Cancer/Viral infections HIV/AIDS/Transplant recipients cancers appear to increase in frequency

Cancer and viral infections in immunocompromised individuals - pdf attached

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International Journal of Cancer

Volume 125, Issue 8, pages 1755-1763, 15 October 2009

Thomas F. Schulz
Institute of Virology, Hannover Medical School, Hannover, Germany

"Outlook: The availability of large scale cohort data on cancer incidence in transplant recipients as well as people with HIV/AIDS now indicates that several, but by no means all, human cancers appear to increase in frequency in the absence of an intact immune system. With the notable exception of NMSC, the cancers showing the most dramatically increased incidence rates are now known to have a viral cause. The role of the incriminated viruses in the development of their associated tumors varies and ranges from a directly transforming effect to a facilitating mode of action. Consequently, in these cases, the immune system may exert its protective effect against tumor development either by limiting the outgrowth of virus-transformed cells or tumor cells that require the continued expression of viral proteins for their survival, or by curbing viral replication at an earlier stage, thus reducing the likelihood of a "tumourigenic hit." A protective effect of the immune system appears to also apply in the case of liver and gastric cancer, where immune-mediated destruction of virus-infected liver cells and subsequent hepatocellular regeneration, or inflammation in response to bacterial persistence, are thought to play an important role in cancer development and where a "weakened" immune system could have been expected to be beneficial. In the case of liver cancer, this may be due to increased viral replication during immune suppression and there is limited evidence for increased H. pylori colonization rates in transplant recipients.143

Given the marked increase of NMSC, in particular SCC, in both transplant recipients and people with HIV/AIDS, and the recently proposed model of how UV-induced mutations could enhance the tumourigenicity of a possibly widespread polyomavirus,112 a (yet to be identified) viral cause for SCC would not be surprising.

Where do these findings leave the concept of immunological tumor surveillance, proposed by Macfarlane Burnet and Thomas nearly a half century ago? It would appear that the examples of several common tumors, in particular of the breast, prostate, ovary, which appear not to be linked to immune suppression (refer to previous section), indicate that there is probably no "general" recognition of tumor cells as "non-self." In virus-associated cancers there will be recognition of tumor cells as long as they express immunogenic viral proteins recognized by effector T-cells. If some of the human cancers occurring more frequently in immunosuppressed individuals are not caused by an infectious agent, this might after all point to the existence of antigenic determinants on some tumor cells that are indeed recognized by the adaptive immune system."

ABSTRACT

Over the last 30 years, the increasing use of organ and stem cell transplantation and the AIDS epidemic have led to the realization that some, but not all, human cancers occur more frequently in immunosuppressed individuals. With the notable exception of non-melanoma skin cancer (NMSC), most tumors that show strongly increased incidence rates in both transplant recipients and AIDS patients have been found to have a viral etiology. Among these are Kaposi sarcoma, diffuse large cell B-cell lymphoma, cervical cancer, liver cancer, Merkel cell carcinoma and a subset of Hodgkin's disease. A viral etiology for NMSC, i.e., é- and γ-subtypes of human papillomavirus, has been suggested and investigated for many years, but remains controversial. In addition, the moderately increased incidence rates of several other cancers in immunosuppressed individuals (e.g., Vajdic and van Leeuwen, Int J Cancer, in press) could indicate that additional infectious causes for at least some human cancers remain to be discovered. The controversy surrounding the role of cutaneous papillomavirus subtypes in the pathogenesis of NMSC illustrates the difficulties encountered when weighing the epidemiological and molecular biology evidence arguing for an involvement of highly prevalent viruses in certain types of cancer. 2009 UICC

The accompanying review by Vajdic and van Leeuwen1 summarizes our current knowledge on cancer in transplant recipients. Although both AIDS and organ transplantation have provided epidemiological data on cancers that are more common in immune suppression, each of these clinical settings also contributes its own bias. Thus, the prevalence of infections with oncogenic viruses in AIDS patients may not be the same as in the general population. This is, for example, the case for KSHV/HHV8, which in Western countries is more common in men who have sex with men (MSM) and also for HCV and HBV, whose transmission is associated with intravenous drug use. Similarly, certain causes of organ failure necessitating organ transplantation may have introduced a bias. However, a comparison of cancer rates in both AIDS patients and organ transplant recipients has identified several cancers that are noticeably more common in both patient groups than in the general population, strongly suggesting a contributory role of immune suppression in their development.

