Review of Medical Microbiology & Immunology: A Guide to Clinical Infectious Diseases, 15e

Chapter 37: Herpesviruses, Poxviruses, & Human Papilloma Virus

HUMAN PAPILLOMAVIRUS
Diseases

Human papillomavirus (HPV) causes papillomas, which are benign tumors of squamous cells (e.g., warts on the skin). Some HPV types, especially types
16 and 18, cause carcinoma of the cervix, penis, and anus. HPV infection is the most common sexually transmitted infection in the United States.

Important Properties

Papillomaviruses are nonenveloped viruses with double-stranded circular DNA and an icosahedral nucleocapsid (see Table 37–2). The HPV genome has
seven early genes (E1–E7) and two late genes (L1 and L2). The early genes encode proteins involved in the synthesis of viral mRNA and in the replication
of the progeny DNA genomes, and the late genes encode the structural proteins of the progeny virions.

Two of the early genes, E6 and E7, are implicated in carcinogenesis. They encode proteins that inactivate proteins encoded by tumor suppressor genes in
human cells (e.g., the p53 gene and the retinoblastoma [RB] gene, respectively). Inactivation of the p53 and RB proteins is an important step in the
process by which a normal cell becomes a cancer cell.

There are at least 100 types of papillomaviruses, classified primarily on the basis of DNA restriction fragment analysis. There is a pronounced
predilection of certain types to infect certain tissues. For example, skin warts are caused primarily by HPV-1 through HPV-4, whereas genital warts are
usually caused by HPV-6 and HPV-11. Approximately 30 types of HPV infect the genital tract.

Summary of Replicative Cycle

A er attachment and uncoating, the genome DNA moves to the nucleus. Messenger RNA is synthesized by host cell RNA polymerase with early viral
protein E2 acting as a transcriptional activator. Early viral protein E1 acts as a helicase that separates the DNA strands of the incoming viral genome. This
allows the host cell DNA polymerase to synthesize the progeny DNA genomes. The initial progeny genomes are maintained as episomes in the nucleus.
Most of the synthesis of progeny viral DNA occurs in conjunction with cellular DNA synthesis during S phase.

Late mRNAs encode both the major structural protein (L1) and the minor structural protein (L2). L1 protein comprises the capsid of HPV virions. L1 has
the ability to self-assemble into capsids in vitro, and it is this form that is the immunogen in the HPV vaccine. L2 protein aids in the packaging of genome
DNA into the progeny virions as well as in uncoating the genome when they infect the next cell.

In human tissues, infectious virus particles are found in the terminally di erentiated squamous cells rather than in the basal cells (Figure 37–12A). Note
that HPV initially infects the cells of the basal layer in the skin, but no virus is produced by the basal cells. Rather, infectious virions are produced by
squamous cells on the surface, which enhances the likelihood that e icient transmission will occur.

FIGURE 37–12
A. Replication of human papillomavirus (HPV) in the skin. HPV initiates replication in the basal cells of the skin at site of abrasion to skin surface. Small
black dots in nucleus of three cells represent viral genome DNA. Early protein synthesis occurs followed by progeny genome synthesis. Late proteins are
then produced and progeny virions are released from squamous cells on the surface of the skin. Large black dots at top of figure represent progeny
virions. B. Malignant transformation by HPV in the skin. HPV initiates replication in the basal cells of the skin. Early protein synthesis occurs. Viral DNA
integrates into cell DNA and large amounts of viral E6 and E7 proteins are produced. E6 and E7 proteins inactivate tumor suppressor proteins p53 and RB
and the cell becomes malignant. No late viral proteins and no progeny virions are produced.
In malignant cells, viral DNA is integrated into host cell DNA in the vicinity of cellular proto-oncogenes, and E6 and E7 are overexpressed (Figure 37–12B).
However, in latently infected, nonmalignant cells, the viral DNA is episomal, and E6 and E7 are not overexpressed. This di erence occurs because
another early gene, E2, controls E6 and E7 expression. The E2 gene is functional when the viral DNA is episomal but is inactivated when it is integrated.

Transmission & Epidemiology

Papillomaviruses are transmitted primarily by skin-to-skin contact, including genital contact. Micro-abrasions in the skin allow access to the basal
epithelial cells where infection begins (see Figure 37–12A).

Genital warts are among the most common sexually transmitted diseases. Skin warts are more common in children and young adults and tend to regress
in older adults. HPV transmitted from an infected mother to the neonate during childbirth causes warts in the mouth and in the respiratory tract,
especially on the larynx, of the infant. Many species of animals are infected with their own types of papillomaviruses, but these viruses are not an
important source of human infection.

