Since 1898, when Martinus Beijerinck discovered the first known virus, the tobacco mosaic virus, >5000 types of viruses have been described in detail (Breitbart and Rohwer, 2005). Peyton Rous discovered the first known tumorigenic virus in birds in 1911 and, more recently, in 1964, Michael Anthony Epstein and Yvonne Barr first discovered a virus known to be involved in human cancer (the Epstein–Barr virus, EBV). We now know that viruses infect all types of cells and cause a variety of human diseases, from the common cold to AIDS and cancer.

Viruses produce disease by different routes, depending on the viral species and the specific organ or organism they affect. Viral infection can lead to asymptomatic effects, acute clinical disease, neurological disorders and induction of various cancer types. The interactions between a virus and its host can produce different consequences, from no apparent change in the infected cell to the death of the host cell arising from alterations of the cell membrane and apoptosis (Roulston et al., 1999). Some viruses can persist over time, despite active immunity, and cause no apparent changes to the infected cell. This latency is a characteristic of the herpes virus group, some members of which, such as the herpes simplex virus, can induce cell proliferation without causing malignancy (Barozzi et al., 2007), or of the human papilloma virus (HPV) group, several members of which can unleash cancer (zur Hausen, 2009).

The proportion of cancers caused by infectious agents, including bacteria, parasitic worms and viruses, was recently estimated to be >20% (Bouvard et al., 2009). The contribution of several viruses is especially high in certain cancer types. For instance, human hepatitis B virus (HBV) and human hepatitis C virus (HCV) are associated with 80% of hepatocellular carcinomas (HCCs), EBV is associated with 30% of Hodgkin's lymphomas and HPV is positive in >95% of cervical carcinomas (zur Hausen, 2006). Many of the products from these oncogenic viruses (oncoviruses) carry out functions that disrupt cell processes, such as apoptosis and cell-cycle checkpoint activation (McLaughlin-Drubin and Munger, 2008). Although oncoviruses from different virus families use diverse strategies that contribute to cancer development, they share many common features, among which the interactions with cellular targets such as p53 and Rb (Javier and Butel, 2008; McLaughlin-Drubin and Munger, 2008) are of particular note.

Known and potential human tumor viruses belong to a number of families, either DNA viruses or RNA viruses that retrotranscribe their genome to DNA. General information about these viruses with known and potential associations with human cancer is provided in Table 1.

Table 1 General information about the viruses associated with human cancer Full size table

Oncoviruses tend to cause persistent infections because they have developed strategies for evading the host immune response. However, viruses are not sufficient for carcinogenesis, and additional factors, including host immunity and cell mutations, are necessary for a tumoral process to be initiated (McLaughlin-Drubin and Munger, 2008).

Viruses that establish latent infections need to avoid recognition by the immune system, as this would otherwise eliminate the infection. Different viral evasion strategies have been identified, but all of them are essentially aimed at camouflaging the virus in the host cell, restricting the expression of viral genes and proteins that are indispensable for viral persistency, and avoiding the expression of genes associated with immune response. Viral DNA methylation could be the masking mechanism by which many viruses are able to achieve this (Fernandez et al., 2009).

DNA methylation is responsible, through the silencing of repetitive genomic sequences, for the inactivation of integrated foreign DNA, that is, retrotransposons such as L1 and ALU elements, proviral sequences from endogenous retroviruses and other transposable elements. (Yoder et al., 1997; Colot and Rossignol, 1999). In this regard, it has been proposed that DNA methylation may have arisen as a genome-defense system to prevent chromosomal instability, translocations and gene disruption caused by the reactivation of these transposable DNA sequences (Yoder et al., 1997; Rollins et al., 2006). In addition, eukaryotic cells have developed several defense mechanisms against the uptake, integration and continued expression of foreign DNA (such as viruses) in which gene-specific sequence methylation has an important role (Doerfler, 1991). This de novo methylation of foreign genes in eukaryotic genomes can be viewed as an ancient cell defense mechanism against the intrusion of foreign genetic material (Doerfler, 1991, 1996).

Many studies have shown that viruses can cause methylation of the host cell genome by interacting with the host epigenetic machinery, thus driving the silencing of host cellular genes. Viruses are also able to alter the activity of proteins associated with the establishment of specific histone marks, chromatin remodeling complexes and miRNA processing (Flanagan, 2007; Javier and Butel, 2008; Ferrari et al., 2009; Whitby, 2009).

In this review, we summarize the epigenetic information available about the main viruses with known and potential associations with human cancer or that are involved in human tumorigenesis. It is widely accepted that the virus genome disrupts the host genome by insertion mutations and chromosomal rearrangements, predisposing the infected cells to cancer. It is also known that, apart from introducing genetic changes, the presence of the viral genome is associated with an aberrant methylation profile in host-specific genes in human cancer. However, little is known about the epigenetic changes in the virus itself, the study of which may help to explain the molecular mechanisms of viral pathogenesis and tumorigenesis. As in eukaryotic cells, DNA methylation is the best-studied epigenetic mark in viruses. We will also describe the specific histone modification marks within the viral genomes and the miRNA profiling associated with their pathogenicity and tumorigenicity, and the main alterations in the epigenetic machinery of the host cell associated with the activity of various viruses. Table 2 lists the viral genes and enomic regions reported to have epigenetic changes, as well as their associated function in the cell and/or various cancers.