Human Cancer Viruses (oncoviruses)

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NS4B is a key scaffold protein in the formation of viral replication complex [ ]. The NS5A protein is composed of three domains. Hepatocarcinogenesis is a multistep process that may last for years; it involves progressive accumulation of different genetic alterations which lead to malignant transformation. Malignant transformation of hepatocytes occurs through increased liver cell turnover, induced by chronic liver injury and regeneration, in the context of inflammation and oxidative stress.

HCV proteins may directly upregulate mitogenic pathways, block cell death and induce reactive oxygen species ROS production. Chronic inflammation exacerbates ROS production, which is considered a main source of genetic mutations. HCV dysregulates host lipid metabolism, causing liver fat accumulation which in many patients is associated with HCC. HCV is also able to induce angiogenic and metastatic pathways. Reproduced with permission from Vescovo, T.

Over-expression of HCV viral proteins has been demonstrated to promote cellular proliferation, transformation, and tumor initiation, suggesting the direct role of HCV proteins in activating tumorigenic pathways [ , ]. Rb protein regulates cell cycle progression by repressing E2F, a transcription factor that is essential for entry into S phase of the cell cycle.

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The impact of HCV viral proteins on the activity of p53 is a topic of debate. Some have reported that low levels of HCV core protein stimulate expression of p53, while others have reported that high levels of core protein suppress transcriptional activity of p53 [ ]. These discrepancies suggest that core protein and p53 have a viral concentration-dependent relationship, but whether it is a direct or inverse relationship is unclear.

The role of HCV non-structural proteins in the regulation of p53 appears to be primarily inhibitory. Oxidative stress is known to induce DNA damage and activate oncogenic signaling pathways [ ]. In the liver, ROS is mainly generated by the mitochondria [ ]. Given that HCV replication is closely associated with the mitochondrial membrane, a strong correlation exists between oxidative stress, mitochondrial injury, and DNA damage. Enhanced expression of HCV core protein is associated with mitochondrial injury, increased ROS levels, and increased lipid peroxidation products [ ].

Viral proteins also play a direct role in the induction of angiogenesis. These are important mediators of endothelial cell growth and vascular formation, and are potential therapeutic targets. As opposed to HBV infection, in which viral proteins are the primary players in oncogenesis, the oncogenic properties of HCV have been attributed primarily to indirect pathways via inflammation and oxidative stress [ ] Figure 6. This notion is supported by the direct correlation between the degree of fibrosis and the increasing risk of HCC in chronic HCV infection [ ].

Lymphotoxin, in particular, plays a critical role in the progression of HCC. Research has demonstrated that HCV viral proteins, especially NS5B, and host immune cells can directly stimulate lymphotoxin release in a human hepatocyte cell line [ ]. Hepatic lymphotoxin overexpression in mice leads to chronic progressive hepatitis, hepatotoxicity, and spontaneous HCC formation [ ].

Host factors, such as metabolic alterations, are closely associated with increased risk of HCC development [ ]. Diabetes mellitus and obesity have been shown to synergistically promote liver inflammation and carcinogenesis in association with HCV infection [ ]. The accumulation of free fatty acids triggers the production of ROS as a consequence of mitochondrial injury and endoplasmic reticulum ER stress [ ].

Oxidative stress can stimulate the inflammatory cascade leading to release of pro-inflammatory cytokines, promotion of collagen expression, which culminates in liver fibrosis, and the induction of gene mutations and chromosomal instability [ ]. Treatment is recommended for all patients, except for those with life expectancy of less than 12 months [ ]. Highest priority for treatment should be given to those with advanced fibrosis, compensated cirrhosis, organ transplant recipients, type 2 or 3 cryoglobulinemia with end-organ manifestations, proteinuria, nephrotic syndrome, or membranoproliferative glomerulonephritis given significant risk of severe complications in these patient populations [ ].

Additional groups of patients that should receive high priority for treatment, include those with fibrosis, HIV-1 coinfection, HBV coinfection, other coexistent liver disease, debilitating fatigue, type 2 diabetes mellitus, and porphyria cutanea tarda [ ]. Antineoplastic properties of IFN are mediated through their inhibitory effects on hepatic stellate cell-mediated fibrogenesis and on inhibitors of MMP, resulting in decreased fibrogenesis and increased fibrinolysis, respectively [ , ].

In addition, IFN works by inhibiting angiogenesis, promoting tumor cell apoptosis, and stimulating hepatic stellate cell death [ ]. Response to IFN-based therapy is partly dependent on genotype. Genotype 5 and 6-infected patients have intermediate response rates [ ]. While limited by its toxicities, IFN remains an important adjunct to DAAs in difficult-to-cure patients, such as patients with genotype 3 infection [ ].

