DNA viruses and cancer: insights from evolutionary biology

Abstract

When it comes to understanding the exact mechanisms behind the virus induced cancers, we have often turned to molecular biology. It would be fair to argue that our understanding of cancers caused by viruses has significantly improved since the isolation of Epstein–Barr virus from Burkitt’s lymphoma. However they are some important questions that remain unexplored like what advantage do viruses derive by inducing carcinogenesis? Why do viruses code for the so called oncogenes? Why DNA viruses are disproportionately linked to cancers? These questions have been addressed from the lens of evolutionary biology in this review. The evolutionary analysis of virus induced cancer suggests that persistent strategy of infection could be a stable strategy for DNA viruses and also the main culprit behind their tendency to cause cancer. The framework presented in the review not only explains wider observations about cancer caused by viruses but also offers fresh predictions to test the hypothesis.

Introduction

Why the DNA viruses are disproportionately linked to cancers caused by infectious agents? [28, 23]. Do these viruses derive any evolutionary advantage from carcinogenic transformation of latently infected cells? Is the strategy of causing persistent infection, the mandatory requirement for virus induced carcinogenesis, an evolutionary adaptation of DNA viruses or it is a mere by-product of their larger coding capacity? These are some important questions that are worth exploring from an evolutionary point of view and this manuscript is a humble attempt to achieve the same.

The persistent infection of DNA viruses often manifests into cancer in a very small percentage of the infected population [39]. It takes almost two decades for somebody to get cancer since the onset of infection [39]. Unlike the oncogenic RNA viruses that cause cancer through mechanisms like the chronic inflammation and production of reactive oxygen species (ROS), the DNA viruses are known to directly interfere with proteins that deal with cell division checkpoints, apoptosis, telomere length regulation, and DNA repair mechanisms of the vertebrate host cell [31]. There has been significant progress towards understanding the exact mechanisms behind the cellular transformation and malignancy induced by the DNA viruses [31]. However, little is known about the selection pressures responsible for the origin and maintenance of such oncogenes.

A persistent infection by DNA viruses is one of the most important pre-requisites for carcinogenic transformation of a cell. This fact raises an important teleological question and i.e. is causing persistent infection a stable evolutionary strategy for DNA viruses? Irrespective of the size of their genome, the DNA viruses are known to cause lifelong persistent infections among their natural hosts. We know for sure that DNA viruses do not get an evolutionary advantage due to cancer. It appears that viral cancers, similar to non-infectious cancers, are biological accidents and in the natural course of the disease the resultant neoplasms are just as deadly to the virus as they are to their hosts. However, more than the etiological role of viruses in cancer, we need an evolutionary justification for the origin and maintenance of the genes that so precisely interfere with the proteins that regulate cancer prevention mechanisms of the host cell.

In the following paragraph arguments are presented to explain the evolutionary origin as well as the utility of persistence among the DNA viruses.

Is persistence a stable evolutionary strategy for DNA viruses?

Persistent infection whether at the cellular or organismic level is found to be a shared strategy among all the double stranded DNA viruses. This potentially indicates a common evolutionary advantage that these viruses achieve by persisting in the primary host for the lifetime. One reason for causing a persistent infection is that the replication in the nucleus of the cell is a slow process compared to replication that happens solely in the cytoplasm [45]. The DNA viruses often need the help of replication enzymes and other accessory proteins for their own replication [45]. This warrants them to either induce the quiescent cells to enter S-phase of the cell cycle or wait for the right time when the cell naturally enters the same phase [45]. An acute style of infection that includes speedy replication accompanied with spike in viremia is neither an option nor practical for most of the DNA viruses. The strategy of persistent infection seems to be a natural choice in such case. However there is a deeper evolutionary reason for going with the persistent strategy of infection. In the following paragraph I would be elucidating the major evolutionary advantage that DNA viruses gain by persisting in the host for the lifetime.

