Papillomaviruses have icosahedral symmetry and are non-enveloped. Seventy-two capsomeres surround the genome. A major and minor capsid protein comprises the outer protein coat of the virus. Approximately 8000 base pairs comprise the closed, double stranded- circular HPV genome.

 Coding information for HPV exists on one strand; it is believed that transcription occurs in a clockwise direction from a single promoter region (P97). Three major regions comprise the HPV genome. The early region (E1-8) consists of genes responsible for transcription, plasmid replication, and transformation. The late region codes for the major (L1) and minor (L2) capsid proteins and the control region contains the regulatory elements for transcription and replication.

 Chart I - HPV Gene Coding Regions

It is believed that the HPV virus enters the body after slight trauma to the epithelium and needs terminally differentiated epithelial cells for replication. Late-region genes are expressed in the differentiated cells near the epithelium’s surface providing an easy mode of viral transmission. Early region genes are expressed in the basal cells of the epithelium but are unable to produce virus since these cells do not make the capsid proteins encoded by the late genes.

All types of HPV replicate only within the host cell’s nucleus, but the mechanism by which HPV types transform cells is unclear. Most studies focus on HPV-16 and HPV-18, the viruses most frequently associated with anogenital carcinomas. The HPV genome replicates as an extrachromosomal episome or plasmid in benign HPV-associated lesions. However, the viral DNA is often integrated into the host’s chromosome in malignant HPV associated lesions. E6 and E7 genes are strongly associated HPV-mediated carcinogenesis. Another study indicating a positive association between HPV 16 and high grade lesions, suggests that additional cofactors, such as cigarette smoking, may be required as a carcinogen to advance HPV-infected cells toward neoplastic progression.(1)

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HPV infection is common in women and is a major risk factor for cervical intraepithelial neoplasia (CIN) and invasive cervical cancer. HPV DNA has been detected in 80% to 90% of CIN 3 lesions and invasive cervical cancers. One study confirms that antibodies against defined HPV epitopes are associated with cervical cancer and provides evidence that seropositivities for HPV types 16,18 and 33 are associated with cervical cancer risk. (2)

Cervical cancer has been designated an AIDS-defining illness; in HIV-infected patients, the prevalence of HPV is 5 times that of the general population.(9) HIV seropositive women have a high rate of persistent HPV infections with the types of HPV that are strongly associated with the development of high grade squamous intraepithelial lesions and invasive cervical cancer. (10) The persistent HPV infections in HIV- seropositive women could explain the increased risk of cervical squamous intraepithelial lesions and invasive cervical cancer. Genital warts caused by HPV are commonly found in patients who are positive for antibodies to HIV. One study suggests that the severity and extent of HPV infection does not depend on the level of immunosuppression of the HIV+ patient. (11) Pap smears must be studied carefully and timely follow up is important for HIV-infected patients since the disease presents itself at a later stage and is less responsive to treatment. Presently, early detection and aggressive treatment and follow-up of pre-malignant lesions offer the best approach to the prevention of cervical cancer. (12) Currently there is no clear understanding of HPV latency, reactivation, subclinical infection without apparent disease, and the triggers required for malignant transformation. Below is one proposed model for transformation.

From Beutner, KR et al, "Human Papillomavirus and Human Disease." Am J Med 1997; 102(5A):9-15.

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HPV alone is not sufficient to progression to cervical cancer. A recent study demonstrates that cellular immune surveillance is important in the control of HPV information and development of CIN. Presentation to T cells of target viral peptides in the context of HLA molecules is influenced by genetic polymorphisms of both HPV and HLA and thereby influences the host response and clinical outcome of HPV infection. (4) Since HPV E6 and E7 are expressed constitutively in the majority of CIN lesions and carcinomas, they are targets for the immune response against HPV and are potential candidates for immunotherapy. In one study, a majority of CIN III patients demonstrated the presence of naturally occurring HPV-specific memory cytotoxic lymphocytes(CTLs) while no HPV-specific memory CTLs were detected in normal subjects. These findings provides information that may support the study of CTLs role in modulating cervical malignancy(5).

Th1-mediated cellular immune response appears to be significant in the immunological control of HPV. It has been shown that CD8 T- cells mount the primary immune response, and recognize HPV-type specific antigens; CD4 cells play a secondary role (J of Vir, white et al 1998). Important cytokines involved in the immune response include: IL-2, TNFg, and GM-CSF. Role of antibodies (Ab) in the immune response is unclear, though L1 and/or L2 have been shown to induce an Ab-specific immune response (Ann Med 1994).

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