Currently, DAA agents are first-line therapies due to higher efficacy in achieving virologic cure and fewer serious adverse events. Moreover, liver related complications, such as hepatic encephalopathy and variceal hemorrhage, are reduced and hepatic function, as indicated by the Model for End-Stage Liver Disease MELD score is improved [ ]. However, the limited availability and high costs of DAAs restrict their use to mainly high-income countries [ ].

Treatment options are based on HCV genotype, history of prior therapy, and presence of cirrhosis Table 1 [ , ]. In general, patients with cirrhosis require longer duration of therapy and addition of ribavirin. Estimates are based primarily on seroprevalence of blood donors, hospitalized, and pregnant patients, so the results may not accurately represent the entire population of these regions [ ].

Seroprevalence in the United States is only 0. HTLV-1 can be transmitted through breast milk, sexual intercourse, and infected blood products [ ]. Transmission via breastmilk occurs Male to female is the most common form of sexual transmission, with a much lower rate for female to male [ , ]. Donor blood transmission is highly uncommon due to the screening of donor blood in many countries, including the United States, Japan, Brazil, France, and the United Kingdom UK [ ].

In , there were worldwide cases of ATLL, with most occurring in endemic regions [ 7 ]. ATLL occurs between age 20 and 80 years, with an average onset age of 58 [ ]. ATLL has infrequently been observed in children and adolescents. ATLL is a clonal proliferation of CD4 T regulatory cells and exists as four different subtypes in the Shimoyama classification: acute, lymphoma, chronic, and smoldering [ ] Table 2.

Classification is based upon organ involvement, leukemic manifestation, lactate dehydrogenase LDH level, and calcium level [ , ]. The acute and lymphoma subtypes are considered to be aggressive and have a large tumor burden, lymph node, and blood involvement, and hypercalcemia [ , ].

Overall survival OS rates are 8. The chronic and smoldering subtypes are considered indolent, with OS rates of Clinical features of ATLL include generalized lymphadenopathy, splenomegaly, hepatomegaly, skin lesions, hypercalcemia, lytic bone lesions, involvement of central nervous system and gastrointestinal tract [ ], and opportunistic infections that are caused by Pneumocystis jirovecci, candida, cytomegalovirus, and Strongyloides stercoralis [ ]. Skin lesions are of a wide variety, including rashes, plaques, papules, and erythrodermic and purpuric lesions [ ] Figure 7. Examples of cutaneous lesions observed in ATL.

A Chronic form with papular pattern; B Acute form showing exfoliative erythroderma; C Smoldering form with a pattern of papules and erythematous scaly plaques; D Primary cutaneous tumoral form. Reproduced with permission from Oliveira P. Reproduced with permission from Marcais, A. ULN, upper limit of normal. The positive-sense strand encodes the usual retroviral structural gene products Gag capsid, nucleocapsid, matrix , Pro, polymerase Pol , and Env from unspliced or singly spliced transcripts [ , , ]. Two long terminal repeats LTRs flank the structural genes [ ]. Upon HTLV-1 cell entry and uncoating, the viral genome undergoes reverse transcription into DNA before integrating into the host genome as a provirus [ ].

Integration often occurs near transcription factor binding sites, including those for STAT1, TP53, and HDAC6 [ , ]; this is 15 kb upstream of host genes that are commonly dysregulated in leukemias [ ]. Viral cell-attachment and spread within the host require interaction of multiple proteins and processes.

Env encodes a precursor protein, which is cleaved into two proteins that are essential for viral infectivity: transmembrane TM and surface SU protein. TM and SU are acquired by the virions as they are released from the infected cell [ , ]. SU binds to the host cell surface receptors glucose transporter 1, neuropilin-1, and heparan sulfate proteoglycans, causing viral-cell membrane fusion and subsequent infection [ , , , , , ]. HTLV-1 infection primarily spreads cell-to-cell within the host via two mechanisms: mitosis and viral synapse transfer [ , ]. In mitosis, daughter cells contain proviral DNA that is inserted into the host genome at the same site as in the parent cell [ ].

During non-mitotic cellular transfer, cell-to-cell contact is required because HTLVpositive cells rarely release free virions, and only 1 of 10 5 to 1,, of released virions are infectious [ , ]. Cell-to-cell transmission is 10, times more efficient than virion infection of a non-neighboring cell [ ] and explains why cell-containing fluids, such as blood, semen, and breast milk are successful in transmitting infection [ ].

When an infected cell contacts an uninfected cell, Gag and Env proteins polarize to the area of contact to facilitate fusion [ ]. The cell transiently expresses high levels of Tax protein and intercellular adhesion molecule-1 ICAM-1 , forming a virological synapse VS [ ] or a viral biofilm [ ]. Virions released from the infected cell enter the VS and bind HTLV-1 receptors before entering the target cell [ , ].