DNA viruses exclusively replicate in the nucleus of the host cell barring one exception of poxviruses that replicate in the cytoplasm [45]. The DNA viruses have no option but to use the cellular DNA replication machinery of the vertebrate host [45]. This includes the use of DNA dependent DNA polymerase enzyme which is known for its high fidelity [24]. Even the DNA dependent DNA polymerase enzyme coded by the viruses of Herpesviridae family is known to possess similar level of fidelity [7]. The replication of the viral genome using high fidelity DNA dependent DNA polymerase enzyme results in viral progenies that are least antigenically variable [38]. The DNA viruses consequently lose their only chance of using the superpowers of antigenic drift.

The antigenic drift is one of the strongest weapons among the arsenal of viruses that they use against the surgical strike of the immune system [2]. However, the antigenic drift is a privilege that is available mostly to the RNA viruses due to the error-prone copying mechanism of their RNA dependent RNA polymerase enzyme [2]. The antigenic drift helps the RNA viruses to re-infect the same host and maintain a non-exhausting stable pool of susceptible ones [2]. However, this is not the case for DNA viruses. The infection with the DNA viruses would result in the lifelong immunity and therefore a host infected once could not be re-infected in most of the cases [18]. DNA viruses would run short of new susceptible hosts. The maintenance of a non-exhausting pool of susceptible hosts is the most important problem that a DNA virus is required to solve. Since unlike their RNA counterparts the DNA viruses cannot come and re-infect the same host, it would make more sense for the DNA viruses to cause persistent infection in the primary host and wait for the right opportunity to spread to a new secondary host. One might argue that since new immunologically naive members are often added to a population either via newly born hosts or immigration of hosts from a different habitat and therefore supply of new hosts should not be a problem for DNA viruses [2]. However, when it comes to making sense of evolutionary adaptations it is often important to consider the selection pressures acting on a species from an historical perspective. DNA viruses are known to be infecting humans since millions of years [27, 26]. This implies that these viruses have survived the hunter-gatherer era when the conditions were highly unfavourable for the rapid transmission of any viral species [46]. An acute style of infection strategy that is manifested as peak in viremea and a rapid transmission event would have been risky in terms of survival within the population [46]. In the absence of easy and continuous availability of immunologically naive host, the rapid elimination of the viral species would have been the obvious fate [46]. The modern catalysts like high birth rate and immigration of new immunologically naive hosts within the concerned population were rare during the pre-agriculture era [46]. The persistent strategy of infection made perfect sense for the viruses that lacked the capacity to maintain the pool of susceptible hosts but had enough genomic economy to code for proteins that could help them inhabit the host for the lifetime. The co-speciation of these viruses with their respective hosts strongly supports these views [26]. Therefore the tendency to cause lifelong persistent infection could be reflections of the evolutionary pressures imposed on these viruses by their ancient environments. It can therefore be argued that the DNA viruses had the dual Darwinian roles to fulfill i.e. 1. The first responsibility was to infect the primary host for the lifetime by causing a persistent or latent infection 2. The second responsibility was to disseminate to the secondary host as per the available opportunity.

Distinct mechanisms of persistence among the DNA viruses and their relevance to oncogenesis

It is important to note that there are two types of viral persistence. One is at the cellular level where a virus infects a cell lineage for a lifetime of the host. Another category of persistence is at the organismic level where the virus persists in the body of the host but not particularly in a cell lineage. Organismic persistence could be considered as the absence of cellular latency. As far as DNA viruses are concerned it is the persistence at the cellular level that is more relevant to their oncogenic potential.

There is enough scientific evidence to claim the causing a persistent infection that is associated with a cellular latency is a costly affair in terms of genomic economy [22]. Apart from the genes that help with latency, the virus also needs genes helping with immune evasion [22]. A larger genome is usually required to cause latent infection in one cell as well as lytic in another. It would be fair to claim the very small single-stranded DNA viruses with smaller genomes would find it very difficult to infect two different cell lineages i.e. one for latency and another for lytic cycle.

There are distinct strategies that DNA viruses could use for causing persistent infections. What exact strategy a virus will use would largely depend on its genome size.

