3
Obstacles and Opportunities for Framing Future Research

OVERVIEW

Humans exist in complex milieus, and their association with disease is affected both by the environment in which they live and by their genetic susceptibility to particular diseases. People live in concert with microbial agents that may or may not cause disease in particular individuals, depending on their environment and their genetics.

There are substantial obstacles to identifying organisms associated with a particular chronic disease. First, organisms can act in a “hit and run” manner, in which they cause disease initially but then are either resolved due to natural immunity or are successfully eliminated with antibiotics. The damage has been done, however, resulting in chronic disease. For some chronic diseases of this type, such as Reiter’s syndrome, Guillain-Barré syndrome, or rheumatic heart disease, it is very difficult to find a fingerprint of the organism in the disease tissue. Second, organisms can be latent at the time of diagnosis. They may not be actively replicating, so there is no active RNA transcription. Third, chronic latent or recurrent infection may be involved in the pathogenesis so that, again, the organism may not be active at the time of diagnosis. Fourth, organisms may need a particular predisposing environment or a host with a particular genetic susceptibility, so the simple presence or absence of the organism may be misleading.

To address these problems, evidence is assembled in a number of ways: from epidemiological studies, from microbiological assessment of pathogenesis and etiology, from studies that mimic the disease process in vitro or in animals, and from clinical treatment trials.



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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary 3 Obstacles and Opportunities for Framing Future Research OVERVIEW Humans exist in complex milieus, and their association with disease is affected both by the environment in which they live and by their genetic susceptibility to particular diseases. People live in concert with microbial agents that may or may not cause disease in particular individuals, depending on their environment and their genetics. There are substantial obstacles to identifying organisms associated with a particular chronic disease. First, organisms can act in a “hit and run” manner, in which they cause disease initially but then are either resolved due to natural immunity or are successfully eliminated with antibiotics. The damage has been done, however, resulting in chronic disease. For some chronic diseases of this type, such as Reiter’s syndrome, Guillain-Barré syndrome, or rheumatic heart disease, it is very difficult to find a fingerprint of the organism in the disease tissue. Second, organisms can be latent at the time of diagnosis. They may not be actively replicating, so there is no active RNA transcription. Third, chronic latent or recurrent infection may be involved in the pathogenesis so that, again, the organism may not be active at the time of diagnosis. Fourth, organisms may need a particular predisposing environment or a host with a particular genetic susceptibility, so the simple presence or absence of the organism may be misleading. To address these problems, evidence is assembled in a number of ways: from epidemiological studies, from microbiological assessment of pathogenesis and etiology, from studies that mimic the disease process in vitro or in animals, and from clinical treatment trials.

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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary Patrick Moore described how the discovery of new pathogens will require the talents of multiple disciplines, including epidemiology, clinical medicine, molecular biology, and pathology. Moore used the example of the identification of the virus that causes Kaposi’s sarcoma, which often strikes gay men, to discuss general issues in causality and to illustrate the limits of current approaches for determining causality for a newly discovered agent and disease. The causative agent, named Kaposi’s sarcoma-associated herpesvirus (KSHV), was identified using a genetic technique called representational difference analysis. Once the virus was identified, in 1994, events moved rather quickly—a fact that speaks to the importance of new pathogen discovery. The virus’s genome has been sequenced, serologic tests have been developed, and studies have been initiated to understand its epidemiology and to test possible treatments. Moreover, the virus has since been found to cause at least two other types of disease. Based on this experience, Moore pointed to the need for researchers to move beyond Koch’s postulates or other traditional guidelines in their efforts to determine disease causality for suspect microbes. Researchers are attempting to do this by applying various new techniques emerging from molecular biology and biotechnology. It seems clear as well that epidemiologists developing new criteria for causality will have to incorporate new pathogenic mechanisms that are not accounted for in current disease models. Mikhail Pletnikov discussed the importance of expanding research to better understand the interplay of genetic and environmental factors in the causation of a number of important developmental behavioral disorders. Among methodological problems of studying the gene-environment interplay is the difficulty in firmly defining environmental factors and making them quantifiable. In this context, virus infections provide a promising research avenue, because of their etiologic connection to several neurodevelopmental disorders, including autism and schizophrenia, and because of the reliability of quantification of viral effects on brain and behavior. In particular, Pletnikov described work using an animal model to study gene-environmental interactions that occur during neonatal infection with Borna disease virus (BDV). Neonatal BDV infection in rats has been shown to produce distinct neuroanatomical, neurochemical, and behavioral abnormalities that resemble pathological and clinical features of some human developmental disorders. The significance of studying neonatal exposure derives from the fact that the effects of many genetic and environmental risk factors are evident either prior to or around the time of birth, and the interaction between them often is apparent well before the onset or diagnosis of the chronic disease condition. Thus, studying the effects of neonatal BDV infection across the entire postnatal period in genetically different strains of rats will aid in understanding the course and time-dependent character of the interaction of genetic background features and the virus infection. In this way, the model system may allow study of some tremendously complex mechanisms relevant to developmental disorders. David Persing provided an overview of recent research in the area of infec-

