HUMAN PAPILLOMA VIRUS – A REVIEW

Sameera Mohotti (BSc, MSc, MD(MA))

INTRODUCTION

HPV is one of the most common sexually transmitted viral diseases. It is
estimated that 80% of sexually active adults have been infected with one or more genital HPV types at one point of their life time. The prevalence of HPV is increasing worldwide. Although it is
difficult to estimate the overall prevalence of HPV infection, it is estimated that the prevalence could be as high as 20 million (Revzina 2005). The total health care cost associated with the screening and treatment of cervical cancer in the U.S. is estimated to be $6 billion per year (Koutsky 1997). A US sero prevalence study performed by Revizina et al revealed that the highest prevalence of
HPV is among college students and women attending STD clinics Data from clinics in Australia indicate a prevalence of 4- 13% among STD clinic attendants Following initial infection, HPV establishes latent infection, from which symptomatic recurrences may develop periodically (Revzina 2005),(Armstrong 1986).

The main aim of this review was to evaluate the current literature regarding the types of HPV, symptoms and its pathogenesis.

SPECTRUM OF HPV INFECTION

Over 200 types of HPV have been classified on the basis of their DNA sequence homology. 85 HPV genotypes are well characterized.

HPV can be grouped as high risk HPV and low risk HPV based on their association with cancer and precursor lesions. High risk HPV’s have a high oncogenic potentials. This group includes serotypes 16,18,31,33, 34, 35,39,45,51,52,56,58,59,66,68. Low risk HPV’s have less oncogenic potentials and usually results in the formation of low grade precancerous lesions. This group includes
serotypes 6, 11, 42, 43, 44. This difference in the capacity to induce malignant transformation is due to the functional difference seen in E6 and E7 proteins of the two groups (Burd 2003; Longworth and Laimins 2004).

Although many HPV infections are sub clinical, symptomatic HPV infection typically results in lesions. Each HPV serotype infects certain parts of the body and responsible for different types of lesions. According to the current classification system (Bethesda system) of HPV lesions, there are three main groups. They are anogenital warts, low grade squamous intraepithelial lesions (cervical / anal intraepithelial neoplasia and mild dysplasia) and high grade squamous intraepithelial lesions (moderate and severe dysplasia).Cervical/anal/vulvar/penile carcinomas usually develop from high grade squamous intraepithelial lesions (University 2001).

Genital warts (proliferative foci of epithelial keratinocytes infected with HPV) appear as bumps or abnormal growths in the genital area. This is one of the commonest clinically recognized disease manifestations of genital HPV. These are usually found in vulva, urethra, anus, and vagina and on the cervix. Warts are extremely contagious and they occasionally lead to cancer of the cervix in
women or cancer of the penis in men (Lacey 2005).

The presence of abnormal cells on the surface of the skin is called dysplasia.
Dysplasia is not a cancer and mild dysplasia is likely to self resolve. However, mild, moderate and severe dysplasia could be progressed in to a cancer, if not detected and treated at its early stage. Studies indicate that even adolescents with low grade squamous intraepithelial lesions and high grade squamous intraepithelial lesions are also at high risk for progression to high-grade cervical abnormalities (Wright, Pinto et al. 2004).



BASIC VIROLOGY



HPV is a nonenveloped, double stranded circular DNA virus with a diameter of 5.5 nm. The genome is approximately 8 Kb in size and encased in an icosahedral capsid which is composed of 72 capsomeres. Capsid comprises of an outer protein coat which consists of two capsid proteins, L1 (major) and L2 (minor) (Sapp, Volpers et al. 1995).

HPV genome is functionally divided in to 3 regions .They are the upstream regulatory region, early region and the late region. The upstream regulatory region involves in viral replication and also controls the transcription of some sequences in the early region. The early region of the genome encompasses 6 open reading frames (ORF’s) named E1, E2, E4, E5, E6 and E7. These encode proteins involved in viral replication, transcription and cellular transformation. E6 and E7 regions are responsible for the oncogenic properties of HPV. The late region encompasses two ORF’s and these encode L1 and L2 structural proteins which is necessary for capsid production (Sapp, Volpers et
al. 1995).

PRODUCTIVE HPV INFECTION

HPV gain entry into the host cells through the basal layer of the epithelium. In initial infection HPV is present as an episome. It has been proposed that HPV-6 attaches to the host cells via ?6-intergrin in the epithelium cells; where as, HPV16 and HPV 33 attach to host cells via cell surface heparin sulphate. The papilloma viral gene expressions are linked with the differentiation stages of the epithelium and virus multiplies as it progresses through the natural epithelial cell maturation (Giroglou, Florin et al. 2001).

During viral replication, the E1 gene product (E1 protein) binds to the viral origin of replication and this result in the extra chromosomal replication of the viral genome. The E2 gene product (E2 protein) down-regulates the E6 and E7 regions to allow the normal differentiation process of the cell. The capsid genes L1 and L2 synthesize the capsid protein and envelopes each episomal DNA in a protein capsid. The E4 gene product (E4 protein) is associated with the maturation and release of papilloma virus particles(Burd 2003),(Longworth and Laimins 2004).

The productive viral stage results in flat or papillary lesions. Since the papilloma virus replication goes hand in hand with the epithelial cell differentiations, as the lesions are formed the superficial and intermediate epithelial layers would contain a large amount of viral DNA. The accumulations of viral particles in the superficial epithelial layers provoke the cells to the koilocytosis cytopathic effect. This gives rise to koilocytes, in which the cellular nucleus is displaced to the side with a 'hollow' appearance of the cytoplasm. The virus particles are released as dying koilocytes are shed (zur Hausen 1991; Longworth and Laimins 2004).