A recent meta-analysis2 of 7 studies3-9 covering 444,172 people with AIDS and 5 studies comprising 31,977 transplant recipients10-14 found increased standardized incidence rates (SIRs) for Hodgkin's lymphoma (HL), Non-Hodgkin's lymphoma (NHL), Kaposi's sarcoma (KS), cancer of the liver, stomach, cervix, vagina/vulva, penis, anus, oral cavity and pharynx, skin (mainly non-melanoma skin cancer), lip, esophagus, larynx, trachea/bronchus/lung, eye and kidney in both patient groups (refer to Figs. 1 and 2 and Fig. 1 in the accompanying review1). Incidence rates for cancer of the bladder, thyroid colon and rectum were only increased in transplant recipients, whereas brain tumors and cancer of the testis were increased moderately only in HIV/AIDS patients.1, 2 In contrast, breast and prostate cancer were not more common in these 2 patient groups than in the general population, with prostate cancer being even slightly rarer in people with HIV/AIDS than expected (for a more detailed review refer to the accompanying review1).

Among cancers with a known viral or bacterial cause (refer to below), the meta-analysis, and several individual studies, found the highest standardized incidence rates in the case of Kaposi sarcoma, NHL, Hodgkin's disease, cervical cancer, cancers of the vulva, vagina, penis and anus, oral cavity, oropharynx and liver cancer (refer to Figs. 1 and 2 and Refs.3-14). The meta-analysis found also a significantly increased risk for gastric cancer (due to H. pylori) in people with HIV/AIDS (SIR 1.9) and transplant recipients (SIR 2.0); this association was seen in 3/3 studies on transplant recipients, but only in 1/7 studies on HIV/AIDS patients.2

Although very rare, and therefore, not addressed in these 12 studies, Merkel cell carcinoma is also much more frequent in AIDS patients than in the general population15 and has recently been found to be caused by a new polyomavirus, MCV.16

Among cancers with no established infectious etiology, non-melanoma skin cancer and cancer of the lip stand out as generally showing higher SIRs in transplant recipients compared to people with HIV/AIDS1, 2 (Fig. 2). Smaller, but significant increases in incidence were also noted for cancer of the esophagus, larynx and eye1, 2 (refer to Fig. 2).

All human oncogenic viruses identified so far have the ability to establish persistent infections in their host. Their replication is controlled by the immune system and the increase of these virus-associated cancers in the context of immune suppression is therefore most likely due to the inability of the host to limit viral replication and/or expansion of infected cells. Where the expression of viral proteins occurs in tumor cells, immune effector cells may recognize these viral proteins and play a role in curbing tumor cell growth, as predicted by the immune surveillance hypothesis of Burnet and Thomas.17

Role of established human tumor viruses in immunodeficiency-associated cancer

Epstein-Barr virus

A recent IARC (International Agency for Research on Cancer) working party confirmed the classification of EBV as a Group 1 carcinogen and concluded that there is sufficient evidence for a causative role of EBV in nasopharyngeal cancer, endemic Burkitt's lymphoma, immune suppression-related NHL, extranodal NK/T-cell lymphoma (nasal type) and a subset of HL. In addition, there is limited evidence for a role of EBV in gastric carcinoma and lympho-epithelioma-like carcinoma.18

Of these EBV-associated cancers, 2, immune suppression-related NHL and HL, are more frequent in immunosuppressed individuals than in the general population (refer to previous paragraph).

EBV-associated NHL in the immunosuppressed, in particular AIDS patients, include Burkitt's lymphoma, diffuse large B-cell lymphoma (DLBCL) with immunoblastic morphology, primary central nervous system lymphoma (PCNSL), KSHV+/EBV+ primary effusion lymphoma (PEL) and plasmablastic lymphoma of the oral cavity type (for a recent review, see Ref.19). The proportion of tumors associated with EBV varies from 40 to 100%, depending on the histological entity.