Once inside of the target cell, HTLV-1 will form a provirus and integrate into the host genome at a site unique from that of the source cell, creating a new clone [ ]. Tax is an HTLV-1 transactivator protein that is coded by the sense strand of the pX provirus region [ , ]. Tax plays an important yet complicated role in ATLL development, as it interacts with more than a hundred cellular proteins to prevent apoptosis, enhance cell signaling, induce cell cycle dysregulation, activate proto-oncogenes, and interfere with DNA repair [ , , ].

Not only does Tax affect transcription and cell-cycle regulation, it also contributes to genetic damage. This damage occurs directly through clastogenic DNA damage and aneuploidic effect, and indirectly through the over-activation of the DDR pathway [ ]. The effects of Tax, however, are seen even after its repression [ ]. HBZ stimulates lymphocyte proliferation through upregulation of E2F1 gene [ ] and prevents apoptosis through the inhibition of the pro-apoptotic Bim gene [ ].

These various functions demonstrate the oncogenic importance of HBZ. Oligoclonal proliferation was previously thought to increase the risk of ATLL development, but it has been shown that the number of clones, not the degree of oligoclonality, increases the risk of ATLL development [ ]. This process is not yet completely understood. Tax is fundamental for initiating ATLL transformation by promoting cellular proliferation, genetic instability, and cell cycle dysregulation [ ], whereas HBZ appears as necessary for the propagation of the transformed cell line [ ].

Epigenetic abnormalities, including alteration in DNA methylation patterns and histone modification, also play a role in ATLL transformation [ ]. H3K27 me3 suppresses miRNAs, tumor suppressors, epigenetic modifiers, and transcription factors [ , ]. ATLL does not have a high response rate to treatment. Clinical response criteria have been defined to assess therapies and guide treatment algorithms [ ]. Antiviral therapy is also now being used. Data are preliminary but suggest that arsenic could also be paired as part of a triple maintenance therapy with ZDV and IFN after successful induction therapy.

This therapy is thought to help transform an immunodeficient T regulatory and Th2 phenotype to an immunocompetent Th1 phenotype [ ]. Monoclonal antibodies, such as an anti-CD25 antibody [ , ] and mogamulizumab, an anti-CCR4 antibody [ , ], have proven successful as ATLL treatment in clinical trials, whereas, A24, an anti-transferrin receptor antibody, has shown promise in preclinical studies [ ]. Watchful waiting is an option for chronic and smoldering subtypes [ ].

For treatment-refractory disease, allogeneic stem cell transplantation alloSCT is a potentially curative option [ ]. Promising new therapies include vorinostat and romidepsin histone deacetylase inhibitors , alemtazumab anti-CD52 antibody , and brentuximab vedotin anti-CD30 antibody [ ]. A recent animal model indicated that pulsed dendritic cell therapy may decrease PVL by stimulating HTLV-1 responsive cytotoxic lymphocytes [ ]. Adjunct treatments are also available to address hypercalcemia and opportunistic infections that are associated with ATLL.

Hypercalcemia can be managed with hydration and bisphosphonates [ , ]. Opportunistic infections should be promptly treated, and prophylaxis for Pneumocystis jirovecci pneumonia, viral infections, and fungal infections is recommended with trimethoprim-sulfamethoxazole, valacyclovir, and anti-fungal agents, respectively [ , ]. Additionally, patients with history of exposure to Strongyloides stercoralis can be given ivermectin and albendazole for prophylaxis against systemic strongyloidiasis [ , ].

Viral oncology is a field of growing interest that is continually under research. Promising new agents are emerging for the treatment of virus-related cancers. As our understanding of the molecular pathogenesis linking oncovirus and human cancer continues to improve, we are seeing a push for the development of a multitude of potential treatments that may enhance the killing of infected tumor cells, while sparing normal, healthy cells, and thereby maximizing the therapeutic index. The seven known human oncoviruses target many of the same host signaling pathways to induce oncogenesis.

Novel therapies that have shown efficacy in one virus-related cancer may be expanded to all virus-related cancers sharing the same pathways. These innovative approaches may finally put a cure for cancer on the horizon. National Center for Biotechnology Information , U.

