The human virome: new tools and concepts
2013; Elsevier BV; Volume: 21; Issue: 10 Linguagem: Inglês
10.1016/j.tim.2013.07.001
ISSN1878-4380
Autores Tópico(s)Animal Virus Infections Studies
Resumo•New sequencing technologies increase our knowledge regarding the composition of the human virome.•There are beneficial and detrimental viruses.•The human virome can impact upon health at body surfaces (skin or gut) and within tissues.•Some animal viruses are transmitted via the oral route by consumption of food. The human virome is the viral component of the microbiome. Its composition, and interindividual and temporal variability are not precisely known. Its impact on human health has received less attention than that of the bacterial microbiome, but is likely to be equally important, both in homeostasis and disease. Here we review the recent advances in this field and the questions that arise in the context of our rapidly increasing knowledge regarding the composition and function of the human virome. With the ever-extending use of next-generation sequencing (NGS) on a variety of clinical samples, rapid progress on the composition of the human virome and its impact upon human health are to be expected in the coming years. The human virome is the viral component of the microbiome. Its composition, and interindividual and temporal variability are not precisely known. Its impact on human health has received less attention than that of the bacterial microbiome, but is likely to be equally important, both in homeostasis and disease. Here we review the recent advances in this field and the questions that arise in the context of our rapidly increasing knowledge regarding the composition and function of the human virome. With the ever-extending use of next-generation sequencing (NGS) on a variety of clinical samples, rapid progress on the composition of the human virome and its impact upon human health are to be expected in the coming years. The human virome is defined as the viral component of the human microbiome, itself defined as the microbial communities of the various niches of the human body. This is indeed a broad definition, and we have excluded from this review endogenous human retroviruses that do not produce replication-competent particles able to ensure horizontal transmission, despite recent results showing that replication-competent retroviruses do in fact emerge in immunodeficient mice, in a process that is dependent on the intestinal microbiota [1Young G.R. et al.Resurrection of endogenous retroviruses in antibody-deficient mice.Nature. 2012; 491: 774-778PubMed Google Scholar]. We have also excluded viruses of bacteria (bacteriophages). The history of human virology has been dominated by the discovery of pathogenic viruses as ultrafilterable infectious particles able to multiply in cultured cells. A second wave of discovery came with the development of molecular techniques which enabled the discovery of major human viral pathogens that were not cultivable in vitro (e.g., hepatitis C virus, HCV [2Houghton M. Discovery of the hepatitis C virus.Liver Int. 2009; 29: 82-88Crossref PubMed Scopus (86) Google Scholar]; hepatitis E virus, HEV [3Reyes G.R. et al.Isolation of a cDNA from the virus responsible for enterically transmitted non-A, non-B hepatitis.Science. 1990; 247: 1335-1339Crossref PubMed Scopus (726) Google Scholar]; and human herpesvirus 8, HHV8 [4Chang Y. et al.Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma.Science. 1994; 266: 1865-1869Crossref PubMed Scopus (5061) Google Scholar]). Nobel prizes have been delivered to virus hunters [5Weiss R.A. On viruses, discovery, and recognition.Cell. 2008; 135: 983-986Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar] in recognition of their contribution to health and science. Currently, the power of new molecular techniques has entirely modified the landscape: although numerous new viruses have been identified, determining their association to disease, if any, will remain a challenging task and a focus for future clinical and pathogenesis investigations. In fact, it is increasingly apparent that viral pathogens are only salient members of a larger group of viruses associated with humans that are not directly linked to disease, analogous to the bacterial component of the microbiome. In particular, viruses abound at the body interfaces with the external environment, on the skin, and in the mucosa. By contrast, the presence of viruses in the blood and organ parenchyma of healthy people tends to be the exception than the rule, although a limited number of viral species establish persistent, albeit mostly silent, systemic infections, more often in immunocompromised individuals (Figure 1). Here we review the current knowledge on the human virome at body barriers and systemic compartments, as well as its impact upon human health, both in homeostasis and disease. The history of medicine teaches us that pathogen discovery has been, until recently, a very difficult, time-consuming and low-throughput task, limited by technical hurdles, and requiring the coordination of clinicians and basic scientists. Moreover, this activity has long been mainly hypothesis-driven, similarly to many other research activities. Recently, the development of DNA arrays [6Chen E.C. et al.Using a pan-viral microarray assay (Virochip) to screen clinical samples for viral pathogens.JoVE. 2011; 50https://doi.org/10.3791/2536Crossref Scopus (65) Google Scholar, 7Berthet N. et al.Massively parallel pathogen identification using high-density microarrays.Microb. Biotechnol. 