Viruses and Human Cancer

115YALE JOURNAL OF BIOLOGY AND MEDICINE 79 (2006), pp.115-122.Copyright © 2006.CANCER MECHANISMSViruses and Human CancerJohn B. LiaoDepartment of Obstetrics, Gynecology, and Reproductive Sciences, Yale UniversitySchool of Medicine, New Haven, ConnecticutAn estimated 15 percent of all humancancers worldwide may be attributed toviruses [1], representing a significant portionof the global cancer burden. Both DNAand RNA viruses have been shown to becapable of causing cancer in humans. Epstein-Barr virus, human papilloma virus,hepatitis B virus, and human herpes virus-8 are the four DNAviruses that are capableof causing the development of human cancers.Human T lymphotrophic virus type 1and hepatitis C viruses are the two RNAviruses that contribute to human cancers.Close study of viruses and human cancerhas led to optimism for the developmentof new strategies for the preventionof the preceding infection that can lead tocarcinogenesis. The presence of viral geneproducts in tumor cells that require them tomaintain their unchecked proliferation alsocan provide important targets for directedtherapies that specifically can distinguishtumor cells from normal cells. The inabilityof traditional cancer therapy, such aschemotherapy and radiation, to distinguishcancer cells from normal cells is a significantdrawback and leads to toxicities forpatients undergoing treatment. Targetedtherapies directed against viral proteins orgenerate immune responses in order to eitherprevent infection or kill infected cellsor cancer cells hold much promise for moreeffective and tolerable strategies.Human tumor virusesAlthough it is convenient to considerhuman tumor viruses as a discrete group ofviruses, these six viruses, in fact, have verydifferent genomes, life cycles, and representa number of virus families. The pathfrom viral infection to tumorgenesis is slowand inefficient; only a minority of infectedindividuals progress to cancer, usuallyyears or even decades after primary infection.Virus infection also is generally notsufficient for cancer, and additional eventsand host factors, such as immunosuppression,somatic mutations, genetic predisposition,and exposure to carcinogens mustalso play a role.Hepatitis B and C virusesHepatitis C virus is an enveloped RNAvirus of the flavivirus family. It is capableTo whom all correspondence should be addressed: John B. Liao, Yale University Schoolof Medicine, P.O. Box 208005, New Haven, CT 06520. Tel: [phone]; Fax: [phone]; E-mail: [e-mail] B. Liao is a Berlex-NICHD Scholar of the Reproductive Scientist Development Programsupported by NIH grant #5K12HD008949.†Abbreviations: EBV, Epstein-Barr virus; HHV-8, human herpesvirus; HPV, Human papillomavirus;HTLV-1, Human T lymphotropic virus type I.of causing both acute and chronic hepatitisin humans by infecting liver cells. It is estimatedthat approximately 3 percent of theworld’s population are hepatitis C carriers[2]. Chronic infection with hepatitis C virusresults in cirrhosis, which in turn can lead toprimary hepatocellular carcinoma. Between1 and 2 percent of infected patients with subsequentcompensated cirrhosis will developprimary hepatocellular carcinoma per year[3]. Transmission of the virus occursthrough the blood, with shared needles in intravenousdrug abuse, sexual activity, andparturition being the primary routes.The hepatitis B virus of the family hepadnaviridaeis, by contrast, a DNA virus,but the features of its resulting disease sharemany similarities with hepatitis C virus.Hepatitis B virus also is a blood-bornepathogen that can result in acute and chronichepatitis. Chronic hepatitis, that is infectionslasting more than three months, can lead tocirrhosis and liver failure. Chronic infectionalso can lead to the development of hepatocellularcarcinoma [4]. Hepatitis B infectionsis a significant global health problemwith an estimated 2 billion people infectedand 1.2 million deaths per year attributed tosubsequent hepatitis, cirrhosis and hepatocellularcarcinoma [5].Hepatocellular carcinoma is an aggressivetumor that can occur in the setting ofliver disease resulting from infections withhepatitis B and/or hepatitis C virus, althoughthe exact mechanism of oncogenesis bythese viruses is unclear. Diagnosis is usuallymade late in the course of liver disease andmedian survival ranges from six to 20months after that time [6]. The traditionalfoundation of treatment is surgical, whethertumor resection or transplantation. However,nonsurgical options such as percutaneousethanol injection, transarterial