Pathogenesis & Immunity

Papillomaviruses infect squamous epithelial cells and induce within those cells a characteristic perinuclear cytoplasmic vacuole. These vacuolated cells,
called koilocytes, are the hallmark of infection by these viruses (Figure 37–13).

FIGURE 37–13
Koilocytes. The black arrowhead points to a koilocyte, seen here in a biopsy specimen of cervical intraepithelial neoplasia caused by human
papillomavirus. Koilocytes have a small condensed nucleus and a large perinuclear cytoplasmic vacuole. 400× magnification. (Reproduced, with
permission, from Kemp WL, Burns DK, Brown TG. Pathology: The Big Picture. New York, NY: McGraw-Hill; 2008.)
Most warts are benign and do not progress to malignancy. However, HPV infection is associated with carcinoma of the uterine cervix and penis. The
proteins encoded by viral genes E6 and E7 interfere with the growth-inhibitory activity of the proteins encoded by the p53 and RB tumor suppressor
genes and thereby contribute to oncogenesis by these viruses. The E6 and E7 proteins of HPV-16 bind more strongly to p53 and RB proteins than the E6
and E7 proteins of HPV types not implicated in carcinomas—a finding that explains why HPV-16 causes carcinomas more frequently than the other types
of HPV.

Both cell-mediated immunity and antibody are induced by viral infection and are involved in the spontaneous regression of warts. Immunosuppressed
patients (e.g., patients with acquired immunodeficiency syndrome [AIDS]) have more extensive warts, and women infected with human
immunodeficiency virus (HIV) have a very high rate of carcinoma of the cervix.

Clinical Findings

Papillomas of various organs are the predominant finding. These papillomas are caused by specific HPV types. For example, skin and plantar warts
(Figure 37–14) are caused primarily by HPV-1 through HPV-4, whereas genital warts (condylomata acuminata) (Figure 37–15) are caused primarily by
HPV-6 and HPV-11. HPV-6 and HPV-11 also cause respiratory tract papillomas, especially laryngeal papillomas, in young children.

FIGURE 37–14
Papillomas (warts) on finger—note dry, raised verrucous lesions caused by human papillomavirus. (Reproduced with permission from Wol K, Johnson
R. Fitzpatrick’s eds. Color Atlas & Synopsis of Clinical Dermatology. 6th ed. New York, NY: McGraw-Hill; 2009.)

FIGURE 37–15
Papillomas (warts) on penis (condylomata acuminata)—note dry, raised verrucous lesions caused by human papillomavirus. (Reproduced with
permission from Wol K, Johnson R. Fitzpatrick’s eds. Color Atlas & Synopsis of Clinical Dermatology. 6th ed. New York, NY: McGraw-Hill; 2009.)
Carcinomas of the uterine cervix, the penis, and the anus, as well as premalignant lesions called intraepithelial neoplasia, are associated with infection
by HPV-16 and HPV-18. The premalignant lesions are named for the organ a ected (e.g., cervical intraepithelial neoplasia [CIN], penile intraepithelial
neoplasia [PIN]). Occult premalignant lesions of the cervix and penis can be revealed by applying acetic acid to the tissue. HPV-16 is also implicated as
the cause of oral cancers.

Laboratory Diagnosis

Infections are usually diagnosed clinically. The presence of koilocytes in the lesions indicates HPV infection. A PCR-based test can be used to detect the
presence of the DNA of 14 high-risk genotypes, including HPV-16 and HPV-18.

Diagnostic tests based on detection of antibodies in a patient’s serum or on isolation of the virus from a patient’s tissue are not used.

Treatment & Prevention

Topical imiquimod or podophyllin is used for the treatment of genital warts. Liquid nitrogen is commonly used for skin warts. Plantar warts can be
removed surgically or treated with salicylic acid topically. Cidofovir is useful in the treatment of severe HPV infections, especially in
immunocompromised patients.

The HPV vaccine is very e ective in preventing carcinoma of the cervix, anal carcinoma, and genital warts. Note that HPV vaccines have no e ect on
existing papillomas.

Gardasil 9 is the only HPV vaccine available in the United States as of 2017. It is a recombinant vaccine against nine types of HPV. It contains the major
(L1) capsid protein of types 6 and 11, which cause genital warts, and types 16 and 18, which are the two most common causes of cervical, penile, and
anal carcinoma. It also contains the L1 capsid protein of five more types (31, 33, 45, 52, and 58) that are less common causes of these cancers. It is
recommended for both males and females, between the ages of 9 and 26 years.

The role of cesarean section in preventing transmission of HPV from a mother with genital warts to her newborn is uncertain. Circumcision reduces the
risk of infection by HPV.

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