It is thought that the contribution of EBV to tumor development varies among different categories of NHL. In normal B-cells EBV can adopt 4 different latent gene expression programs, depending on the B-cell differentiation stage and reflecting the needs for its persistence in these different environments. Thus, the "growth" or "latency III" program, involving the expression of 6 nuclear proteins (EBNA-1, -2, -3A, -3B, -3C, -LP), 3 non-structural membrane proteins (LMP-1, -2A, -2B) and 2 untranslated RNAs (EBER-1, -2) is normally employed in na•ve B-cells to drive their proliferation. In vitro, the latency III program is sufficient to induce B-cell immortalisation. Since several of the "latency III" proteins are good targets for cytotoxic T-lymphocytes (CTLs), B-cells expressing this program in vivo are normally quickly eliminated. However, in immunocompromised individuals, particularly in transplant recipients, expression of this "growth" program becomes possible and leads to the virus-driven transformation of B-cells and development of poly- or oligoclonal B-cell proliferation, which can progress to monoclonal lymphoma (reviewed in Ref.20). This group of lymphoproliferations is referred to as post-transplant lymphoproliferative disease (PTLD) and is classified histologically as DLBCL. These tumors can respond to therapy with adoptively transferred EBV-specific CTLs, indicating that EBV is the main driving force for their development (reviewed in Ref.21). EBV-associated DLBCL have therefore been considered as EBV-driven lymphoproliferations occurring in the context of defective T-cell immunity against EBV.22

In AIDS-associated DLBCL, viral gene expression patterns are more variable but the transforming EBV protein LMP1 (latent membrane protein 1) is frequently expressed.23, 24 LMP1 plays a crucial role in the transformation of B-cells by EBV (reviewed in Ref.20). Knockdown of LMP1 in EBV-transformed B-cell lines results in apoptosis, suggesting a requirement of LMP1 for their survival.25 In DLBCL, expression of LMP1 correlates inversely with the expression of BCL-6, a marker for germinal center B-cells, suggesting that, among DLBCL, the impact of LMP1 is likely to be strongest in tumors representing a post-germinal center plasmacytic differentiation profile.26 In contrast to PTLD, AIDS-associated DLBCL is always a monoclonal tumor.

Burkitt lymphoma (BL) occurs about 100 times more frequently in people with HIV/AIDS than in the general population of industrialized countries.18, 27, 28 About 30-60% of AIDS-BL are EBV positive.19 In BL EBV adopts, the "latency I" program, which involves only the expression of EBNA-1 and EBERs; it thus provides only the viral functions required to maintain the circular viral genome in dividing B-cells (EBNA-1) without expressing the classical EBV transforming proteins such as LMP-1 (reviewed in Ref.20). The absence of EBV from the majority of sporadic or AIDS-associated BL indicates that it is not essential in the pathogenesis of this tumor. The key pathogenic event in BL is thought to be the Ig/c-myc translocation found in all BL tumors, which maintains BL cells, displaying a post-germinalcenter phenotype, in proliferation (reviewed in Refs.20 and29). However, EBV is likely to contribute to the survival of continuously c-mc expressing B-cells by protecting them against apoptosis30 and EBNA-1 may contribute to DNA damage in these cells.31

In AIDS patients, HL is more frequently associated with EBV infection (80-100% of cases) than in the general population; in these cases the Hodgkin Reed-Sternberg (HRS) cells, the malignant component of this tumor, show evidence of the EBV "latency II" or "default" program, which involves expression of the transforming EBV protein LMP1, as well as EBNA-1 and LMP2A.19, 32-35 Since the "default" program is physiologically expressed in normal germinal center B-cells (reviewed in Ref.36) and HL HRS cells show evidence of deleterious mutations in the hypermuted Ig variable regions,37, 38 the majority of HL in HIV-infected persons are therefore thought to be derived from post-germinal center B-cell clones that escaped physiological apoptosis by virtue of the anti-apoptotic effects of EBV LMP1. The role of EBV in the pathogenesis of HL is discussed in more detail in the accompanying review by R. Jarrett.39

While in many PEL cases the lymphoma cells harbor both EBV and KSHV, some are only positive for KSHV (reviewed in Ref.19). This, and the fact that the (non-transforming) EBV latency I program is expressed in dually positive PEL cells, suggests that KSHV, rather than EBV, is the driving force behind the development of PEL.

Kaposi sarcoma herpesvirus/human herpesvirus 8

A recent evaluation of the available epidemiological and molecular mechanistic evidence by an IARC working group resulted in the classification of KSHV as a Group 1 carcinogen.18 In the case of Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL) the evidence supporting a causative role for KSHV was considered sufficient; KSHV is also associated with the plasma cell variant of Multicentric Castleman's disease (MCD).18

The epidemiological evidence supporting a causative role for KSHV in the pathogenesis of Kaposi's sarcoma is now compelling. Not only is the virus found in virtually all KS tumors, irrespective of the clinical form ("classic," African-endemic, HIV-associated, post-transplant), data from more than 20 cohort studies and 80 case-control studies show an association between KSHV and Kaposi's sarcoma, with relative risks higher than 10. In transplant recipients and people with HIV/AIDS, the risk of Kaposi sarcoma increases with the increasing titre of antibodies directed against KSHV, which are markers of the viral load.40-43 Detection of KSHV in the peripheral blood of asymptomatic individuals predicts the subsequent progression to Kaposi sarcoma.44

