Important properties of papillomaviruses are listed in Table 1.

Table1. Important Properties of Papillomaviruses ^a

Classification

 The Papillomaviridae family is a very large virus family currently divided into 16 genera, of which five contain members that infect humans (Alpha-, Beta-, Gamma-, Mupa-, and Nupapillomavirus). The papillomaviruses are former members of the Papovaviridae family. Although papillomaviruses and polyomaviruses share similarities in morphology, nucleic acid composition, and transforming capabilities, differences in genome organization and biology led to their separation into distinct virus families. The papillomaviruses are slightly larger in diameter (55 nm) than the polyomaviruses (45 nm) and contain a larger genome (8 kbp vs 5 kbp). The organization of the papillomavirus genome is more complex (Figure 1). There is widespread diversity among papillomaviruses. Because neutralization tests cannot be done since there is no in vitro infectivity assay, papillomavirus isolates are classified using molecular criteria. Virus “types” are at least 10% dissimilar in the sequence of their L1 genes. Almost 200 distinct HPV types have been recovered.

Fig1. Map of the human papillomavirus genome (HPV-6, 7902 base pairs). The papillomavirus genome is circular but is shown linearized in the upstream regulatory region (URR). The URR contains the origin of replication and enhancer and promoter sequences. Early (E1–E7) and late (L1, L2) open reading frames and their functions are shown. All the open reading frames are on the same strand of viral DNA. Biologic functions are extrapolated from studies with the bovine papillomavirus. The organization of the papillomavirus genome is much more complex than that of a typical polyomavirus. (Reproduced with permission from Broker TR: Structure and genetic expression of papillomaviruses. Obstet Gynecol Clin North Am 1987;14:329. Copyright Elsevier.)

Papillomavirus Replication

Papillomaviruses are highly tropic for epithelial cells of the skin and mucous membranes. Viral nucleic acid can be found in basal stem cells, but late gene expression (capsid proteins) is restricted to the uppermost layer of differentiated keratinocytes (Figure 2). Stages in the viral replicative cycle are dependent on specific factors that are present in sequential differentiated states of epithelial cells. This strong dependence of viral replication on the differentiated state of the host cell is responsible for the difficulties in propagating papillomaviruses in vitro.

Fig2. Schematic representation of a skin wart (papilloma). The papillomavirus life cycle is tied to epithelial cell differentiation. The terminal differentiation pathway of epidermal cells is shown on the left. Events in the virus life cycle are noted on the right. Late events in viral replication (capsid protein synthesis and virion morphogenesis) occur only in terminally differentiated cells. (Reproduced with permission from Butel JS: Papovaviruses. In Baron S [editor]. Medical Microbiology, 3rd ed. Churchill Livingstone, 1991.)

Pathogenesis and Pathology

Transmission of viral infections occurs by close contact. Viral particles are released from the surface of papillomatous lesions. It is likely that microabrasions allow infection of proliferating basal layer cells at other sites or within different hosts.

Papillomaviruses cause infections at cutaneous and mucosal sites, sometimes leading to the development of different kinds of warts, including skin warts, plantar warts, flat warts, anogenital warts, laryngeal papillomas, and several cancers, including those of the cervix, vulva, penis and anus, and a subset of head and neck cancers (Table 2). The multiple types of HPV isolates are preferentially associated with certain clinical lesions, though distribution patterns are not absolute. HPV genital infections are sexually transmitted and represent the most common sexually transmitted disease in the United States. Cervical cancer is the second most frequent cancer in women worldwide (about 500,000 new cases annually) and is a major cause of cancer deaths in developing countries.

Table2. Examples of Association of Human Papillomaviruses with Clinical Lesions

Based on the relative occurrence of viral DNA in certain cancers, HPV types 16 and 18 are considered to be high cancer risk; about 16 other less common types are somewhat less frequently associated with neoplasms but are also considered high risk. Many HPV types are considered benign.

Integrated copies of viral DNA are usually present in cervical cancer cells, though HPV DNA is generally not integrated (episomal) in noncancerous cells or premalignant lesions. Skin carcinomas appear to harbor HPV genomes in an episomal state. Viral early proteins E6 and E7 are synthesized in cancer tissue. These are HPV-transforming proteins, able to complex with Rb and p53 and other cellular proteins.

The behavior of HPV lesions is influenced by immunologic factors. Cell-mediated immunity is important. The majority of HPV infections are cleared and become undetectable within 2–3 years. Development of HPV-associated carcinomas requires persistent infection.

Cervical cancer develops slowly, taking years to decades. It is thought that multiple factors are involved in progression to malignancy; however, persistent infection with a high-risk HPV is a necessary component to the process (Figure 3).