2008; 1: 79-86PubMed Google Scholar] and new high-throughput DNA sequencing techniques (also known as NGS) have paved the way for quick, unbiased, and sensitive discovery and characterization of pathogens. In addition to these paradigm-shifting technological improvements, global networks dedicated to surveillance of animal and human infectious diseases have been set up, both at the regional and global scale, providing access to highly valuable clinical samples, which is key for pathogen discovery. Moreover, clusters of cases of infectious diseases of unknown origin are identified and pinpointed by diffusion lists such as ProMed (www.promedmail.org) on an almost daily basis. Finally, there is a growing list of microbes associated with chronic conditions including cancers [8De Martel C. et al.Global burden of cancers attributable to infections in 2008: a review and synthetic analysis.Lancet Oncol. 2012; 13: 607-615Abstract Full Text Full Text PDF PubMed Scopus (1925) Google Scholar], suggesting that increased efforts in microbial investigation of clinical conditions of unknown etiology will be decisive for future personalized diagnostics and therapeutics. Analysis of the recent literature shows a very rapid increase in NGS usage in the field of environmental microbiology, physiology, and pathogenesis. Recently, very broad and sensitive methodologies have been developed to detect and characterize previously unknown or variant viruses. Technological pipelines for pathogen discovery that create an interface between clinicians, virologists, molecular biologists, and bioinformaticians can uncover viruses referenced in databases with a threshold of sensitivity equivalent to that of quantitative PCR, and are now becoming even more sensitive than PCR with the increasing depth of sequencing [9Cheval J. et al.Evaluation of high-throughput sequencing for identifying known and unknown viruses in biological samples.J. Clin. Microbiol. 2011; 49: 3268-3275Crossref PubMed Scopus (137) Google Scholar, 10Wylie K.M. et al.Sequence analysis of the human virome in febrile and afebrile children.PLoS ONE. 2012; 7: e27735Crossref PubMed Scopus (149) Google Scholar, 11Greninger A.L. et al.A metagenomic analysis of pandemic influenza A (2009 H1N1) infection in patients from North America.PLoS ONE. 2010; 5: e13381Crossref PubMed Scopus (143) Google Scholar]. This type of pipeline also allows the acquisition and assembly of de novo full-length genomes from biological samples, and therefore the discovery of new viruses even when very distant from known viruses (see [12Chiu C.Y. Viral pathogen discovery.Curr. Opin. Microbiol. 2013; https://doi.org/10.1016/j.mib.2013.05.001Crossref PubMed Scopus (177) Google Scholar] for recent review). These tools have begun to reveal the existence and composition of the human virome and unravel its intrinsic complexity and interindividual variability in healthy individuals. Even so, the precise composition and potential impact on health of the human virome at the body surfaces (such as the skin and gut) and within tissues largely remains to be determined. Skin is the most obvious body barrier. The presence of a complex ecosystem at the cutaneous barrier plays a well-established role in preventing adherence and invasion of pathogens, which involves competition between commensal species and their colonization of favorable ecological niches. Similarly to the skin microbiome, the skin virome is composed of both resident and transient viruses. Cutaneous β and γ human papillomaviruses (β- and γ-HPVs) are commonly present on the superficial layers of the skin in most individuals [13Antonsson A. et al.Prevalence and type spectrum of human papillomaviruses in healthy skin samples collected in three continents.J. Gen. Virol. 2003; 84: 1881-1886Crossref PubMed Scopus (166) Google Scholar, 14Chen A.C-H. et al.Human papillomavirus type spectrum in normal skin of individuals with or without a history of frequent sun exposure.J. Gen. Virol. 2008; 89: 2891-2897Crossref PubMed Scopus (46) Google Scholar]. Several studies have described the interindividual and temporal genetic diversity of cutaneous HPV, and new human virus species belonging to the Polyomaviridae family have recently been described, including the tumorigenic Merkel's virus [15Dalianis T. Hirsch H.H. Human polyomaviruses in disease and cancer.Virology. 