**1. Introduction**

Human Papillomavirus (HPV) is arguably the most common sexually transmitted agent worldwide, either in its clinical (genital warts) or subclinical presentation in men and women. The main interest in HPV relates to its recognized as a causal and necessary factor for cervical cancer one of the most common cancers in women (80% of cases in most developing countries, with an annual incidence of almost half a millon and a mortality rate of approximately 50%) [1-5], and other types of cancer, such as penis, anal or oral cancer [6].

The overall prevalence of HPV in cervix in women in the general population is 10%. This prevalence is higher in the less developed world than in more developed regions [7, 8]. A review of studies has also shown prevalence of HPV in men as usually 20% or greater, depending on population tested and the type and number of anatomic sities evaluated [9].

HPV infection is most common in sexually active young women 25 years of age or younger but cervical cancer is common in older woman, suggesting infection at younger age and slow progression to cancer [10].

The most significant predictor for adquiring HPV infection in men or women appears to be the life time number of sexual parteners [11,12,13]. For women, the sexual activity of their partner(s) is also important, with increased risk of adquiring HPV if their partner had, or currently has, other partners [12].

Not all women infected with high-risk HPV develop cervical cancer, other factors are neces‐ sary: genotype, persistent infection, viral variants, viral load, integration, coinfection, age of 30 years old, inmunosupresión, smoking, condom use, coinfections, long-term use of oral contraceptives, parity and circumcision. [10, 12, 14-24]

About 189 HPV genotypes have been sequence and classified according to their biological niche, oncogenic potential and phylogenetic position [25]. From them, about 40 can infect the genital tract [26]. HPV types are classified based on their association with cervical cancer and precursor lesion into low-risk types (**LR-HPV),** which are found mainly in genital warts, highrisk types (**HR-HPV)**, which are frequently associated with invasive cervical cancer and undetermined risk types (table 1) [27, 28, 29].

**2. Etiopathogenesis of HPV**

the viral genome. (Figure 1).

**Figure 1.** Organization of the HPV genome. Adapted from Doorbar J. [45]

The HPV virion has a double-stranded, circular DNA genome of approximately 7900bp, with eight overlapping open reading frames, comprising early (E), and late (L) genes and an untranslated long control region, within an icosahedral capsid. The L1 and L2 genes encode the mayor and minor capsid proteins. The capsid contains 72 pentamers of L1, and a pproxi‐ mately 12 molecules of L2. The early genes regulate viral replication and some have transfor‐ mation potential. Late genes L6 and L7 code for structural capsid proteins which encapsidate

Molecular Diagnosis of Human Papillomavirus Infections

http://dx.doi.org/10.5772/55706

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Infection by papillomaviruses requires that virus particles gain access to the epithelial basal layer and enter the dividing basal cells. Having entered the epithelial tissues, the HPV virus enters the nucleus of a basal epithelial cell, where early genes E1 and E2 are expressed, replicating the viral genome and transcribing messenger RNA needed for viral replication; in addition to its role in replication and genome segregation, E2 can also act as a transcription factor and can regulate the viral early promoter and control expression of the viral oncogenes (E6 and E7). At low levels, E2 acts as a transcriptional activator, whereas at high levels E2 represses oncogene expression [45]. As the host cells differentiate, genes E4 and E5 assist in the production of the viral genome by controlling epidermal growth factor. E6 and E7 are viral oncogenes which now become important. E6 causes degradation of the tumour suppressor gene p53, while E7 completes for retinoblastoma protein (pRb), allowing the transcription factor E2F to drive cell proliferation processes. The p16 protein, encoded by the suppressor gene CDKN2A (MTS1, INK4A) at chromosome 9p21, is an inhibitor of cyclin dependent kinases (cdk)which slows cell cycle by inactivating the function of the complex-cdk4 and cdk6 cyclin D. These complexes regulate the control point of the G1 phase of the cell cycle with subsequent phosphorylation and inactivation of retinoblastoma (pRb), which E2F released and which allows cells to enter S phase. It has been demonstrated existence of a correlation between pRb and p16 reciprocal, which is why there a strong overexpression of p16 both in carcinomas


**Table 1.** HPV types classification according their oncogenic potential

Worldwide, HPV-16 is the most common HPV type across the spectrum of HPV related cervical lesions. In women with ICC (invasive cervical cancer), the most common HPV types are HPV-16,18,33,45,31 and 58 [30, 31], but among these genotypes, certain variants have linked to different clinical outcomes. It is now generally accepted that HPV has co-existed with its human host over a very long period of time and has evolved into multiple evolutionary lineages [25, 32]. Intratypic variants of HPV16 have been identified from different geographic locations and are classified according to their host ethnic groups as European (including prototypes and Asian types), Asian American, African and North American [33]. Through epidemiological and in-vitro experimental studies, natural variants of HPV16 have shown substantial differences in pathogenicity, immunogenicity and tumorigenicity. IARC Study [34] and IARC Meta-analysis [31] are very robust in identifying that HPV-16 and 18 contibute approximately 70% of all ICC. HPV-16,18 and 45 are the three most relevant types in cervical adenocarcinoma [30]. The geographical variation in type distribution is of minor significance variation.

Among men and women, cancers of the ano-genital tract and their precursor lesions have been strongly linked to infection with sexually transmited human papillomavirus. In men, HPV infection has been strongly associated with anal cancer and is associated with approximately 85% of the anal squamous cell cancers that accur annually worldwide. Likewise, approxi‐ mately 50% of cancers of penis have been associtated to HPV infection [35]. Genital warts are a common sexually transmitted condition with an estimated prevalence of 1-2% of young adults [36]. Although having genital warts is not associated with mortality, represent a significant public health problem (clinical symptoms and psychosocial problems) and healthcare costs for society [37-39]. More than 90% of genital warts are related to HPV-6 and 11 (low risk genotypes) in general these types are not associated with malignant lesions, however 20-50% of these also contained coinfection with oncogenic HPV types [39-41].

On the other hand, between 33-72% of oropharyngeal cancers, and 10% of cancer of the larynx may be attributed to HPV infection [42-44].