In immunosuppressed individuals, KS can often regress as a result of a reduced immunosuppressive therapy (in transplant recipients) or anti-HIV therapy (HAART). As assessed by clonality of the viral episome, KS can be oligo- as well as monoclonal.45 In the context of immunosuppression, at least some cases of KS may therefore represent virus-driven, oligoclonal proliferations that are still susceptible to immune surveillance. In experimental in vitro systems, KSHV has been shown to induce the formation of spindle cells in primary endothelial cell cultures (endothelial cells of a spindle cell morphology are thought to represent the neoplastic component in the KS tumor) and to reduce their dependence on growth factors46, 47; in primary endothelial cells, it also induces a partial re-differentiation of lymphatic endothelial cells towards vascular endothelial cells and vice versa by modulating the expression of Prox-1, a transcription factor determining lymphatic endothelial cell differentiation, followed by the increased expression of podoplanin and VEGFR-3-markers for the lymphatic endothelial cell lineage.48-50 In HPV E6/E7 immortalized endothelial cells, KSHV leads to extended survival, growth-factor independence, evidence of loss of contact inhibition and growth of infected cells in soft agar (i.e., signs of transformation).47, 48, 51, 52 The outgrowth of fully tumorigenic clones was also noted.53 KSHV establishes a latent gene expression program in the majority of infected endothelial spindle cells in KS tumors; however, a small proportion of infected cells in these tumors show evidence of productive infection. Several (latent and lytic) KSHV proteins have been shown experimentally to have transforming or tumorigenic potential. Among these are the latency-associated nuclear antigen LANA, the D-type cyclin homologue vcyc, the FLIP (caspase inhibitor) homologue vFLIP (mRNA expression for these latent genes has been observed in tumor cells in vivo), as well as the lytic cycle proteins K1, vIRF1/K9, the viral chemokine receptor vGPCR and kaposin A (reviewed in Ref.54). The exact contribution of these individual viral proteins to the development of KS has not yet been established.

PEL is a very rare lymphoma, encountered in AIDS patients and transplant recipients. Because of its rarity, only case reports and no systematic case-control or cohort studies are available and the epidemiological argument in favor of a causative involvement of KSHV is therefore limited to the fact that KSHV is consistently found in this lymphoma. From an experimental point of view, the same latent viral proteins (LANA, vcyc, vFLIP, kaposin) found in KS (refer to previous section) are also expressed in PEL; in addition, one of the KSHV interferon regulatory factor homologues, vIRF-3, shows a latent gene expression pattern in B-lymphoma cells and there is also substantial expression of an interleukin 6 homologue, vIL6. Knockdown of vIRF-3 and vFLIP have been shown to induce cell death in PEL cell lines, suggesting that the continuous expression of these viral proteins is required for PEL cell survival.55-57

MCD is a polyclonal lymphoproliferative disease that can be a precursor to frank lymphoma. In KSHV-associated MCD, LANA, v-myc, vFLIP, vIL6 and vIRF3 are expressed in MCD B-cells (refer to previous section). Since vIL6 is a potent stimulator of B-cell growth, it is likely that this protein plays an important role in the B-cell proliferation seen in MCD. In addition, the role of vFLIP and vIRF3 in protecting against apoptosis in B-cells56, 57 is likely to contribute to B-cell survival. KSHV has also been detected in occasional solid plasmablastic lymphomas in people with AIDS.19