2013; 437: 63-72Crossref PubMed Scopus (254) Google Scholar]. Unbiased analysis of viral DNA sequences by NGS at the surface of the skin revealed three predominant families [Papillomaviridae (β- and γ-papillomaviruses), Polyomaviridae, and Circoviridae] [16Foulongne V. et al.Human skin microbiota: high diversity of DNA viruses identified on the human skin by high throughput sequencing.PLoS ONE. 2012; 7: e38499Crossref PubMed Scopus (301) Google Scholar]. This provides definitive evidence for the asymptomatic carriage of numerous HPV strains (up to 17 different strains on individual skin samples). Furthermore, 13 new γ-HPV strains have been identified, which suggests that the diversity of the resident cutaneous γ-HPV group might actually be larger than previously described [16Foulongne V. et al.Human skin microbiota: high diversity of DNA viruses identified on the human skin by high throughput sequencing.PLoS ONE. 2012; 7: e38499Crossref PubMed Scopus (301) Google Scholar], and their complete inventory thus remains to be established. Merkel cell polyomavirus (MCPyV), human polyomavirus 6 (HPyV6), human polyomavirus 7 (HPyV7), and human polyomavirus 9 (HPyV9) are newly discovered skin-tropic polyomaviruses [17Feltkamp M.C.W. et al.From Stockholm to Malawi: recent developments in studying human polyomaviruses.J. Gen. Virol. 2012; 94: 482-496Crossref PubMed Scopus (69) Google Scholar], which indicate that chronic carriage and shedding at the surface of healthy skin is also a hallmark of human polyomaviruses with cutaneous tropism. Numerous Circoviridae members are also present at the skin surface, mainly belonging to the Cyclovirus genus. Cycloviruses mainly infect animals with cross-species transmission appearing likely. They have also been detected in the feces of primates including humans, suggesting that the relevance of the detection of cycloviruses on the skin remains to be established [18Li L. et al.Possible cross-species transmission of circoviruses and cycloviruses among farm animals.J. Gen. Virol. 2011; 92: 768-772Crossref PubMed Scopus (120) Google Scholar, 19Li L. et al.Multiple diverse circoviruses infect farm animals and are commonly found in human and chimpanzee feces.J. Virol. 2010; 84: 1674-1682Crossref PubMed Scopus (316) Google Scholar]. Persistent or intermittent shedding of enteric viruses from healthy people is well established. For example, human enterovirus (HEV) [20Witsø E. et al.High prevalence of human enterovirus a infections in natural circulation of human enteroviruses.J. Clin. Microbiol. 2006; 44: 4095-4100Crossref PubMed Scopus (95) Google Scholar] and parechovirus (HPeV) [21Kolehmainen P. et al.Human parechoviruses are frequently detected in stool of healthy Finnish children.J. Clin. Virol. 2012; 54: 156-161Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar] are excreted by a large fraction of children under the age of five without any evidence of association with disease. A 1 year NGS longitudinal study of the stool of two healthy infant siblings in samples taken at 1 week intervals demonstrated that viruses were continuously excreted [22Kapusinszky B. et al.Nearly constant shedding of diverse enteric viruses by two healthy infants.J. Clin. Microbiol. 2012; 50: 3427-3434Crossref PubMed Scopus (109) Google Scholar]. The most frequently observed viruses, in decreasing order, were anellovirus (Torque teno viruses, TTV, but also TT-like mini viruses, TTMV), picobirnavirus, and HPeV types 1 and 6. Bocavirus (HBoV-1), adenovirus groups C and F, Aichi virus, astroviruses, and rotavirus were less frequently detected. Surprisingly, other enteric viruses such as noroviruses, coronaviruses, cardioviruses, cosaviruses, saliviruses, and sapoviruses were not detected, although they are frequently detected in stool, indicating that the results of this survey only provide a first indication of the composition of the gut virome, which would benefit from the study of larger samples. Some viruses, including adenoviruses, anelloviruses, picobirnaviruses, parechoviruses, and human bocavirus, were shed for months. These viruses are more likely to represent a significant portion of the normal human virome, owing to their ability to establish persistent infections. The gut virome is not only composed of fully adapted human viruses: an intriguing feature is the presence of some animal viruses that can be transmitted by the oral route by consumption of contaminated food, and whose kinship to the human virome remains unclear. The first is HEV, which is typically responsible for acute hepatitis in humans. Genotypes 1 and 2 are human-specific but types 3 and 4 have a reservoir in pigs [23Smith D.B. et al.Genetic variability and the classification of hepatitis E virus.J. Virol. 