Journal List J Clin Med v. J Clin Med. Published online Nov Haley , 1 and Stephen K. Tyring 1, 2. Find articles by Uyen Ngoc Mui. Christopher T. Find articles by Christopher T. Stephen K. Author information Article notes Copyright and License information Disclaimer. Received Oct 24; Accepted Nov This article has been cited by other articles in PMC. Introduction In , the first human oncovirus was discovered, when Epstein-Barr virus EBV was detected in Burkitt lymphoma cells by electron microscopy [ 1 ]. Epstein-Barr Virus Epstein-Barr virus, formerly known as human herpesvirus-4, is one of eight known human viruses belonging to the herpesviridae family.

Open in a separate window. Figure 1. EBV Oncogenic Proteins LMP-1 is generally considered as the main oncogenic protein of EBV, and it is essential for the transformation of resting primary B cells into proliferating lymphoblastoid cells [ 33 , 34 , 43 ]. Therapeutic Options The standard treatment of EBV-positive malignancies is no different than that of EBV-negative malignancies, and consists of systemic chemotherapy and radiotherapy [ 72 ].

Human Herpesvirus-8 Human herpesvirus-8, also known as Kaposi sarcoma-associated herpesvirus, is another member of the herpesviridae family best known for its association with Kaposi sarcoma KS. Figure 2. Figure 3. Figure 4. Pathogenesis and Carcinogenesis The carcinogenic role of HPV has been studied to a great extent in cervical cancer, and it is assumed that HPV has a similar, albeit not identical, role in other HPV-associated cancers.

Cervical Cancer Cervical cancer is the fourth most common cancer in women, with , new cases and , deaths occurring annually [ ]. Penile Cancer Penile cancer is rare, comprising only 0. Indirect Mechanism of HBV Oncogenesis Chronic inflammation is linked to several critical events that are involved in tumor initiation and promotion. Figure 5. Therapeutic Options One of the challenges in treating HCC is that the majority of HCC cases develop in the background of a cirrhotic liver, and therapies such as radiation and chemotherapy damage surrounding normal hepatocytes, which can exacerbate liver failure [ ].

Figure 6. Indirect Mechanism of HCV Oncogenesis As opposed to HBV infection, in which viral proteins are the primary players in oncogenesis, the oncogenic properties of HCV have been attributed primarily to indirect pathways via inflammation and oxidative stress [ ] Figure 6. Figure 7. Figure 8.

Conclusions Viral oncology is a field of growing interest that is continually under research. Author Contributions All authors equally contributed to the paper. Conflicts of Interest The authors declare no conflict of interest. References 1. Epstein M. Rous P. A sarcoma of the fowl transmissible by an agent separable from the tumor cells.

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Searching for human oncoviruses: Histories, challenges, and opportunities

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Genome Res. Brianti P. Review of HPV-related diseases and cancers. New Microbiol. Handler M. Human papillomavirus vaccine trials and tribulations: Clinical perspectives. Doorbar J. The biology and life-cycle of human papillomaviruses. Instead, in a Machiavellian twist, viruses recruit human proteins to methylate DNA and thus turn off important other bits of human DNA. Of course, it makes sense that viruses would choose to turn off genes that the immune system needs to fight the virus, "like interferon-b, which is a highly anti-viral gene expressed in virtually all cell types; or genes that T cells need to recognize virus-infected cells," Kuss-Duerkop says.

The result is an immune system less able to fight the virus, and, if the virus causes cancer, a "microenvironment" near the tumor in which the immune system is suppressed. In fact, we see this in many cancers -- tumors may specifically cloak themselves from the immune system, and they may also suppress the immune system more globally near the places they grow. Sitting opposite these cancer-causing viruses and their ability to undercut the immune system are doctors and researchers who would like to recruit the immune system to attack cancer.

Again: viruses turn down the immune system against the cancers they cause, and doctors would like to turn up the immune system against these same cancers. And, in fact, these doctors and researchers are finding incredible success with this strategy; for example, PD-1 inhibitors remove this "cloak" that cancers use to hide from the immune system, and CAR-T cell therapies use specially engineered T-cells to seek cancer-specific proteins and destroy the cancer cells to which they are attached. But challenges to immune-based therapies against cancer remain. Not least among which is the fact that while some patients respond to these therapies, others do not.

The answer to increasing the effectiveness of immune therapies, or perhaps at least to choosing which patients are most likely to benefit from immune therapies, may lie in understanding the ways viruses and cancers themselves have evolved to evade the immune system. Maybe if virus-related cancers have methylated DNA promoter regions of immune-related genes, the answer to increasing the effectiveness of immune-based therapies against cancer is to demethylate these genes. Note: Content may be edited for style and length. Science News.

Viruses , ; 10 2 : 82 DOI: ScienceDaily, 2 March University of Colorado Anschutz Medical Campus. Here's how viruses inactivate the immune system, causing cancer. Retrieved September 25, from www. These designer viruses alert the immune system and cause it to send killer cells to help fight the tumor. The results