Human papillomavirus

The recent IARC evaluation18 of biological carcinogenic agents confirmed the classification as Group 1 carcinogens of several human papillomavirus types belonging to a few phylogenetically related mucosotropic "high-risk" species (alpha-5, 6, 7, 9, 11).18, 58, 59 These include the types most frequently found in cervical cancer (HPV-16, 18, 31, 33, 35, 45, 52, 58) and 4 less frequently encountered types (HPV-39, 51, 56, 59). Of these, HPV-16 carries by far the highest risk of cancer. Other types were classified as probably or possibly carcinogenic to humans.18 A detailed review of the epidemiological evidence linking these HPV types to cervical cancer can be found in previous IARC evaluations.59, 60 Since then, several comprehensive studies have confirmed that these high-risk HPV types cause virtually all cases of cervical cancer worldwide.61, 62 HPV-16 is also the most important cause of anal cancer.18 Figure 2 shows standardized incidence rates of HPV-related cancers (cervical, anal, vulva, vaginal, penile, oropharynx) in immunocompromised individuals. Whereas EBV-associated NHL and KSHV-associated KS show standardized incidence rates of 100-1000 in AIDS patients (Fig. 1), these rates are lower (5-10-fold) for most HPV-related cancers, with the exception of anal cancer (-30-fold; refer to Fig. 2). This may reflect differences in the biology of the oncogenic viruses involved in these different malignancies and/or the susceptibility of their target cells to virus-induced transformation. Epidemiological data also provide clues to the role of immune suppression in the development of HIV-associated cancers. Many EBV- and KSHV-related malignancies, in particular DLBCL, primary CNS lymphoma and KS have become much rarer after the widespread introduction of highly active antiretroviral therapy (HAART) in 1995, illustrating the role of immune suppression in their pathogenesis.9, 63 Likewise, the detection of HPV and the incidence of squameous intraepithelial lesions (SILs) in cervical smears of HIV-infected women is strongly linked to a low CD count or high viral load.64, 65 However, cervical cancer does not appear to have decreased after the introduction of HAART.9, 63 Therefore, the early stages of HPV replication and/or persistence, but not, or less so, the progression to cervical cancer may be influenced by HIV-associated immune deficiency.3

Experimental evidence for the oncogenic potential of some of these high-risk HPVs (in particular HPV-16 and -18) and some of their proteins (particularly their E6 and E7 proteins) comes from many studies using transformation assays in rodent cell lines such as NIH 3T3, Rat1 or oncogene cooperation assays in primary baby rat kidney or mouse kidney cell cultures co-transfected with E6 or E7 and a cellular oncogene such as activated ras or fos. In addition, human keratinocyte cultures could be immortalized by joint expression of high-risk E6 and E7 proteins. Furthermore, silencing of the expression of E6/E7 in cervical carcinoma cell lines has been shown to induce senescence or apoptosis, providing a clear indication that the continued expression of these proteins is required for the proliferation of cervical carcinoma cell lines. A detailed review of these studies can be found in IARC monographs volumes 64 and 90.59, 60

An important biochemical property of the E6 protein of many HPV types is its ability to target cellular binding partners for degradation through the combined activity of a cellular ubiquitin ligase, E6AP and the cellular ubiquitin proteasome pathway.66 There are many cellular binding partners targeted by E6 in this way and their precise contribution to the overall activity of E6 has been difficult to disentangle.67 Of particular importance for the transforming potential of mucosal HPV types appears to be the E6-mediated degradation of the tumor suppressor protein p53.68 Another important mechanism appears to be the ability to induce telomerase activity69-71 and to inhibit both p53-dependent and -independent apoptosis.72-74

HPV E7 also recruits a cellular ubiquitin ligase, the multi-protein Cullin ubiquitin ligase complex, to target a range of cellular interaction partners for proteasomal degradation. Most important among them are the Rb tumor suppressor protein and the related p107 and p130 pocket proteins, whose removal allows progression through S-phase.75, 76 Other key regulators of cell cycle that are known interacting partners of E7 include the p21/p27 cdk inhibitors and a subset of cyclins and E7 also associates with the AP1 family of transcription factors, HDACs and MPP2.76, 77

One important consequence of E6 and E7 targeting, respectively, p53 and pRB as well as the p21/p27 cdk inhibitors is its ability to abrogate normal DNA damage responses, and this is hypothesized to contribute to the accumulation of genetic alterations in HPV-positive cells including those that might contribute to HPV-associated cancers. One of the hallmarks of E6- and E7-expressing keratinocytes, therefore, is genomic instability resulting in multiple chromosomal abnormalities.76 The role of E7 in genomic instability may also involve pRB-independent mechanisms, such as an effect on centrosome biogenesis, and the consequent defects in segregation of daughter chromosomes during cell division.78-80

Hepatitis B and C virus

Hepatitis B and hepatitis C virus infect, respectively, over 300 million and 170 million people world wide. Extensive epidemiological evidence shows a strong association of HBV with hepatocellular carcinoma in immunocompetent persons (relative risks in prospective studies in the range of 10-60). References81-84 serve as examples. The earlier literature is reviewed in IARC monograph vol. 59.85 Likewise, many cohort and case-control studies have established an association of HCV with hepatocellular carcinoma, with relative risks in studies that controlled for confounding factors, including chronic HBV infection, ranging from 2.5-88. References86-88 serve as examples for more recent studies, while case-control studies and the earlier literature is reviewed in IARC monograph 59.85 On the basis of this substantial body of evidence, both HBV and HCV continue to be classified a Group 1 carcinogens.18