2013; 87: 4161-4169Crossref PubMed Scopus (70) Google Scholar]. Although HEV infection is considered to be silent in pigs, this is difficult to ascertain because the main target of HEV in humans are the elderly with previous liver injury and this is not a clinical situation that can be observed in pig husbandry. Furthermore, even in humans, the morbidity rate of HEV is low, which may preclude the identification of disease in pigs. Acute infection is the rule in humans, and the virus can be seen as a typical zoonotic virus. Nevertheless, long-term chronic infections have been described in immunocompromised patients, highlighting the importance of the host immune status on virome composition and its potentially pathogenic properties [24Lhomme S. et al.Hepatitis E virus quasispecies and the outcome of acute hepatitis E in solid-organ transplant patients.J. Virol. 2012; 86: 10006-10014Crossref PubMed Scopus (88) Google Scholar, 25Koning L. et al.Clinical implications of chronic hepatitis E virus infection in heart transplant recipients.J. Heart Lung Transplant. 2013; 32: 78-85Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar]. Also, some genotypes (1 and 2) are circulating between humans, which suggests that genotypes 3 and 4, which very frequently infect humans from the animal reservoir (up to 50% of the population is antibody-positive in some areas [26Kamar N. et al.Hepatitis E.Lancet. 2012; 379: 2477-2488Abstract Full Text Full Text PDF PubMed Scopus (792) Google Scholar]), might be adapting to humans. The situation is even less clear for gyroviruses. Within the Circoviridae family, only the chicken anemia virus (CAV) was previously known as a member of this genus until recently. The first gyrovirus in humans (HGyV), a member of the Circoviridae family, was initially found by NGS at the surface of the skin of healthy people [27Sauvage V. et al.Identification of the first human gyrovirus, a virus related to chicken anemia virus.J. Virol. 2011; 85: 7948-7950Crossref PubMed Scopus (97) Google Scholar]. A very similar virus, AGV2, was found a few months later in chickens, and then a third gyrovirus was detected in human stool, in which CAV and HGyV/AGV2 were also identified [28Phan T.G. et al.A third gyrovirus species in human faeces.J. Gen. Virol. 2012; 93: 1356-1361Crossref PubMed Scopus (72) Google Scholar]. A fourth gyrovirus, GyV4, was also found in China in chickens and in human stool [29Chu D.K.W. et al.Characterization of a novel gyrovirus in human stool and chicken meat.J. Clin. Virol. 2012; 55: 209-213Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar]. Some reports [29Chu D.K.W. et al.Characterization of a novel gyrovirus in human stool and chicken meat.J. Clin. Virol. 2012; 55: 209-213Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar] reveal a high frequency of these four gyroviruses in human stool, possibly owing to cross-species transmission of gyroviruses and their replication in humans, or alternatively to passive transit of animal viruses via food intake, as has been observed for plant viruses [30Zhang T. et al.RNA viral community in human feces: prevalence of plant pathogenic viruses.PLoS Biol. 2006; 4: e3Crossref PubMed Scopus (577) Google Scholar]. Within the Circoviridae family the cycloviruses constitute a new genus, and are found in the feces of humans and other animal species, posing similar questions as gyroviruses [31Delwart E. Li L. Rapidly expanding genetic diversity and host range of the Circoviridae viral family and other Rep encoding small circular ssDNA genomes.Virus Res. 2012; 164: 114-121Crossref PubMed Scopus (128) Google Scholar]. In healthy individuals there seem to be a paucity of viruses in the plasma, with the exception of anelloviruses. Although anelloviruses are so far considered to be non-pathogenic, they cause persistent viremia and can be identified in more than 70% of the general population worldwide [32Hino S. Miyata H. Torque teno virus (TTV): current status.Rev. Med. Virol. 2007; 17: 45-57Crossref PubMed Scopus (161) Google Scholar]. Recently, plasma samples from febrile and afebrile children under the age of 3 years were compared using PCR and NGS [10Wylie K.M. et al.Sequence analysis of the human virome in febrile and afebrile children.PLoS ONE. 2012; 7: e27735Crossref PubMed Scopus (149) Google Scholar]. Plasma from afebrile children contained no viral reads other than anelloviruses, whereas sequences from other viral species were recovered from approximately 70% of samples from children with unexplained fever. Virus reads obtained by NGS were on average fivefold more abundant in samples from febrile children than from afebrile children, and enterovirus/rhinoviruses and roseoloviruses were particularly abundant. Herpesviridae, including herpes simplex virus types 1 and 2 (HSV1 and HSV2), cytomegalovirus (CMV), Epstein–Barr virus (EBV), and HHV types 6 to 8, are well-characterized human viruses. Their prevalence in human plasma is high and increases with age. PCR surveys in healthy, febrile and/or immunosuppressed patients have shown that each of these viruses can be detected in human tissues, including blood samples. CMV, EBV, HHV6, and HHV7 are leukotropic viruses and their corresponding viral DNA sequences can be readily detected from circulating human leucocytes [33Zumla A. Mandell G.L. