Papovaviruses

The family Papovaviridae is comprised of two genera namely Polyomaviruses (poly – multiple, oma - tumor) and the Papilloma viruses. The Polyomaviruses contain the simian vacuolating virus (SV-40) . Papillomaviruses contain human and animal Papilloma viruses. They are ubiquitous in nature and affect humans, monkeys and mice. Infections caused by both the genera are species specific. These viruses are small, non-enveloped viruses containing circular, double stranded DNA.

Human infections caused by Polyomaviruses

JC virus and BK viral infections both belong to Polyomaviruses. The terms JC and BK are the initials of the patients in whom these viruses were first isolated. Both viruses were first isolated in 1971.

• Progressive multifocal leucoencephalopathy (PML): PML is attributed to JC viral infections. It is a progressive, demyelinating disease encountered in immunosuppressed patients and can be isolated from the brain tissue of affected patients. PML was first described in 1958 in patients suffering from Hodgkin’s lymphoma and chronic lymphocytic leukemia (CLL).  The infection frequently occurs in adulthood and remains dormant. Reactivation of the virus takes place in patients who are immunosuppressed by therapy, as seen in organ transplant patients, or disease such as AIDS and leukemia. PML is characterized by multiple foci of cerebral demyelination. Occasionally other parts of the central nervous system may also be involved. The areas surrounding the zones of demyelination show swollen oligodendrocytes with hyperchromatic nuclei and basophilic inclusion bodies. These cells contain the virus which can be observed by electron microscopy. The virus replicates in the nucleus and causes destruction of the myelin sheath. The surrounding astrocytes may sometimes undergo a malignant transformation. JCV is consistently associated with PML and the clinical features of the disease depend on the areas affected. Patients often die with six months of presenting with symptoms.
• BK virus has often been isolated from the urine or kidneys of immunocompromised patients. The infection usually occurs in childhood. Though the virus is known to remain dormant, there are a few reports of children with primary BKV infection suffering from acute respiratory disease or hemorrhagic cystitis. Reactivation of the virus of frequently leads to clinical disease, especially in immunocompromised patients. It has been observed that up to 40% of renal allograft recipients excrete the virus during the early months of transplantation. Reactivation is also common during pregnancy with up to 3% to 7% of women excreting the virus in their urine, especially in the second and the third trimesters. There is no evidence that BK virus is transmitted across the placenta.

Human infection with Papilloma viruses

The different types of Human Papilloma viruses (HPV) were recognized in the 1960s.Today, there are more than 100 types of HPV identified based on DNA hybridization studies. They were primarily classified as the causative agents of cutaneous and genital warts depending on the site of involvement. Types 1, 2, 3 and 4 usually affect the keratinized epithelium of the hands and feet. Types 6, 11, 16,18,31,33 and 45 are the common HPV types that are associated with mucosal epithelium of the anogenital or orolaryngeal region. HPV types 2 and 57 can infect both the skin and genital mucosa. The property of tissue tropism and genetic relatedness has been studied using molecular methods. Phylogenetic studies have clearly demonstrated that the cutaneous HPV types form one branch while the genital HPV types form a second branch.

• Cutaneous warts:  They commonly affect the keratinized epithelium of the hands and feet. Cutaneous warts are typically seen in children and adolescents. The immune system plays an important role in the progress of these lesions. Both T cell and  B cell system immune responses are observed with cutaneous HPV infections. The cellular immune response is important for the regression of the lesions. In patients with a deficient T cell function, cutaneous warts are likely to be extensive and recurrent. Patients suffering from epidermodysplasia verruciformis (EV), a rare genetic skin disorder in which there is selective deficiency of T cell clones, suffer from large extensive plane warts with HPV type 5 and 8 which persist for life. Similar lesions have also been seen in patients who have undergone organ transplants where T cell functions are often suppressed.
• Anogenital warts: They are also called as condyloma acuminata and are common among sexually active adults. In women, the lesions are seen on the vulva, on the vaginal walls or on the cervix. In men, the common sites are the shaft of the penis, peri-anal skin or the anal canal. Sub-clinical or latent infections are quite common and manifest when the immune functions are depressed. The acetic acid test can be performed to identify flat, non-condylomatous lesions. Application of 5% acetic acid to the cervix or the shaft of the penis causes whitening of the epithelium where there is a high concentration of nuclear material. Thus, this test is useful in identifying latent lesions in order to initiate early therapy. Prevalence of genital warts is greater in women than in men. HPV types 6 and 11 are commonly associated with benign penile or vulvar warts. Malignant and premalignant epithelial transformation of anogenital warts is associated with HPV type 16 and 18 commonly and rarely with types 31, 33and 45.
• Orolaryngeal warts: HPV types 6 and 11 are commonly associated with squamous papillomatas of the respiratory mucosa. These are common both in children and adults. While adults acquire the infections through orogenital contact, children become infected by swallowing the infected maternal genital secretions during birth. Recurrent respiratory papillomatosis has a bimodal age distribution with peak incidences in children less than 5 years of age and adults over 15 years of age. HPV types 2, 7, 13, and 32 are associated with oral warts. The 5% acetic acid test can be used to identify sub-clinical lesions. Heck’s disease is a similar kind of focal epithelial hyperplasia associated with HPV commonly seen in Eskimos. 
• Premalignant and malignant lesions: It is well known that the HPV types associated with genital warts have the greatest potential for malignant transformation. Accordingly, based on their oncogenic potential, different HPV types have been classified as low, intermediate and high risk for malignant transformation. HPV types 6 and 11 are associated with low grade disease whereas types 16 and 18 are associated with invasive cancers. It has been documented that 99% of invasive cervical cancers contain HPV DNA. Risk factors which favor the development of genital malignancies are as follows: 1. multiple sexual partners 2. Age of first intercourse (the younger the onset of intercourse the greater the risk for disease) 3. Use of oral contraceptives and 4. Occurrence of sexually transmitted diseases. Factors responsible for the malignant transformation at extra-genital sites are smoking, chewing betel-quid, exposure to UV light or ionizing radiation, immunosuppression and a genetic susceptibility towards malignant transformation.

HPV Vaccines used to prevent cervical cancers

A quadrivalent vaccine, Gardasil, which contains HPV- virus like particles (VLPs) is recommended for use in girls of 11 to 12 years of age, ideally before their first sexual contact. Vaccinations can, however, be given to girls from 13 years to 26 years of age if they have not completed their scheduled inocculations. It is administered as three intramuscular doses with the 2nd and 3rd doses given two and six months after the first dose. This vaccine protects against both cervical and genital warts and contains HPV types 6, 11, 16 and 18. The vaccine has no effect on existing disease.