DNA viruses are known to use the following distinct mechanisms to cause persistent infection in the human host:

1. In the first strategy, the DNA viruses infect two different cell lineages. One cell lineage is used for persistence via cellular latency. Another cell lineage is used to cause lytic infections. The lytic infections often cause death of the infected cells. This tragic fate of the infected cells not only attracts strong immune response but also leads to the clearance of the virus from the infected site [22]. The acute lytic infections are mainly used to spread to the secondary host as per the available opportunity via episodic re-activation [22]. This strategy requires a larger genome size and therefore is favored among large DNA viruses of the family Herpesviridae [22].

2. Another strategy the DNA viruses employ for persistence is to cause a perennial lytic infection in a single cell lineage [22, 27]. These DNA viruses continuously produce new virions for the lifetime [22]. They usually achieve the persistence by infecting cells that also confer protection from the immune system due to their immune privilege status like the renal epithelium in humans [22]. This strategy is mainly employed by the small DNA viruses like the Polyomavirus because these viruses are incapable of infecting two different cell lineages like the large double-stranded DNA viruses [22]. It should be noted that unlike the large double-stranded DNA viruses, the smaller double-stranded DNA viruses do not cause an intracellular persistence infection in a separate cell lineage. They, however, do stay in the body of the host for a lifetime at the organismic level.

These two distinct strategies have very different outcomes in terms of their potential to cause cancer.

DNA viruses, persistence and cancer: an evolutionary analysis

The coding capacity and the nature of the DNA dependent DNA polymerase enzyme encoded by the large DNA viruses are the two most important aspects of this evolutionary analysis. The predictions of this analysis and the assessment of the oncogenic potential of the DNA viruses would be based on the following parameters i.e. The genome size of the virus and the nature of DNA dependent DNA polymerase enzyme encoded by the large DNA viruses. By the nature of DNA dependent DNA polymerase, I mean their level of fidelity.

The following are the major predictions of this evolutionary analysis

1. The genome size and the oncogenic potential of the DNA viruses would be directly proportional to each other. The large DNA viruses would have much higher potential to cause cancer than the small DNA viruses. This argument is based on the fact that large DNA viruses are capable of latently infected a specific host cell for a lifetime compared to DNA viruses with a smaller genome [22].

2. DNA viruses that cause only lytic infections in the natural host would be incapable of causing cancer. Lytic infections lead to cell death and therefore leave no chance of malignant transformation that often results from persistent infections of a cell lineage [22]. This is possibly the most important prediction as it helps to solve a major puzzle in viral oncology. It has been known since long that viruses like JC Virus and BK virus cause malignant transformation of cells in vitro [27]. However, as of now, we do not have a single case of human cancers caused by these viruses [27]. This is due to the fact that all of these viruses only cause lytic infections in the human host [25]. Since none of them cause an intracellular persistent infection or cellular latency, they are incapable of causing cancer in the primary cell lineage that they infect for their perpetuation. Persistent infection of a cell lineage is, therefore, a mandatory requirement for virus-induced carcinogenesis. However, it is possible for these viruses to cause cancer in case of accidental integration of their genome within that of the host or continuous expression of oncogenes in non-permissive cells. This happens in the case of Merkel Cell carcinoma which is caused by a polyoma virus infecting skin [29, 33].

One might wonder that since the polyomaviruses like JC and BK virus do not cause cancer in their natural host then why they code for genes that are capable of transforming the cells in tissue cultures? [27]. The answer lies in the replication strategy of small double-stranded DNA viruses where they need these genes for their own replication. One of the reasons that certain DNA viruses are potentially oncogenic is that they need to kick-start the cell-replicative machinery—the S phase of the cell division cycle—in order to replicate themselves [46]. The small DNA tumor viruses, such as HPV and Polyomaviruses, do not encode all the enzymes for DNA replication in the viral genome and require cellular enzymes to achieve replication [25, 32]. This reasoning may explain the convergent evolution of disparate DNA tumour viruses to target the inactivation of host tumour suppressors, such as retinoblastoma protein and p53 that specifically control the entry of cells from G1 phase to S phase.