embolization,radiofrequency ablation, chemotherapy, andradiotherapy are also utilized. The choice oftherapies frequently depends on the extentof disease and the amount of liver functionthe patient has in reserve [7,8].Research into novel therapies have focusedon the use of virally targeted and immunologicalstrategies with an eye onpreventing infection. Unfortunately, hepatitisC virus has proved to be poorly suited tovaccines because its genome possesses avery high mutation rate, especially in the hypervariableregion of the genome coding forthe envelope proteins allowing it to escapeimmune recognition and elimination by thehost. There are 11 distinct genotypes andseveral subtypes identified.The introduction of vaccines againsthepatitis B virus in the early 1980s markeda major milestone with what might be consideredthe first cancer prevention vaccine,although the primary goal of this vaccinewas to prevent hepatitis. Since that time,more than 110 countries have adopted a universalpolicy of immunizing all newborns,according to theWorld Health Organzation.Additionally, countries that have successfullyimplemented this program significantlyhave decreased the carrier rate andinfection in their populations [9]. However,vaccine coverage is often low in many developingcountries due to the cost, lack ofheath care infrastructure for delivery of thevaccine, and the need for three needle injectionsover six months. Even in some developednations, universal vaccination has notbeen implemented because of the belief thatit is a limited public health problem and theexpense is not justified [10,11].New challenges for combating hepatitisB infection center around efforts to addressthe limitations of the current vaccine: theneed for multiple injections, the presence ofup to 10 percent nonresponders to the vaccine,the discovery of hepatitis B virus Sgene escape mutants in infants that were infecteddespite an adequate response to thevaccine, and the cost for developing nations.The current multiple dosing schedule isbeing addressed with attempts to combine itwith other required vaccines or decrease thenumber of doses. Oral vaccination also isbeing investigated as a way to obviate theneed for trained personnel to administer injections.TheWorld Health Organization estimatesthat from $8 to $12 billion will beneeded to immunize children from the poorestcountries from 2005-2010, which hasprompted efforts from public and private or-116 Liao: Viruses and human cancerganizations to advocate for funding to fillthe need.Medical therapy for patients infectedwith hepatitis B has focused on the use ofinterferon to reduce viral replication, whichdecreases the incidence of life-threateningliver complications in patients who respondto the treatment [12]. Interferon alpha treatmentis effective in 20 to 30 percent of casesin inducing loss of the hepatitis B e antigen.However, the impact of interferon therapyon subsequent hepatocellular carcinomarates is less clear [13,14]. Interferon therapyis also limited by cost and side effects.The limitations of interferon therapyhave been partly circumvented with the useof targeted antiviral agents. Lamivudine hasbeen shown in a large multicenter randomizedplacebo-controlled trial to be effectivein reducing both the incidence of hepatic decompensationand the risk of hepatocellularcarcinoma [15]. Other antiviral agents continueto join the armamentarium; lamivudine,adefovir, entecavir, and telbivudinehave been shown to be effective in hepatitisB disease. These agents are nucleotide analoguesthat exploit the need for the hepatitisB virus to use reverse transcriptase to replicateviral DNA. Since these agents specificallytarget the viral replication machineryand are given orally, they are better tolerated.However, it has been observed thatlong-term therapy with lamivudine can leadto the emergence of genotypic resistancemutations [16], but this does not negate thebenefits of lamivudine therapy in reducingthe rates of hepatocellular carcinoma [15].The success of these therapies has reachedthe point where patients with advanced cirrhosissecondary to hepatitis B can betreated and transplanted without the developmentof hepatitis B in the transplantedliver.Medical treatment of infection withhepatitis C has not progressed at the samespeed. Pegylated interferon with ribavirin,an antiviral agent that may act as a nucleosideanalogue and inhibitor of RNAdependentRNA polymerase, has been shown to besuccessful in eradicating infection in half ofpatients [17]. However, therapy is expensiveand side effects