The pathogenesis of HBV-induced hepatocellular carcinoma (HCC) is thought to involve both direct (virus-mediated) and indirect mechanisms. The latter are thought to be the result of hepatocellular regeneration in chronic hepatitis and cirrhosis and involve a loss of proliferation control, reactivation of telomerase activity, oxygen radical-induced DNA damage. The former are thought to involve the HBV x protein, a truncated form of the HBsAg envelope protein and the consequences of integration of the HBV genome into cellular DNA. The HB x protein has been shown to activate a number of genes involved in cell cycle control and progression, DNA repair, apoptotic cell death and cellular adhesion and to disturb the function of p53 and the DNA damage specific DNA-binding protein DDB-1.89, 90 The HB x protein binds to specific sequences in the C-terminal end of p53, preventing its entry into the nucleus, abrogating its sequence-specific DNA-binding and transcriptional activity and inhibiting the interaction of p53 with the DNA repair proteins xBP and xPD, thereby compromising the role of p53 in the DNA damage response and DNA repair.91, 92 The truncated preS/S protein modulates protein kinase C signal transduction and affects several cellular transcription factors such as NFkB and AP-1.93

Although chronic HCV infection is a major risk factor for hepatocellular carcinoma (refer to previous section), it remains uncertain how HCV causes this tumor.94 Chronic ER stress in HCV-infected hepatocytes, destruction of infected hepatocytes by virus-specific T-cells and the accompanying inflammatory damage and oxidative stress may lead to the accumulation of genomic damage95, 96; HCV-induced changes in MAPK signaling, which regulates both cell metabolism and growth may also contribute.97 In addition, several HCV proteins affect intracellular signaling, metabolism and cellular growth control, by, e.g., modulating the function of p53 or p73 family members in the case of the HCV core protein.98-100 The HCV core protein, NS3, NS4B and NS5A have all been shown to have transforming properties when transfected in tissue culture, or expressed in transgenic mice carrying individual viral proteins or an HCV polyprotein.98, 101-103 However, these findings need to be substantiated in the context of a viral infection, which is currently difficult, given the lack of a suitable in vivo experimental system. Overall, the current view is that synergistic effects between the consequences of chronic inflammation and direct virus-host cell interactions represent the most likely mechanisms of pathogenesis.

Although HCC is more frequent in HIV-infected persons and transplant recipients than in the general population, the exact role of HIV and/or immune suppression in HCC development is not clear. HIV-related immune deficiency worsens the risk of cirrhosis in HCV-infected individuals.104-106 In a meta-analysis105 of several studies, the increased risk of HIV on HCV-related cirrhosis was found to be -2-fold. One study106 observed an increased risk for cirrhosis in HIV/HCV-co-infected individuals only in the pre-HAART era (prior to 1996), which would underline the role of HIV-induced immune suppression in the accelerated progression towards cirrhosis. However, a direct link of HIV-related immune suppression to HCC risk has not yet been demonstrated: when adjusted for HCV infection and/or alcohol use, 2 studies106, 107 found no independent association of HIV-infection with the rate of HCC.

Merkel cell carcinoma virus

Although Merkel cell carcinoma (MCC) is very rare, and therefore, not covered by most large cohort studies, it has been noted to be much more frequent in people with AIDS.15 This observation stimulated the search for an infectious cause, which resulted in the discovery of Merkel cell carcinoma virus.16 About 70-80% of MCC cases appear to harbor clonally integrated MCV genomes,16, 108-110 although this may vary depending on the geographic region studied.111 Using PCR, MCV genomes have also frequently been detected in uninvolved skin and other body sites/fluids.16, 108, 109, 112 Interestingly, mutations have been observed in the MCV genomes integrated into the cellular genome of MCC tumor cells: these lead to premature truncations of their large T (LT) proteins, which consequently lack their helicase domain and are no longer able to replicate an episomal MCV genome.112 In contrast, MCV genomes derived from other body sites possess full-length, replication competent, LT proteins.112 Mutations observed in the MCV genomes obtained from MCC samples often involve pyrimidine dimers, suggesting that exposure to UV light, a known risk factor for MCC, could have contributed to their accumulation.112 Since the monoclonal integration pattern of MCV genomes in tumor samples suggests that integration preceded tumor development,16 and since LT-catalyzed replication of an integrated viral genome would be expected to induce a cellular DNA damage response, the loss of replication competence, caused by UV-induced mutations, could provide a key step in the survival of MCV containing tumor cell precursors.112 The role of immune suppression in MCC development is likely to be linked to the fact that several other polyomaviruses are known to show increased replication in immunosuppressed individuals. The mechanism of tumourigenicity proposed for MCV could therefore serve as a precedent for other skin cancers, in particular SCC, where UV-exposure and immune suppression are also recognized as major risk factors (refer to below).