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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary tion, cancer, and the immune response. Current evidence suggests that inherited predisposition to cancer probably accounts for only a subset of total cancer patients, and in most models of the development of neoplasia, an underlying assumption is the contribution of an array of intrinsic and extrinsic factors within a multistep process. A basic prerequisite of many models is an increase in the baseline proliferation rates of essentially normal cell populations that leads to dysregulation of normal growth control mechanisms. Since many infectious processes often lead, directly or indirectly, to increased cell turnover and proliferation, certain agents are now widely regarded as carcinogens. Some of the pathogens that have been linked to cancer include human papillomaviruses (cervical cancer and other skin cancers), human T-cell leukemia viruses (adult T-cell leukemias and lymphomas in endemic areas), hepatitis B virus (liver cancer), Epstein-Barr virus (Burkitt’s lymphoma and nasopharyngeal carcinoma), and Helicobacter pylori infection (gastric carcinoma and MALT lymphoma).In addition, new disease associations are being made with respect to previously known pathogens, such as the association of chronic hepatitis C virus infection with non-Hodgkin’s lymphoma in certain populations. In a separate presentation, Persing described recent and continuing advances in the development and application of techniques for identifying pathogens that cause chronic diseases. Although a paper on these subjects does not appear in this chapter, the following paragraph notes the highlights. The ability to detect and manipulate nucleic acid molecules in microorganisms has created a powerful means for identifying previously unknown microbial pathogens and for studying the host-pathogen relationship. Although a paper on these subjects does not appear in the ensuing text, the highlights of his presentation are discussed here. Among the new technologies that Persing described is broad-range polymerase chain reaction, which has proved instrumental in linking a growing number of pathogens with chronic diseases, and representational difference analysis, which is an efficient means for finding differences between complex genomes and for identifying specific DNA sequences from the genomes of unknown pathogens. Researchers also are making use of sophisticated new DNA microarrays and biosensors that, among other things, can monitor host response as an indicator of the presence of infection or inflammation. In addition, new methods for generating “libraries” of genetic information from very small amounts of material are making it easier to conduct very specific and sensitive serologic tests. Equipped with these and other advanced tools, researchers are becoming better able to move beyond the limitations of Koch’s postulates and to link infectious agents with chronic diseases more precisely and with greater confidence than ever before. In the ensuing discussions, participants began to sketch in some of the characteristics of a comprehensive and coordinated effort that would enhance efforts both to identify links between infectious microorganisms and chronic diseases and to develop and implement interventions to minimize their health conse-

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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary quences. The goal was not to set specific priorities, but to identify opportunities. Highlighting a selection of the traits identified may provide a glimpse of the overall picture envisioned. Participants agreed, for example, on the need to develop standardized definitions of infections and disease, to enable comparisons across studies and conclusions about causality, and on the need to ensure that laboratory assays maintain universally high standards of specificity, sensitivity, and reproducibility. New laboratory technology also is needed that can meet such performance standards while handling high throughput rates, in order to handle analyses of large cohorts in a reasonable amount of time, a trait that likely will be required in many future projects. Comparable efforts are needed to ensure that epidemiological studies are conducted with vigor and in an appropriate manner. One step will involve linking of databases that are designed (or modified) to be compatible. Peer review journals can reinforce performance standards if publication depends on the use of sound laboratory assays and epidemiologic design capable of supporting the conclusions. Continued studies are needed to define temporal relationships between infections and disease—that is, what stage of infection determines outcome (e.g., first infection, reinfection, persistent infection, coinfection, or subsequent cross-reacting infection). Studies also are needed to clarify at which stage infection must be prevented or treated in order to minimize or eliminate chronic sequelae. It will be important to determine the expected benefit of actions, to ensure that the benefits will outweigh any possible risks. In other words, intervention should decrease chronic disease burden without unduly endangering the people who receive care. There is a need to better understand the natural history, especially the earliest stages, of chronic diseases of unknown or incompletely known origins. What makes this task especially important is the hit-and-run nature of some diseases in which microbes set adverse events in motion and then disappear, the increased difficulty of imputing causation to microbes detected late in the course of disease, and the increased ease of treating or preventing disease at early time points. Toward this aim, clinicians should be increasingly encouraged to identify patients who have recently developed or seem to be developing various suspect chronic diseases, to collect in an orderly manner a range of clinical specimens, and then to follow the course of the disease in order to identify tell-tale early clinical features. Calls were made for more effort devoted to developing animal models of chronic diseases, and to teaching health professionals about their value and their limitations. Animal models can be powerful tools when the etiology or pathogenesis of a disorder is unknown. Psychiatric modeling with animals may present an especially ripe area for probing a variety of important questions, yet many practitioners in the field are not accustomed to working with such models. Increased emphasis should be placed on longitudinal studies, as well as on follow-up studies and “look back” studies of cohorts and surveillance results that have been generated in the past. Longitudinal studies may prove particularly valu-