Genome size and the oncogenic potential of the DNA viruses

Large double-stranded DNA viruses

As discussed earlier the ability to cause persistent infection depends a lot on the genome size of the DNA viruses. Large double-stranded DNA viruses, therefore, would naturally have the highest oncogenic potential. Since these type of viruses have higher coding capacity due to their larger genomes, they would be able to infect two different cell lineages for two different outcomes. One of the cell lineages would be used for a lifelong infection in the primary host and another cell lineage would be used for lytic infections to spread to the secondary host. What is more important to us is the choice of cells that these DNA viruses prefer for causing persistent infections. Natural selection favours infection of cell types that have favourable traits for viral persistence. It would be revealed in the model later that it is the persistent infection of these high-risk cell lineages that lead to malignant transformation after decades of infection.

Insights from Evolutionary thinking suggest that cells with the following traits would be most suitable for a persistent infection

1. Most of the cells in the human body have a short limited lifespan and therefore are not a good candidate for persistent infections [14]. Long-lived cells of the immune system can provide ideal shelter for persistent viral infections, as in the case of Epstein–Barr virus (EBV), which resides in the resting memory B-cell compartment [22]. The long life of the cell would ensure that the virus inside the cell would survive naturally for a longer time [22]. The terminally differentiated cells of the neurological system are also an ideal candidate for latent infections [22]. Neurons are long-lived, terminally differentiated cells, providing the virus with a virtually everlasting home within the host.

2. Natural selection could also favour infection of cells that proliferate with higher frequency like Stem cells or lymphocytes. The higher frequency of proliferation would mean that multiple copies of viral genomes are maintained in the body of the primary host.

3. The third category of cells could have both of these properties i.e. they are long-lived as well as they have a higher frequency of cell division. The persistent infection and subsequent transformation of such cell types would naturally send them at the brink of Cancer.

As per this evolutionary logic, the viruses with large double-stranded DNA genome would be disproportionately associated with Cancer. This category of viruses would have highest oncogenic potential. This is mainly due to the fact that these viruses dysregulate the gene products associated with apoptosis and cell cycle arrest in the cell lineages they infect for persistence [11]. They also interfere with the cellular checkpoints that deal with DNA repair mechanisms [6]. Examples from this family include viruses like EBV that causes Burkitt's lymphoma, Hodgkin's lymphoma, Herpes Simplex 8 that causes Kaposi Sarcoma [41]. The herpes virus family is also widely associated with cancer among animals like cottontail rabbit, Monkeys and Chickens [19]. Another example is mouse cytomegalovirus that infects the cells of salivary glands for acute infections and that of myeloid linkage for latent infections [42]. Other viruses of the Herpes family like Varicella-Zoster virus show latency in the long-lived neurons [9].

Small double-stranded DNA viruses

The double-stranded DNA viruses are either small or large [18]. Since the small double-stranded DNA viruses have the limited coding capacity they would not be able to infect two different cell types for two different purposes i.e. 1. One cell lineage for persistent infections 2. One cell lineage for acute lytic infections. Natural selection could favour the following two types of solutions to achieve persistence in case of small DNA viruses.

Solution 1

Natural selection could favour infection of a cell lineage that serves a dual purpose i.e. it not only acts as a reservoir for persistent infection but also helps in infecting new hosts. Such cell types would have a dual role due to their different environment that changes temporally with differentiation. The Stem cells of the transformation zone in the cervix help HPV in fulfilling its dual Darwinian role in a similar proposed fashion. The selective and temporally varied expression of proteins helps this small virus to evade host defenses as well as infection of new secondary hosts. The daughter stem cells left behind serve as the reservoir for the lifelong infection of HPV [43]. As per this model, it is the lifelong infection of basal stem cells that cause cancer in the cervix. The upper differentiating layer is sloughed off to infect the secondary host.

