change in the virus capsid that facilitates efficient infection. The virion enters the host cell via endocytosis. During virus trafficking, L1 protein dissociates from the viral DNA and the genomic DNA is released to the host nucleus. The virion assembly takes place within the cell nucleus. Encapsulates the genomic DNA together with protein L2.

Minor capsid protein L2 (P03107)

Function

Minor protein of the capsid that localizes along the inner surface of the virion, within the central cavities beneath the L1 pentamers. Plays a role in capsid stabilization through interaction with the major capsid protein L1. Once the virion enters the host cell, L2 escorts the genomic DNA into the nucleus by promoting escape from the endosomal compartments and traffic through the host Golgi network. Mechanistically, the C-terminus of L2 possesses a cell-penetrating peptide that protudes from the host endosome, interacts with host cytoplasmic retromer cargo and thereby mediates the capsid delivery to the host trans-Golgi network. Plays a role through its interaction with host dynein in the intracellular microtubule-dependent transport of viral capsid toward the nucleus. Mediates the viral genome import into the nucleus through binding to host importins. Once within the nucleus, L2 localizes viral genomes to host PML bodies in order to activate early gene expression for establishment of infection. Later on, promotes late gene expression by interacting with the viral E2 protein and by inhibiting its transcriptional activation functions. During virion assembly, encapsidates the genome by direct interaction with the viral DNA.

Replication protein E1 (P03114)

Function

ATP-dependent DNA helicase required for initiation of viral DNA replication. It forms a complex with the viral E2 protein. The E1-E2 complex binds to the replication origin which contains binding sites for both proteins. During the initial step, a dimer of E1 interacts with a dimer of protein E2 leading to a complex that binds the viral origin of replication with high specificity. Then, a second dimer of E1 displaces the E2 dimer in an ATP-dependent manner to form the E1 tetramer. Following this, two E1 monomers are added to each half of the site, which results in the formation of two E1 trimers on the viral ori. Subsequently, two hexamers will be created. The double hexamer acts as a bi-directional helicase machinery and unwinds the viral DNA and then recruits the host DNA polymerase to start replication.

Regulatory protein E2 (P03120)

Function

Plays a role in the initiation of viral DNA replication. A dimer of E2 interacts with a dimer of E1 in order to improve specificity of E1 DNA binding activity. Once the complex recognizes and binds DNA at specific sites, the E2 dimer is removed from DNA. E2 also regulates viral transcription through binding to the E2RE response element (5'-ACCNNNNNNGGT-3') present in multiple copies in the regulatory regions of the viral genome. Activates or represses transcription depending on E2RE's position with regards to proximal promoter elements including the TATA-box. Repression occurs by sterically hindering the assembly of the transcription initiation complex.

Protein E4 (P06922)

Function

Contributes to multiple aspects of the viral life cycle including viral genome amplification, suppression of suprabasal cell differentiation and egress of newly formed virions. Induces host cell cycle arrest at the G2 phase by associating with and preventing the nuclear entry of host CDK1/cyclin B1 complexes. Inhibits cellular DNA replication by preventing loading of host replication licensing proteins MCM2 and MCM7 onto chromatin. Within the cytoplasm, associates with host kinase SRPK1, a splicing factor regulator, and inhibits its activity. Therefore, E4 favors expression of late viral transcripts by inhibiting SRPK1-mediated phosphorylation of host serine-arginine (SR) proteins that have critical roles in mRNA metabolism. Late in the infectious cycle, E4 also acts to diminish the integrity of the keratinocyte by disrupting the keratin cytoskeleton and inducing apoptosis through alteration of mitochondrial function to facilitate egress of the newly formed virions.

Probable protein E5 (P06927)

Function

Acts to keep host cells in a proliferation-competent state upon differentiation. Enhances host epidermal growth factor receptor (EGFR) activation after stimulation by EGF by inhibiting EGFR internalization. Induces a redistribution of host caveolin-1 and glycosphingolipid (ganglioside GM1) components of lipid rafts to the plasma membrane. Since GM1s inhibit cytotoxic T-lymphocytes, block immune synapse formation, and enhance proliferative signaling by the EGFR, E5 may enhance immune evasion and cell proliferation via a common mechanism. E5 also alters endosomal pH by interacting with the vacuolar H+-ATPase, which is a proton pump responsible for acidifying cellular organelles. Additionally, E5 prevents transport of the major histocompatibility class I to the cell surface and retains the complex in the Golgi apparatus.

Protein E6 (P03126)

Function

Plays a major role in the induction and maintenance of cellular transformation. Acts mainly as an oncoprotein by stimulating the destruction of many host cell key regulatory proteins. E6 associates with host UBE3A/E6-AP ubiquitin-protein ligase, and inactivates tumor suppressors TP53 and TP73 by targeting them to the 26S proteasome for degradation. In turn, DNA damage and chromosomal instabilities increase and lead to cell proliferation and cancer development. The complex E6/E6AP targets several other substrates to degradation via the proteasome including host DLG1 or NFX1, a repressor of human telomerase reverse transcriptase (hTERT). The resulting increased expression of hTERT prevents the shortening of telomere length leading to cell immortalization. Other cellular targets including BAK1, Fas-associated death domain-containing protein (FADD) and procaspase 8, are degraded by E6/E6AP causing inhibition of apoptosis. E6 also inhibits immune response by interacting with host IRF3 and TYK2. These interactions prevent IRF3 transcriptional activities and inhibit TYK2-mediated JAK-STAT activation by interferon alpha resulting in inhibition of the interferon signaling pathway.

Protein E7 (P03129)

Function:

Plays a role in viral genome replication by driving entry of quiescent cells into the cell cycle. Stimulation of progression from G1 to S phase allows the virus to efficiently use the cellular DNA replicating machinery to achieve viral genome replication. E7 protein has both transforming and trans-activating activities. Induces the disassembly of the E2F1 transcription factor from RB1, with subsequent transcriptional activation of E2F1-regulated S-phase genes. Interferes with host histone deacetylation mediated by HDAC1 and HDAC2, leading to transcription activation. Plays also a role in the inhibition of both antiviral and antiproliferative functions of host interferon alpha. Interaction with host TMEM173/STING impairs the ability of TMEM173/STING to sense cytosolic DNA and promote the production of type I interferon (IFN-alpha and IFN-beta).

Protein E8^E2C (P0DKA0)

Function

Plays a role in limiting the replication of viral DNA in keratinocytes. Recruits the host NCoR/SMRT complex to viral replication foci to mediate repression of both viral replication and transcription.

Reference:

1.Fernandes, José & Fernandes, Thales. (2012). Human Papillomavirus: Biology and Pathogenesis. 10.5772/27154.

2.Munõz, N., Bosch, FX., de Sanjosé, S., Herrero, R., Castellsagué, X., Shah, KV., Snijders, PJF., Chris, JLM. & Meijer, MD. (2003). Epidemilogic classification of human papillomavirus types associated with cervical cancer. The New England Journal Medicine, Vol. 348, No 6, (Feb 2003), pp. 518-527, ISSN 0028-4793.

3.Stanley MA. (2010). Pathology and epidemiology of HPV infection in females. Gynecologic Oncology, Vol. 117, Suppl 2, (May 2010), pp. S5-10, ISSN 0090-8258.

4.Jo, H. & Kim, JW. (2005). Implications of HPV infection in uterine cervical cancer. Cancer Therapy, Vol. 3, (July 2005), pp 419-434, ISSN 1543-9135.