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. Churchill Livingstone, 2000: 1937-2022Google Scholar]. The determination of the significance and imputability of such findings requires careful analysis that integrates the immune status of the host, comorbidities, and concomitant symptoms, as well as the sensitivity of the detection technique. Also, the latent stage of cell-associated viral DNA should be distinguished from productive cycles leading to the production of virus particles. Under homeostatic conditions, these viruses could be considered to be a non-pathogenic component of the human virome. Nevertheless, most of these viruses can be associated with either acute disease at the time of primary infection or with active viral replication upon immunosuppression (Figure 2), and either directly or indirectly with pathologic conditions such as lymphoma or sarcoma (EBV and HHV8), encephalitis (HSV, CMV, EBV, and HHV6), or digestive symptoms (CMV and HHV6). It is also likely that the interplay between the host, these viruses, and the microbiome translates into medically significant outcomes, such as inflammatory conditions [34Cadwell K. et al.Virus-plus-susceptibility gene interaction determines Crohn's disease gene Atg16L1 phenotypes in intestine.Cell. 2010; 141: 1135-1145Abstract Full Text Full Text PDF PubMed Scopus (730) Google Scholar, 35Kuss S.K. et al.Intestinal microbiota promote enteric virus replication and systemic pathogenesis.Science. 2011; 334: 249-252Crossref PubMed Scopus (470) Google Scholar]. The case of HHV6 merits particular attention because the genome of this virus can be chromosomally integrated and transmitted vertically. The significance for health of this chromosomal integration remains unclear [36Pellett P.E. et al.Chromosomally integrated human herpesvirus 6: questions and answers.Rev. Med. Virol. 2012; 22: 144-155Crossref PubMed Scopus (284) Google Scholar]. Of note, some viruses that persistently infect the gut can also be transiently or more persistently present in the blood. A pathogenic strain of simian immunodeficiency virus (SIV), as opposed to a non-pathogenic strain, has recently been described to expand the enteric virome [37Handley S.A. et al.Pathogenic simian immunodeficiency virus infection is associated with expansion of the enteric virome.Cell. 2012; 151: 253-266Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar] in nonhuman primates. It was suggested that immunosuppression results in an increased level of enteric viral infection that promotes and accelerates acquired immune deficiency syndrome (AIDS) via the modification of the intestinal mucosa and the induction of systemic immune activation. In support of the relationship between immune suppression and expansion of the enteric virome, evidence of HGyV was found in the blood of three of 100 solid organ transplant recipients and in one HIV-infected person, and circulating HGyV was detected transiently in longitudinal plasma samples [38Maggi F. et al.Human gyrovirus DNA in human blood, Italy.Emerg. Infect. Dis. 2012; 18: 956-959Crossref PubMed Scopus (42) Google Scholar]. HGyV was also detected in 3 of 352 (0.85%) plasma samples from healthy persons [39Biagini P. et al.Human gyrovirus in healthy blood donors, france.Emerg. Infect. Dis. 2013; 19: 1014-1015Crossref PubMed Scopus (27) Google Scholar]. This illustrates that the immune system has an impact upon virome composition. Future studies should focus on studying the impact of virome changes as an indicator of immunosuppression and as a causal factor for disease progression and even occurrence. It has often been assumed that perfectly adapted viruses are clinically silent, having found an ideal equilibrium with their host to avoid their counter-selection, thereby leading to viral persistence and favoring transmission. However, in some cases, symptoms such as cough, diarrhea, and aggressiveness (for example, in animal rabies increased biting behavior facilitates increased virus transmission) increase the dissemination of the virus. In view of the number of new orphan viruses that are discovered, the question arises as to whether some viruses have actually been selected because they provide a selective advantage to their hosts. For example, some viruses could participate in physiological processes, as is well established for commensal bacteria. The formation of a syncytium layer at the maternal–fetal interface has been demonstrated in primates, rodents, lagomorphs, carnivores, and recently in ruminants [40Cornelis G. et al.Captured retroviral envelope syncytin gene associated with the unique placental structure of higher ruminants.Proc. Natl. Acad. Sci. U.S.A. 2013; 110: E828-E837Crossref PubMed Scopus (105) Google Scholar], and is governed by genes that now encode syncytin protein but that were captured millions of years ago from retroviral genes encoding envelope glycoproteins. Most papillomaviruses are considered to be innocent