are significant. Phase II trialsof oral antivirals such as protease inhibitorsand polymerase inhibitors arecurrently under way [18]. Unlike hepatitisB, treatment of hepatocellular carcinomadue to hepatitis C infection with transplantationalmost always results in recurrent infectionof the transplanted liver [19].The search for targeted therapies thatcan block hepatitis C viral replication by selectivelyinhibiting viral replication has formany years been hampered by the lack ofexperimental infection systems, in either cellculture or animal models to test candidatetherapies. The recent development of viralreplicons, subgenomic RNAs that are expressedand autonomously replicate withincells, has led to the use of hepatitis C viralreplicons that can replicate in human hepatomacells lines [20] and the developmentof mouse models of the disease [21,22].These advances may herald more rapidprogress in the development of virally targetedtherapies such as hepatitis C virus specificprotease and polymerase inhibitors.Epstein-Barr virus (EBV) and humanherpesvirus 8 (HHV-8)EBV and HHV-8 (also known as Kaposisarcoma herpesvirus) are both herpesvirusesthat possess largedouble-stranded DNA genomes. As with allherpesviruses, they encode enzymes involvedin DNA replication and repair andnucleotide biosynthesis. They also both possessthe ability to establish latency in B lymphocytesand reactivate into the lytic cycle.Both also are associated with naturally occurringtumors in humans.EBV is a ubiquitous virus that is mostcommonly known for being the primaryagent for infectious mononucleosis. Up to95 percent of all adults are estimated to beseropositive, and most EBV infections aresubclinical. EBV also is associated with anumber of malignancies: B and T cell lymphomas,Hodgkin’s disease, post-transplantlymphoproliferative disease, leiomyosarcomas,and nasopharyngeal carcinomas. Ofthese cancers, Burkitt’s lymphoma, posttransplantlymphoproliferative disease, andLiao: Viruses and human cancer 117leiomyosarcomas show an increased frequencyin patients with immunodeficiency,suggesting a role for immunosurveillance inthe suppression of malignant transformation.The primary site of infection is theoropharyngeal cavity, and EBV is capable ofinfecting both B cells and epithelial cells andswitching between the two [23]. The majorsurface glycoprotein, gp350/220, binds to thecd21 receptor on B cells. Transformation ofB cells is a highly efficient process requiringa large portion of the EBV genome, whichbecomes circular for replication and latency.Virus will directly enter the latent gene expressionstate with suppression of the lyticcycle. Production of a number of latent geneproducts are required for immortaliztion.Immune therapy of EBV-associated tumorshas been target of research since standardtherapy generally has entailed the useof multi-agent chemotherapy, radiation therapy,and surgery. This work has centeredaround adoptive transfer of EBV-specificcytotoxic T-cells [24,25] and shown successbut must overcome obstacles such as potentialgraft vs. host disease and resistance dueto mutation of selected EBV epitopes [26].Vaccines capable of preventing primaryEBV infection or boosting immune responsesagainst EBV-associated tumors areunder investigation. Much of the developmentthus far has focused on gp350/220 subunitvaccines [27], since it is one of the mostabundant proteins on the virus coat and alsothe protein against which the human EBVneutralizing antibody response is directed[28]. Another strategy involves the use of arecombinant vaccinia viral vector to expressan EBV membrane antigen [29]. A successfulvaccine would have the greatest impactin regions of the world that have an especiallyhigh incidence of specific malignancies.Burkitt’s lymphoma is the mostcommon childhood malignancy in the centralpart of Africa where EBV and malariaare considered cofactors in its carcinogenesisand 95 percent of children are infectedby age 3, compared to the United States,where infection is usually delayed until adolescence[30]. Nasopharyngeal carcinoma isrelatively rare but has an exceptionally highincidence in southern China, approachingmore than 20 times greater than that of mostpopulations [31].In 1994, HHV-8 DNAwas identified inbiopsies from tumors of a patient with Kaposisarcoma [32], a relatively rare malignancyprior to the AIDS epidemic. Inaddition to it likely being an essential cofactorfor the development of Kaposi sarcoma,HHV-8 also is believed to have a role inCastleman’s disease and primary effusionlymphoma [33]. The viral genome