Human T-cell lymphoma virus I

Whether adult T-cell leukemia/lymphoma (ATL), the malignancy associated with HTLV-I, is more common in immune suppressed individuals relative to the general population has so far not been addressed systematically. However, case reports suggest that HTLV-I infected transplant recipients may progress more quickly to ATL.113

Disputed human tumor viruses in immunodeficiency- associated human cancer

As discussed earlier and in the accompanying review,1 non-melanoma skin cancer-this entity comprises squameous cell carcinoma (SCC) and basal cell carcinoma (BCC) of the skin-as well as cancer of the lip, are markedly more frequent in both transplant recipients and in people with HIV/AIDS. Of note, the incidence appears to be higher in transplant recipients than in HIV-infected individuals (refer to Fig. 2). Also, while BCC is about 5-fold more common than SCC in immunocompetent persons, this ratio is reversed after immune suppression, with SCC reported to be between 18-fold and 250-fold more common in transplant recipients than in the general population, compared to an increase of BCC bin the order of 1.2-fold to 16-fold.114-117

The question whether the marked increase in SCC could reflect a viral etiology of this tumor, and whether cutaneous (é, γ) types of human papillomaviruses could be the cause, has been investigated intensely over many years. Multiple studies have shown that cutaneous HPV types are frequently found on the skin, in plucked hair follicles and in SCC tissue; however, in SCC tissue the viral load is generally much lower than 1 copy per cell and the role of the cutaneous HPV types in SCC pathogenesis, if any, must therefore be fundamentally different from that of all other known human DNA tumor viruses, whose genomes are always found, and at least a few viral genes expressed, in each tumor cell. In addition, unlike the situation in cervical or anal cancer (refer to previous section), where a few mucosal HPV types such as HPV-16 or HPV-18 account for most human cervical and anal cancers, a plethora of cutaneous HPV types has been found in SCC, mostly by PCR techniques, with only HPV-5 and HPV-8 being perhaps more frequently encountered. Recent PCR-based studies have not provided consistent evidence of an etiological role for any viral type or groups of types.118-120

Recent serological case-control studies have also not come to consistent conclusions. While some studies121-123 suggested an association of skin cancer with beta-1 or beta-2 papillomaviruses, in particular HPV-5 or HPV-8, another report observed associations with SCC for other types (beta-15, -17, -38; gamma-50, -95).124

In addition, one strong risk factor for SCC, previous exposure to UV light, could have led to confounding in some studies, if HPV replication were enhanced in UV-damaged skin. Heavily light-exposed areas were reported be much more likely to test HPV positive, raising the important possibility of confounding playing a role in the reported weak associations between SCC and HPV detection.119 In another study,123 individuals with tumors on chronically sun-exposed sites were more frequently seropositive for beta HPV types than individuals with SCC at other anatomic sites. A small cohort study125 found no association between the presence of antibodies to é-type HPVs and the subsequent emergence of SCC, but did note a (not-significant) higher rate of HPV antibodies in SCC cases after the tumors were diagnosed. The possibility of "reverse causality," i.e., the more frequent detection (at low copy number) of many HPV types in SCC samples compared to normal skin being the consequence, rather than the cause, of UV-damage or increased HPV replication in premalignant or malignant tissue, cannot therefore be categorically excluded at present. In a recent study in transplant recipients,126 no association between HPV antibodies and SCC was found, although the expected significant associations between HPV-16 antibodies and a self-reported abnormal PAP smear, as well as between HPV-6 antibodies and a history of genital warts, was observed.