Solution 2

In solution 2 natural selection could favour infection of a cell type where the virus can cause lytic infection for transmission to new hosts as well as persist at the organismic level due to the protection offered by the tissue against the host immunity. The renal epithelium is also the site of persistence for several polyomaviruses, including simian virus 40 (SV40) 40), the K virus of mice, and the JC and BK viruses of humans [22], suggesting that the specific architecture of the kidney may provide a particularly attractive environment for the establishment of a long-term infection. The virus causes a lytic infection of the renal epithelium cells and also persists there for the lifetime due to the immune privilege conferred at the site [22]. This strategy helps the polyomaviruses to fulfill their dual roles even with the limited coding capacity. Since this strategy does not lead to persistent infection inside a cell lineage, there is no chance of carcinogenic transformation. We can also claim that those DNA viruses that only cause lytic infection would never be able to induce cancer in humans. Persistent infection in a cell and its transformation are mandatory for a virus to be carcinogenic.

Single-stranded DNA viruses

Single-stranded DNA viruses do not code for enzymes that could induce the resting cells to enter S phase [18]. In such cases, the natural selection favors the infection of actively dividing cell types and therefore an acute lytic strategy of infection. Such viruses are usually incapable of causing persistent infection in a cell lineage and therefore are incapable of causing cancer in the host.

Retroviruses: the special category

Retroviruses are being included here because of their carcinogenic potential in spite of them not being a DNA virus [34, 47]. The replication strategy of these viruses is what makes them a potential carcinogen even though they have an RNA genome. These viruses use reverse transcriptase enzyme to convert their RNA genome to a DNA one [30]. This newly formed DNA genome is integrated into the genome of the host cell as a provirus [30]. The provirus replicates with the replication of the genome of the host. The small retroviruses are required to infect actively dividing cells however certain viruses like HIV can also infect non-dividing cells [47]. The retrovirus very much like the DNA viruses has a dual role to fulfill. They could achieve their Darwinian outcome by causing lytic infection in one cell type and causing a lifelong infection in another one. Sometimes they achieve their evolutionary outcome by causing persistent infection in a cell type that has a higher frequency of cell division like the cells of the immune system. It is this persistent infection that leads to cancer in a small proportion of infected individuals. The best example of such a case is the HTLV-I virus that causes a very aggressive form of leukemia [4, 30, 36]. In such cases of infection, there are no free virions produced [4, 30, 36]. The virus is transmitted from one host to another host either through the exchange of a whole infected cell via breast milk or exchange of fluids [4, 36].

Oncogenes or the genes for immune evasion

There have been several recent studies that are pointing towards a different role of genes that we have often linked with cellular transformation and carcinogenesis. The major conclusion derived from these studies is that the genes that drive latently infected cells towards transformation also play a vital role in immune evasion [32]. It has been argued that apoptosis is also a basic strategy employed by the host cells to prevent the spread of the infection [32]. It is therefore natural for the viruses to have genes that prevent apoptosis. This means that genes blocking the host proteins responsible for apoptosis have immune evasion as their primary responsibility and cellular transformation could be an unfavorable outcome.

Sexual route of transmission and persistence

An alternative framework offered to explain the oncogenic potential of viruses has emphasized on the mode of transmission as a prospective cause of the origin of oncogenicity [11]. As per the model, most of cancer-causing viruses are transmitted by the sexual route [11]. Since the opportunity of transmission via sexual route is often limited on a daily basis, the evolution of persistence becomes an adaptive feature for the viruses.

According to the analysis presented in this paper, it can be claimed that persistence is a more fundamental part of DNA viruses and it comes before the mode of transmission. Persistence whether at the organismic level or at the cellular level is an evolutionarily stable strategy for the DNA viruses. In most of the cases, the sexual route is a default mode of transmission because the other modes like respiratory and oral-fecal route are mainly favored for acute infections. DNA viruses are mainly transmitted via the exchange of fluids and therefore the sexual route becomes inevitable for transmission. It should be noted that Polyomavirus that persist at the organismic level are transmitted via urine as well as the oral-fecal route [3]. Adenovirus are also known to latently persist in the lymphocytes but are transmitted by the oro-faecal route not via sexual route [12].

In short, persistence is a more fundamental feature of DNA viruses and its connection with the sexual mode of transmission is not causal but correlational.