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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary able given that rapid advances in the field may mean that we might not know today which pieces of evidence will be needed in the future. Human specimen collections, such as the National Children’s Study that will begin in 2004, may be especially important for longitudinal research. Participants identified a number of specific populations that should receive additional attention. One such group includes people who move from rural areas into cities, both in the developing and the developed world. Studies are needed to see whether they bring new infections with them, or whether they prove to be susceptible to new infections that they previously had not encountered. With the world’s changing demographics, gathering such information may provide a window into pathogenesis of a number of chronic diseases. Efforts are needed to address problems related to informed consent. Many workshop participants expressed concern that current regulations and guidelines are too complex, too uncertain, or too restrictive to allow for meaningful sharing of data—and sometimes all three. There was general agreement that informed consent is and must remain an important part of research involving human subjects. But participants also agreed that all parties—from government, academia, and private funding agencies—need to work together to develop a more standardized method for gaining patient consent, for gathering identifying information, and for being able to use this identifying information in the future. This may be an opportunity for multiple institutions and multiple governments, domestic and foreign, to cooperate in devising a system of patient consent that operates more smoothly, protects patient rights, and allows for expanded research on infections and chronic diseases. Given the magnitude of the outstanding scientific questions, and of the health consequences at stake, an increasing share of future research likely will involve groups of investigators representing a variety of disciplines, or groups of institutions working collaboratively. Although there remains a clear role for individual investigators, it is becoming apparent that large multidisciplinary projects often can best marshal the critical mass needed to address the thorniest biological problems. In many cases, these large projects will include a multinational component, in order to ensure that sufficient attention is paid to multiracial, multiethnic, and multicultural differences. Participants called on the overall scientific community to evaluate whether it is organized and structured properly to address these issues, and whether its various components communicate effectively. The community also should mount a concerted effort to identify gaps in current knowledge about the etiology of chronic diseases, pinpoint what needs to be done to close those gaps, chart the obstacles that stand in the way, and then identify and provide the necessary financial resources (monetary and human) to drive progress. Government can play an important role by reorienting its funding priorities. Indeed, the time is ripe. The government is now investing nearly $1 billion in rebuilding the nation’s public health system, and part of the money will go to-

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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary ward linking state health departments more closely with local health departments than has historically been the case. At the same time, government research centers are launching major new interdisciplinary projects, and universities, which often have been in competition with one another, are beginning to join in collaborations. Thus, foundations are beginning to be built for bridges linking public health, clinical medicine, and research. But these promising efforts need to be nurtured to ensure continued cooperation. PATHOGENS AND DISEASE: ISSUES IN DETERMINING CAUSALITY Patrick S. Moore University of Pittsburgh Pittsburgh, PA Successful new pathogen discovery requires the talents of multiple disciplines, including epidemiology, clinical medicine, molecular biology, and pathology. In this paper, the identification of Kaposi’s sarcoma-associated herpesvirus (KSHV) illustrates general issues in causality and shows the limits on our ability to determine a causality for a newly discovered agent and disease (Moore and Chang, 1998). The mysterious outbreak of Kaposi’s sarcoma among gay men was the harbinger of the AIDS epidemic. It is now clear, however, that the AIDS-associated Kaposi’s sarcoma epidemic was actually due to the collision of two independent viruses in a susceptible population: HIV and a new virus, KSHV or HHV8, which was found using molecular techniques (O’Brien et al., 1999). Over 20 different agents had been put forward as the cause of KS before 1994. To look for the “KS agent” (Beral et al., 1990), Yuan Chang used representational difference analysis (RDA) to compare DNA from a Kaposi’s sarcoma lesion to uninvolved, sterile-site tissue from the same patient on the assumption that the two samples would be genetically identical except for the presence of the putative agent’s genome (Chang et al., 1994). As shown in Figure 3-1, RDA is a subtractive hybridization technique in which PCR adapters are ligated onto digested DNA from the KS tissue (tester) (Lisitsyn et al., 1993). The tester DNA was then rehybridized back to a ten-fold excess of uninvolved sample DNA (driver) that had been identically digested. For human genomic fragments present in the KS sample, 90 percent of these fragments will form pairs with the corresponding antisense strand lacking the adapter from the normal tissue DNA. PCR with a primer specific to this adapter linearly amplifies these common sequences and, of course, there was no amplification of the DNA rehybridized from the driver alone. Sequences that were unique to the KS lesion, however, reanneal to each other and have adaptors on both ends, so that amplification occurs exponentially. The initial PCR products are then

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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary FIGURE 3-1 Representational differential analysis comparing DNA from a Kaposi’s sarcoma lesion to sterile-site tissue from the same patient.