bystanders of the skin, with no significant tissue damage resulting from their replication and chronic asymptomatic shedding. Nonetheless, it has been speculated that β-HPV could be a human symbiont and actively participate in the proliferation of keratinocytes during wound healing. Local inflammation might transiently decrease the expression of members of the EVER/ZnT-1 complex (which maintains cellular zinc homeostasis) together with barrier efficacy against β-HPV infection [41Lazarczyk M. et al.The EVER proteins as a natural barrier against papillomaviruses: a new insight into the pathogenesis of human papillomavirus infections.Microbiol. Mol. Biol. Rev. 2009; 73: 348-370Crossref PubMed Scopus (119) Google Scholar]. Some viral infections also seem to confer better fitness to infected individuals in the context of other infections. The GBV-C (GB virus type C), also known as hepatitis G virus, is a lymphotropic virus classified in the Flaviviridae family. Similarly to the closely related GBV-A and GB-V viruses of New World primates, it is distantly related to a major human pathogen, HCV. GBV-C is frequently found in humans, with viremia detected in approximately 1–4% of healthy donors in developed countries but in up to 20% in some developing regions. GBV-C is not responsible for any known disease but, conversely, a set of studies associate survival in HIV-infected individuals with GBV-C infection. These epidemiological results are experimentally supported by the observation of an inhibition of HIV replication by GBV-C, which is demonstrable in T cell cultures, although the underlying mechanisms are only partly understood. GBV-C infection is thought to alter the expression of HIV entry receptors, inhibit HIV replication, enhance innate immune responses, polarize cytokines towards a T helper 1 (Th1) profile, protect CD4+ T cells from apoptosis, decrease lymphocyte activation, and interfere with IL-2-induced CD4+ T cell expansion [42Bhattarai N. Stapleton J.T. GB virus C: the good boy virus?.Trends Microbiol. 2012; 20: 124-130Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar]. It has been shown that latent infection by mouse herpesviruses highly similar to human EBV and CMV activates the innate immune response and protects mice against distant microorganisms including bacteria [43Barton E.S. et al.Herpesvirus latency confers symbiotic protection from bacterial infection.Nature. 2007; 447: 326-329Crossref PubMed Scopus (585) Google Scholar]. It is tempting to speculate that this beneficial effect of infection might extend to human herpesviruses. Among the possible mechanisms, latent herpesvirus infection was sufficient to arm natural killer (NK) cells [44White D.W. et al.Latent herpesvirus infection arms NK cells.Blood. 2010; 115: 4377-4383Crossref PubMed Scopus (58) Google Scholar]. Even if such protection against acute infections was shown to be relatively short-lived [45Yager E.J. et al.Gamma-herpesvirus-induced protection against bacterial infection is transient.Viral Immunol. 2009; 22: 67-72Crossref PubMed Scopus (55) Google Scholar], host fitness could be improved when there is a high risk of infection. How fitness is increased and balanced with the rare complications associated with these viruses, such as EBV-malignancies and CMV infections in immunocompromised patients, together with implications regarding the benefit of vaccination against herpesviruses, has been the subject of discussion [46Barton E.S. et al.Herpesvirus latency and symbiotic protection from bacterial Infection.Viral Immunol. 2009; 22: 3-4Crossref PubMed Scopus (16) Google Scholar]. Moreover, fitness may vary as a function of the environment and also over time. Beneficial viruses may have turned into enemies in modern times because of longer lifespans and the introduction of new therapies such as immunosuppressive drugs (e.g., leading to possible long-term deleterious effects of persistent viruses on the immune system and cell survival). It is noteworthy that gyroviruses harbor an apoptin gene, which encodes a protein that has the rare quality of being specifically cytotoxic for cancer cells. Indeed, natural infection could be of benefit in controlling the development of tumor cells [47Los M. et al.Apoptin, a tumor-selective killer.Biochim. Biophys. Acta. 2009; 1793: 1335-1342Crossref PubMed Scopus (95) Google Scholar]. Because these viruses have been found in human stool and at the surface of the skin, they could potentially be of benefit in controlling the early amplification of transformed cells. For example, the expression of polyomavirus large T is sufficient to render cells susceptible to apoptosis upon expression of apoptin. The biological significance of these observations, particularly in light of the many new polyomaviruses found at the surface of the skin or in stool, merits further studies. For viruses to be part of the human virome they must be able to persist in humans. Because
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