Viruses and cancer caused by them: individual case studies

It is generally the abrogation of major cellular defenses against the cancer like Cell cycle regulation, telomerase regulation, and suppression of p53 function and apoptosis that often results in cancer [5, 10, 40]. DNA viruses that cause persistent infections in a particular cell lineage often lead to such oncogenic transformation by abrogating all the major barriers or defenses against cancer at the same time [11, 10, 40]. The cell lineages naturally selected for persistence are inherently more prone to turn cancerous due to some of their cancer defenses not in place. In the following section, I would consider individual cases of viruses and how selection pressures acting on them have made them a potential carcinogen.

HPV and cervical cancer

The HPV life cycle is closely linked to the differentiation program of the infected epithelial cell [15]. Basal cells undergo asymmetric mitosis with one daughter cell remaining a proliferating basal cell while the other daughter cell becomes a suprabasal, differentiating cell [15]. The suprabasal cell withdraws from the cell division cycle and undergoes a program of terminal differentiation, thus ensuring the mechanical stability of the skin and protecting the proliferating basal cells from direct exposure to environmental mutagens [48]. In order to establish a stable infection, PVs need to infect basal cells through mechanisms that remain poorly understood [16, 17]. Following initial infection, the genomes are maintained at a low copy number in the basal cells and persistent infection is established. The production of the infectious virus occurs in the terminally differentiated layers of the epithelium and progeny virions are sloughed off within the terminally differentiated, de-nucleated epithelial squames. The shed virus is stable and retains infectious properties over extended periods [16, 17].

As predicted by the evolutionary analysis, the stem cells of the basal layer in the transformation zone could be a perfect target for small double-stranded DNA viruses like HPV in order to fulfill their dual Darwinian duties. The virus is not required to express its protein in the actively dividing stem cells of lower layers. This also helps is hiding from the immune system. The virus can persist in the basal layer as well as shed via the upper layer to infect the new secondary host. It is persistent with high-risk HPV types that lead to cancer in the long term.

HHV-8 and Kaposi's sarcoma

In 1994, HHV-8 DNA was identified in biopsies from tumors of a patient with Kaposi sarcoma [8], a relatively rare malignancy prior to the AIDS epidemic. In addition to it likely being an essential cofactor for the development of Kaposi sarcoma, HHV-8 also is believed to have a role in Castleman's disease and primary effusion lymphoma [8]. The viral genome is expressed in these tumors and encodes transforming proteins and anti-apoptotic factors. The virus is also able to enhance the proliferation of microvascular endothelial cells [8]. As with EBV, the predominant infected cell is the B lymphocyte, although here the lytic cycle is embraced rather than repressed. This may play a crucial role in the pathogenesis of Kaposi's sarcoma by elaboration of viral and host cytokines promoting cell proliferation, angiogenesis, and enhancement of viral spread.

HTLV-I and leukemia

As predicted by the model the retroviruses that cause persistent infection in high-risk cell types like stem cells or cells of immune systems could be a potential carcinogen [13]. HTLV-I is known to cause a very aggressive form of leukemia that manifests itself after a very long duration of persistence [35].

In the last section of this manuscript, I would like to outline the falsifiable predictions of my model that could be tested to disapprove the presented hypothesis.

Testable predictions of the model

The following are some important testable predictions of the evolutionary model presented in this paper:

1. As per the prediction of this model, cells like lymphocytes, neurons, and stem cells would be naturally favoured cell types for persistent and latent viral infections. We might find the viruses to be disproportionately associated with the cancers of the stem cells and lymphocytes over any other cell in the human body. Lymphomas would be one of the most common types of cancers caused by viruses among humans as well as the wildlife populations. It is equally possible that we could one day find DNA viruses in other immune-privilege sites like the testes. The DNA viruses might actually be contributing to infection induced infertility. Indeed, the study of cancers among the wildlife has shown that lymphoma is the most common type of cancer across the animal species [1].

2. The double-stranded DNA viruses would have the highest oncogenic potential. The Herpesviridae family is known to cause lymphoma not only in humans but also among animals like Cottantail Rabbit, Chickens and Monkeys [19].