Fig3. Relationship among cervical human papillomavirus (HPV) infection, precancer, and cancer. The HPV curve shows the high incidence of infection soon after women initiate sexual activity and the subsequent decrease because many infections are self-limited and cleared. Precancer incidence curve illustrates the delay between acquisition of HPV infection and precancer development and that only a subset of infected women develop premalignant lesions. The cancer incidence curve shows the relatively long interval between precancer and progression to invasive cancer. (Reproduced with permission from Lowy DR, Schiller JT: Prophylactic human papillomavirus vaccines. J Clin Invest 2006;116:1167. Permission conveyed through Copyright Clearance Center, Inc. Modified from Schiffman M, Castle PE: The promise of global cervical-cancer prevention. N Engl J Med 2005;353:2101.)

Clinical Findings and Epidemiology

 An estimated 660 million people worldwide have HPV genital infections, the most common viral infection of the reproductive tract. An estimated 20 million Americans are infected, with about 6 million new infections occurring annually in the United States. The peak incidence of HPV infections occurs in adolescents and young adults younger than 25 years.

HPVs are accepted as the cause of anogenital cancers. Over 99% of cervical cancer cases and over 80% of anal cancer cases are linked to genital infections with HPVs. Papillomaviruses illustrate the concept that natural viral strains may differ in oncogenic potential. Although many different HPV types cause genital infections, HPV-16 or HPV-18 is found most frequently in cervical carcinomas, although some cancers contain DNA from other types, such as HPV type 31 (see Table 2). Epidemiologic studies indicate that HPV-16 and HPV-18 are responsible for more than 70% of all cervical cancers, with type 16 being most common. HeLa cells, a widely used tissue culture cell line derived many years ago from a cervical carcinoma, contain HPV-18 DNA.

Anal cancer is associated with high-risk HPV infection. Immunocompromised patients are especially at risk, as are men who have sex with men. Multiple HPV types have been commonly found in the anal canals of HIV-infected men in the latter group. Oropharyngeal cancers, a subset of head and neck squamous cell carcinomas, are also linked to HPV infections, especially by type 16. About 25% of mouth and 35% of throat cancers are associated with HPV. The oral cavities of both HIV-positive and HIV-negative individuals contain an abundant number of different HPV types.

The role of men as carriers of HPV as well as vectors for transmission of infections is well documented; however, most penile HPV infections in men are subclinical and do not result in HPV-associated disease.

Anogenital warts are usually (90%) caused by low-risk HPV types 6 and 11. Laryngeal papillomas in children, also called recurrent respiratory papillomatosis, are caused by HPV-6 and HPV-11, the same viruses that cause benign genital condylomas. The infection is acquired during pas sage through the birth canal of a mother with genital warts. Though laryngeal papillomas are rare, the growths may obstruct the larynx and must be removed repeatedly by surgical means. About 3000 cases of this disease are diagnosed annually; up to 3% of children will die.

There is a high prevalence of HPV DNA in normal skin from healthy adults. It appears that these asymptomatic HPV infections are acquired early in infancy. A great multiplicity of HPV types are detected in normal skin. Transmission is thought to occur from those in close contact with the child, with a high concordance (about 60%) between types detected in infants and their mothers.

Immunosuppressed patients experience an increased incidence of warts and cancer of the cervix. All HPV- associated cancers occur more frequently in persons with HIV/AIDS.

Prevention and Control

Widespread use of the Papanicolaou (Pap) smear for cervical cancer detection has led to substantial decrease in deaths due to cervical cancer. The cytological test aims to detect precancerous cellular changes in morphology, allowing for lesion removal prior to cancer development. Testing for the presence of HPV types 16 and 18, or for all high-risk HPV (HR-HPV) types, enhances the detection sensitivity and specificity for precancerous lesions. Laboratory testing is by DNA hybridization or PCR methods. Testing algorithms include reflex testing of abnormal Pap smears, co-testing, or primary HR HPV screening. Studies have indicated that primary HR HPV screening algorithms may be the preferred method in most settings. Women younger than 20 years should not be tested due to frequent HPV clearance in initial infections.

Vaccines against HPV are expected to be a cost-effective way to reduce anogenital HPV infections, the incidence of cervical cancer, and the HPV-associated health care burden. Three HPV vaccines consisting of noninfectious recombinant virus-like particles composed of HPV L1 proteins have been approved in the United States. The bivalent vaccine (2007) contains types 16 and 18, the quadrivalent vaccine (2006) adds types 6 and 11, and the 9-valent vaccine (2014) adds types 31, 33, 45, 52, and 58. All three vaccines are effective at preventing persistent infections by the targeted HPV types and the development of HPV-related genital precancerous lesions.

They are not effective against established HPV disease. Adolescent and young adult females were the initial target population for vaccination, with adolescent and young adult males recommended for vaccination in 2011. It is not known how long vaccine-induced immunity lasts, but it appears to extend for at least 10 years.

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دار الكفيل تنهي طباعة كتاب (لمَ لا) تمهيدًا لمناقشته في ملتقى غيث السماء القرآني الثاني

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العتبة العباسية المقدسة تكرّم 1000 طالبة من المرتديات العباءة العراقية في مدارس الديوانية

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Pathogenesis and Pathology of Rabies Virus

Properties of the Rabies Virus

Coronavirus Infections in Humans

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Hendra Virus and Nipah Virus Infections