PATHOGENESIS OF ONCOGENIC HPV

When a person gets infected with high-risk HPV, it may take up to 20 years for the
cancer changes to appear. This persistency of HPV infection is necessary for the malignant transformation of the cells. In HPV associated benign lesions, the HPV DNA is usually located extra chromosomal where as in HPV associated cancers , the HPV DNA is usually found integrated in to host genome. Integration of high risk HPV DNA in to the host cell disrupts the E2 region. This results in the loss of normal E2 down-regulation of E6 and E7 which leads to the up-regulation of the two HPV viral oncogenes; E6 and E7.These E6 and E7 gene products has the ability to destabilize the cell growth regulatory and modify the cellular environment in which it replicates (Jan M. M. Walboomers 1999; Yoshinouchi, Hongo et al. 1999; Burd 2003).

pRB and pRb related proteins are critical components of the cell cycle as they seize the
transcription factor E2F which is necessary for the functions of the cell cycle. When E7 proteins bind to the pRB, pRB-E2F complex gets disrupted and this results in the E2F liberation. This disruption affects the normal functions of the cell. E6 viral gene product, the E6 protein, targets the immunosuppressor protein p53 (low risk HPV type’s bind p53 in decreased affinity). The p53 protein prevents cells from completing the cell cycle and up-regulates genes involved in DNA repair, if it comes across any DNA damage. Another important function of the p53 protein is to instruct a cell with DNA damage to commit suicide. If the p53 function is inactivated then these damaged cells would continue to divide and accumulate mutations which would eventually lead to the formation of a tumor.

When E6 protein binds to p53, E6 associated ubiquitin ligase catalyzes ubiquitin ligase mediated p53 degradation. This destroys the tumor suppressive properties of p53 (Syrjanen 1999; Ha and Califano 2004).

The ability of E6 and E7 gene products to disrupt the cellular p53 and pRB protein functions result in, increase cell proliferation and genomic instability. Eventually the cell accumulates damaged DNA/mutations which may lead to the formation of fully transformed cancerous cells. The low risk HPV’s appear to be unable to integrate in to the host genome. But low risk serotypes like HPV 6, 11 may result in chromosomal instability which would lead to the accumulation of mutational events, which in turn may form fully transformed cancerous cells .In addition to the E6 and E7 protein function, methylation of viral DNA, telomere activations, humoral and immunogenic factors also contribute to the cellular transformations (Holowaty, Miller et al. 1999; Burd 2003).

REFERENCES

Armstrong, B. K., O. V. Allen, B. A. Brennan, I. A. Fruzynski, N. H. de Klerk, E. D. Waters, J.
Machin, and M. M. Gollow (1986). "Time trends in prevalence of cervical cytological abnormality in
women attending a sexually transmitted diseases clinic and their relationship to trends in sexual
activity and specific infections." Br J Cancer 54: 669-75.



Burd, E. M. (2003). "Human Papillomavirus and Cervical Cancer." Clin. Microbiol. Rev. 16: 1-17.


Burd, E. M. (2003). "Human Papillomavirus and Cervical Cancer." Clin. Microbiol. Rev. 16(1): 1-17.


Giroglou, T., L. Florin, et al. (2001). "Human Papillomavirus Infection Requires Cell Surface Heparan Sulfate." J. Virol. 75(3): 1565-1570.



Ha, P. K. and J. A. Califano (2004). "The role of Human Papilloma Virus in oral carcinogenesis." Crit Rev Oral Biol Med 15(4): 188-196.



Holowaty, P., A. B. Miller, et al. (1999). "Natural History of Dysplasia of the Uterine Cervix." J. Natl. Cancer Inst. 91(3): 252-258.



Jan M. M. Walboomers, M. V. J., M. Michele Manos, F. Xavier Bosch, J. Alain Kummer, Keerti V. Shah,
Peter J. F. Snijders, Julian Peto, Chris J. L. M. Meijer, Nubia Muñoz, (1999). "Human papillomavirus is a necessary cause of invasive cervical cancer worldwide." The Journal of Pathology 189(1): 12-19.



Koutsky, P., Laura. (1997). "Epidemiology of Genital Human Papillomavirus Infection." The American Journal of Medicine 102: 3-8.


Lacey, C. J. N. (2005). "Therapy for genital human papillomavirus-related disease." Journal of
Clinical Virology Supplement: Human Papillomaviruses 32(Supplement 1): 82-90.



Longworth, M. S. and L. A. Laimins (2004). "Pathogenesis of Human Papillomaviruses in Differentiating Epithelia." Microbiol. Mol. Biol. Rev. 68(2): 362-372.



Revzina, N. V., and R. J. Diclemente (2005). "Prevalence and incidence of human papillomavirus infection in women in the USA: a systematic review." Int J STD AIDS 16: 528-37.



Sapp, M., C. Volpers, et al. (1995). "Organization of the major and minor capsid proteins in human papillomavirus type 33 virus-like particles." J Gen Virol 76(9): 2407-2412.



Syrjanen, S. M., and K. J. Syrjanen. (1999). "New concepts on the role of human papillomavirus in cell cycle regulation." Ann Med 31: 175-187.



University, J. s. H. (2001). "HPV-induced Anal Dysplasia: What Do We Know and What Can We Do About It?" (Online)



Wright, J. D., A. B. Pinto, et al. (2004). "Atypical Squamous Cells of Undetermined Significance in Girls and Women ." Obstet Gynecol 103(4): 632-638.



Yoshinouchi, M., A. Hongo, et al. (1999). "Analysis by Multiplex PCR of the Physical Status of Human Papillomavirus Type 16 DNA in Cervical Cancers." J. Clin. Microbiol. 37(11): 3514-3517.



zur Hausen, H. (1991). “Human papillomaviruses in the pathogenesis of anogenital cancer." Virology
184: 9-13.