is expressedin these tumors and encodes transformingproteins and anti-apoptotic factors.The virus is also able to enhance the proliferationof microvascular endothelial cells[34].As with EBV, the predominant infectedcell is the B lymphocyte, although here thelytic cycle is embraced rather than repressed.This may play a crucial role in thepathogenesis of Kaposis sarcoma by elaborationof viral and host cytokines promotingcell proliferation, angiogenesis, and enhancementof viral spread.Targeted antiviral agents such as ganciclovirdirected against viral DNAreplicationhave had a dramatic affect on decreasing theincidence of Kaposi sarcoma in AIDS patientsthrough both therapy and prophylaxis[35]. Ganciclovir is phosphorylated into aGTP analog, which acts as a competive inhibitorof viral DNApolymerase resulting intermination of viral DNA elongation. Furthermore,a G protein coupled receptor(vGPCR) has been identified as a viral oncogenein HHV-8 infected cells that can exploitcell signaling pathways to induce transformationand angiogenesis [36]. vGPCR alsohas been proposed as a target for novel moleculartherapies because of its key role indisease progression [37]. But the therapyregimen most responsible for the decreasingincidence of Kaposi sarcomamay well be thesuccess of highly active antiretroviral therapy(HAART) regimens targeting HIV [38],since it was the emergence of HIV that led tothe increasing incidence of Kaposi sarcoma.Human papillomavirus (HPV)HPV are small non-enveloped DNAtumor viruses that commonly cause benign118 Liao: Viruses and human cancerpapillomas or warts in humans. Persistentinfection with high-risk subtypes of humanpapillomavirus (HPV) is associated with thedevelopment of cervical cancer [39]. HPVinfects epithelial cells, and, after integrationin host DNA, the production of oncoproteins,mainly E6 and E7, disrupts naturaltumor suppressor pathways and is requiredfor proliferation of cervical carcinoma cells[40]. HPV also is believed to play a role inother human cancers, such as head and necktumors, skin cancers in immunosuppressedpatients, and other anogenital cancers.Cervical cancer is the second leadingcause of cancer mortality in women worldwide,causing 240,000 deaths annually [41].Of approximately 490,000 cases reportedeach year, more than 80 percent occur in thedeveloping world, where effective but costlyPap smear screening programs are not inplace [41]. Early precancerous changes andearly cancers detected by Pap smears are effectivelytreated and cured with surgical therapyor ablation. In the absence of effectivescreening, the disease is detected late. Traditionaltherapeutic options for cervical cancerthat have advanced beyond definitive surgicaltreatment are chemotherapy and radiationtherapy, which are associated with many toxicitiesand do not offer a lasting cure.The immune system plays an importantrole in the prevention of persistent HPV infectionand progression of precancerous lesions.Human papillomavirus is a poornatural immunogen; as a double strandedDNA virus, there is no RNA intermediate,nor does infection cause cytolysis, allowinginitiation of innate immune responses [42].HPV mainly encodes non-secreted nucleoproteins,which are poorly cross-presentedand compared to other viruses its non-structuralproteins are expressed at low levels.However, genital infection with HPV is usuallytransient.Additionally, inadequate T cellresponses may lead to failure to clear HPVinfectedcells. AIDS patients, renal transplantpatients receiving immunosuppressivetherapy, and individuals with T cell deficiencieshave increased rates of HPV persistence,anogenital lesions, and cervical cancer[43-46].In 2006, an effective prophylactic vaccineagainst HPV 16 and 18 based on viruslikeparticles (VLP) of recombinant L1, themajor capsid protein [47,48], was approvedfor use by the FDA based on clinical trialsthat demonstrated nearly 100 percent protectionfrom persistent infection through thegeneration of high levels of neutralizing antibodies.Since these types are the causativeagent of approximately 70 percent of cervicalcancers, development of such an effectivevaccine holds much promise for theprevention of cervical cancer [47]. However,the vaccine currently costs $360 for a completecourse of three injections given oversix months, does not provide protectionagainst other high risk HPV types, will presumablyhave limited benefit to women alreadyinfected, and has an unknown durationof protection.Because of these limitations, therapeuticvaccination is being explored to treatwomen already