How strong is the experimental evidence that links cutaneous HPV types to skin cancer? Some cutaneous beta HPV types show transforming activity in rodent cell transformation assays127, 128 (e.g., HPV-5, -8 and -47) or primary rodent cell co-transformation assays (e.g., HPV-12, -14, -15, -24, -36 and -49).129 HPV-8 and -38 show immortalizing activity in primary human keratinocyte assays.128, 130 HPV-38 induces the p53 repressor, ΔNp73, to inhibit p53 responsive pathways131 and activates telomerase.132, 133 A property common to the E6 proteins of several mucosal high risk and cutaneous HPV types (HPV-16, -18, -11, -5, -8, -20, -22, -38, -76, -92 and -96) appears to be the interaction with, and inhibition of, the pro-apoptotic protein Bak.134-136 The E7 proteins of some cutaneous é-type HPVs can target pRB.130 Transgenic mice expressing the HPV8 early genes in the epidermis are prone to benign and malignant skin cancers137 and HPV38E6E7 mice developed skin cancers following treatment with chemical carcinogens.138

Although these experimental data support the carcinogenic potential of at least some beta HPV types, the currently available inconsistent epidemiological evidence does not permit the firm conclusion that these HPV types play a causative role in SCC in immunosuppressed individuals. The recent IARC working group considered the available epidemiological evidence as inconclusive; in the context of epidermodyplasia verruciformis, a genetically determined susceptibility to HPV-induced skin cancer, the beta types HPV-5 and HPV-8 were considered an exception and classified as "possibly carcinogenic" (group 2B).18

Following the recent discovery of MCV (refer to previous section), a few studies have examined an association of this virus with SCC and BCC. Although MCV appears to be detected more frequently in SCC and BCC of immunosuppressed compared to immune competent individuals,109 no evidence of clonal integration in these tumors has been so far reported and it is currently unclear, if MCV plays a role in the pathogenesis if these tumors.

An infectious cause for other cancers associated with immune suppression?

Among common epithelial cancers not yet linked to a viral cause, only cancers of the trachea, bronchus and lung show a noticeable and consistent (at least in transplant recipients) increase during immune suppression (refer to Fig. 2 in this review and Fig. 1 in the accompanying review1). In kidney transplant recipients, the increase in lung cancer rates is much higher after transplantation than during dialysis suggesting a role of immune suppression.13 Several studies have shown lung cancer to be more frequent in AIDS patients than in the general population, in particular after the widespread use of highly active antiretroviral therapy (HAART). However, the recent IARC working group felt that residual confounding by smoking, a very strong risk factor for lung cancer, could not be ruled out18 (exemplary Refs.9, 139-141).

In kidney transplant recipients, the increased incidence rates for myeloma, kidney and bladder cancer are already seen during and before dialysis, suggesting that the increase of these tumors in transplant recipients may not be genuinely linked to immune suppression.1, 13 The involvement of an infectious agent in leukemia has been the subject of speculation for some time.142

Outlook

The availability of large scale cohort data on cancer incidence in transplant recipients as well as people with HIV/AIDS now indicates that several, but by no means all, human cancers appear to increase in frequency in the absence of an intact immune system. With the notable exception of NMSC, the cancers showing the most dramatically increased incidence rates are now known to have a viral cause. The role of the incriminated viruses in the development of their associated tumors varies and ranges from a directly transforming effect to a facilitating mode of action. Consequently, in these cases, the immune system may exert its protective effect against tumor development either by limiting the outgrowth of virus-transformed cells or tumor cells that require the continued expression of viral proteins for their survival, or by curbing viral replication at an earlier stage, thus reducing the likelihood of a "tumourigenic hit." A protective effect of the immune system appears to also apply in the case of liver and gastric cancer, where immune-mediated destruction of virus-infected liver cells and subsequent hepatocellular regeneration, or inflammation in response to bacterial persistence, are thought to play an important role in cancer development and where a "weakened" immune system could have been expected to be beneficial. In the case of liver cancer, this may be due to increased viral replication during immune suppression and there is limited evidence for increased H. pylori colonization rates in transplant recipients.143

Given the marked increase of NMSC, in particular SCC, in both transplant recipients and people with HIV/AIDS, and the recently proposed model of how UV-induced mutations could enhance the tumourigenicity of a possibly widespread polyomavirus,112 a (yet to be identified) viral cause for SCC would not be surprising.

Where do these findings leave the concept of immunological tumor surveillance, proposed by Macfarlane Burnet and Thomas nearly a half century ago? It would appear that the examples of several common tumors, in particular of the breast, prostate, ovary, which appear not to be linked to immune suppression (refer to previous section), indicate that there is probably no "general" recognition of tumor cells as "non-self." In virus-associated cancers there will be recognition of tumor cells as long as they express immunogenic viral proteins recognized by effector T-cells. If some of the human cancers occurring more frequently in immunosuppressed individuals are not caused by an infectious agent, this might after all point to the existence of antigenic determinants on some tumor cells that are indeed recognized by the adaptive immune system.