3. The double-stranded DNA viruses might be associated with more neoplasias than we are currently aware of. Surveillance of lymphomas among wildlife and research w.r.t link with infectious causation might help to prove this hypothesis.

4. Viruses that persist at the organismic level would rarely cause cancer of the infected cell. Since the Polyomaviruses like JC and BK are incapable of latently infecting a cell lineage, it would be not possible for them to transform a cell and induce carcinogenesis. However in rare cases when their genome is integrated into the genome of the host cell, carcinogenesis can certainly be a possible outcome. The rare cases of Merkel cell carcinoma supports this line of though on the role of Polyomaviruses in causing cancer [32].

5. Since the large and small DNA viruses cause persistent infection at the organismic as well as cellular level, they should be also widely associated with many chronic diseases in humans that have not been assigned an infectious angle. The rising evidence on the role of the Herpes virus in neurological diseases like Alzheimer's is one such example [21]. JC and BK virus have also been linked to chronic kidney disease [37]. Research programs dedicated to finding a causal link between DNA viruses and chronic diseases might help us to uncover infectious causation of diseases that are considered chronic but non-communicable.

6. Single-stranded DNA viruses would never be able to cause cancer since intracellular persistent infection is just not their cup of tea.

Some evidence against the model

There are some facts about the life-strategy of the DNA viruses that do not strictly follow the predictions of the verbal model presented in this manuscript. For example, even though the cytomegalovirus is a large double-stranded DNA virus, it is able to re-infect the same host due to the large array of genes it carries against immune evasion [44]. However most of the DNA viruses still fall within the framework of the hypothesis that due to the lack of antigenic drift the DNA viruses are not able to re-infect the same host and therefore prefer the life-strategy of persistent infections over the acute style.

The cells that are selected for latent infections by DNA viruses are more prone towards a carcinogenic outcome over the other cell line infected by the same virus. This statement too is one of the important hypotheses proposed in this manuscript. However in the case of the cancers caused by the Epstein—Barr virus the cancers of epithelial cells are far more common than the latently infected lymphocytes [20]. In short, the EBV induced gastric carcinoma is far more common than lymphomas induced by the same virus [20]. This contradiction could be understood by the fact that a large chunk of virus induced cancers are mere biological accidents. One of the most common reasons of these carcinogenic accidents is the over-expression of genes capable of transformation in the wrong cell type or the non-permissive cell types.

Adenoviruses too do not perfectly fit within the realm of the hypothesis presented in this manuscript. Adenovirus do cause latent infections of the lymphocytes and like the viruses of the family Herpesviridae are also known for episodic reactivation [12]. However we still do not have any evidence on the role of Adenovirus in causing human cancer.

Alternate hypothesis to justify the persistent strategy of infection among the DNA viruses

The core hypothesis of this manuscript is that the persistent infection strategy of the DNA viruses is an evolutionary stable strategy that has helped them to thrive among the human populations for millions of years. The strategy of causing persistent infections could be considered a natural option as DNA viruses are challenged with two major bottlenecks against adopting the acute strategy of infection and they are as follows:

1. DNA viruses inherently lack the ability of antigenic drift owing to the high fidelity of DNA dependent DNA polymerase enzyme [22, 24].

2. Most of them exclusively replicate in the nucleus and are strictly dependent on the host DNA replication machinery for the replication of their genome [22, 24]. It warrants them to express their genes in two different phases i.e. early and late. It is therefore not possible for them to cause the speedy, rapid and acute infections in most of the cases. Unlike the RNA viruses that replicate mostly in the cytoplasm, the DNA viruses cannot start their replication right after they enter the permissive cell.

On the other hand we could also argue that DNA viruses could cause persistent infection by which I mean latent infection in one cell and lytic in other because they have the required genomic bandwidth or economy to do the same unlike the RNA viruses. In short the capability of the DNA viruses to cause persistent infections could just be the matter of coding capacity available at their disposal.

Compliance with ethical standards

Conflict of interest

The author declares that he does not have any conflict of interest.