infected and accelerate theimpact of prophylactic vaccination in decreasingcervical cancer incidence. Traditionaltherapy for early cervical cancer andprecancerous lesions involves surgical excisionor ablation. Therapeutic vaccinationseeks to generate a population of cytoxic Tcells that will recognize and kill tumor cells.Since patients with T cell deficiencies areknown to be more susceptible to HPV infectionand disease progression, boosting T cellresponses to HPV may be crucial to a therapeuticimmune strategy. In the case of cervicalcancer, E6 and E7 oncoproteins areexpressed in all malignancies and are notfound in uninfected normal cells. Therefore,they represent ideal targets for a therapeuticimmune response.Anumber of strategies togenerate immune responses against theseantigens are under investigation. Viral andbacterial vectors have been used in mousemodels to generate immune responses. Vacciniavirus delivery of HPV 16 and 18 modifiedE6 and E7 proteins has demonstratedsafety and specific immune responses inearly clinical trials [49]. DNA vaccinationstrategies also are under active investigation,and several are in various stages of clinicaltrials. Vaccination with plasmid DNAencap-Liao: Viruses and human cancer 119sulated in biodegradable micorparticles hasshown histological and immunological responseswhen used to treat patients withhigh grade cervical dysplasia [50-52].Human T lymphotropic virus type I(HTLV-1)HTLV-1 is a slow transforming, singlestrandedRNAretrovirus and is associatedwithadult T-cell leukemia [53]. It possesses adiploid genome similar to other retroviruses:two long terminal repeats flanking gag, pol,and env genes as well as a number of accessorygenes.HTLV-1 has aworldwide distribution,with an estimated 12 to 25million peopleinfected.However, disease is only observed inless than 5 percent of infected individuals. It istransmitted through blood transfusions, sexualcontact, and during parturition. HTLV-1 displaysa special tropism for CD4 cells, whichclonally proliferate in adult T cell leukemia,though how this is effected is not known.HTLV-1 infection has a very long latencyperiod of 20 to 30 years, but once tumorformation begins, progression is rapid. Standardchemotherapy often can bring about aninitial response with a partial or complete remission;however, relapse is common, andmedian survival is eight months. The HTLV-1 Tax gene has been postulated to play an importantrole in tumorgenesis [54] through theactivation of viral transcription and the hijackingof cellular growth and cell divisionmachinery, but the mechanisms leading toadult T cell leukemia are not well understood.It has been suspected that HTLV-1 infectionmay not be sufficient to transform, and recentevidence suggests that the decreased diversity,frequency, and function of HTLV-1 specificCD8 T cells in the host may play animportant part in the development of adult Tcellleukemia [55]. Therefore, targeted therapiesusing peptide, recombinant protein,DNA, and viral vectors with the goal of generatingneutralizing antibody against HTLV-1 and multivalent cytotoxic T cell responseagainst Tax are under investigation [56].SummaryThe viruses reviewed here illustrate thediverse biological pathways to malignancyand the challenges of treating the resultingdiseases. Yet the presence of the viral geneproducts in cancer and precancerous cellspresent attractive targets that may be exploitedin novel therapies that distinguishthese cells from normal cells. Antiviralssuch as lamuvidine used in heptatitis B andganciclovir for Kaposi sarcoma specificallytarget the viral replication machinery. Targetingcancer cells specifically would haveadvantages over traditional modalities suchas chemotherapy and radiation, which caninclude significant toxicities. Cervical cancer,because it retains HPV viral oncoproteinsE6 and E7 and requires their continuedexpression for proliferation, provides anideal model for cytotoxic immune therapiesagainst these known antigens.Given the prevalence of these cancersin the developing world and the limitationsof health care infrastructure, strategies forvaccine design to prevent primary infectionand targeted therapies for the treatment ofdisease must be carefully considered in thiscontext. Use of needles, refrigeration, multipledoses, and cost are all significant barriersto the delivery of an effective vaccine[41]. Cost, need for trained personnel andsophisticated equipment and facilities mayimpede global use of the most advanced targetedtherapies. 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