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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary rehybridized again to the adapter-less healthy tissue DNA and the process is repeated, each time selectively enriching for the unique sequences found only in the KS lesion (Gao and Moore, 1996). Four RDA fragments were generated by this process, two of which were found to be specific for the KS agent. Although these two fragments account for less than 1 percent of the entire 145-kilobase viral genome, the few base-pairs worth of unique information they provided made it possible to develop enough tools to identify the agent. The two fragments were used as Southern hybridization probes and tested against KS lesions, showing that about three-quarters of the KS lesions were positive for viral DNA. Using internal specific primers from the KS 330 band, a PCR assay was developed that showed 25 out of 27, or 93 percent, of the initial KS lesions tested positive. Moreover, the negative samples were equally telling: one of the two negatives had degraded DNA and was not amplifiable by using cellular primers, and the other one was mislabeled normal human kidney. KSHV is a gamma herpesvirus belonging to the same class as Epstein-Barr virus (EBV). It is associated with three different major proliferative diseases: Kaposi’s sarcoma, primary effusion lymphoma (PEL) (Cesarman et al., 1995a), a monoclonal B cell lymphoma, and multicentric Castleman’s disease (Soulier et al., 1995), which is a polyclonal hyperplasia caused by a virus-encoded cytokine expressed by KSHV (Parravicini et al., 1997). Nearly all KS and PEL patients have KSHV infection, but only about half of HIV-negative, multicentric Castleman’s disease patients are positive for KSHV infection indicating that this disease has a heterogeneous pathogenesis. The two aforementioned RDA fragments of the KSHV genome facilitated the identification of infected cell lines to serve as source material for viral DNA and as a reagent for biologic studies (Cesarman et al., 1995b). Genomic library walking was performed using cosmid and lambda libraries from one of these cell lines allowing sequencing of the remainder of the genome (Russo et al., 1996). Using this information, various techniques were used to identify likely antigens and generate serologic tests (Gao et al., 1996a,b; Kedes et al., 1996; Simpson et al., 1996). While identification of high-titered infected cell lines sped up this process, isolating the agent was not essential for developing tools to detect it. Molecular biology has reached the point where it is straightforward to identify a new agent, sequence its genome and develop serologic tests for it without ever having actually purified, living sample of the agent. The virus does not have to be grown in order to apply traditional techniques for determining whether or not an agent is present. The virus itself is a tremendously interesting scientific problem. It has a long unique coding region containing all of the viral open reading frames. Unlike most viruses, KSHV has pirated cellular genes over its evolution and the viral genes are recognizable homologues to cellular genes of known function. Many of these

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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary genes provide new insights into tumor virology through their control of the cell cycle, prevention of apoptosis, or immune evasion properties. One might conclude that this virus is completely different from other viruses and not much can be learned from it to extend to other viruses. In fact, the opposite is true. EBV, for example, induces cellular cyclin D2 to drive the cell through the G1/S cell cycle checkpoint; KSHV encodes its own version of a cyclin D with an analogous function. Other examples of functional correspondence between the KSHV homologues and viral genes encoded by even distantly related viruses can be readily seen (Moore and Chang, 1998a, 2001). For this reason KSHV might be considered something like a molecular Rosetta stone because by using it, we can begin to interpret the language of molecular virology in terms of cell biology for many different viruses. The importance of new pathogen discovery is illustrated by a timeline of KS research. This would be equally true also for hepatocellular carcinoma and hepatitis C or a wide range of diseases where a new pathogen has been found. The point is that things change quite rapidly once the agent is finally found. Moritz Kaposi initially described the disorder in 1873, but not until 70 years later was there a suggestion of an infectious etiology. In 1981, the onset of the AIDS epidemic brought a tremendous increase in scientific interest in this cancer. There was still, however, little known about the pathogenesis of this disorder in 1993 when there were over 200,000 cases of AIDS in the United States. At that time over 20 different agents had been proposed at one time or another as the causal agent for Kaposi’s sarcoma. The description of KSHV was first published in 1994 and within two years its viral genome was completely sequenced (Neipel et al., 1997; Russo et al., 1996). By that time it was known that the virus was found in all forms of Kaposi’s sarcoma (Boshoff et al., 1995; Chang et al., 1996; Moore and Chang, 1995), serologic tests had been developed (Gao et al., 1996a,b; Kedes et al., 1996; Miller et al., 1996; Simpson et al., 1996) and studies initiated to understand the epidemiology of this virus in KS (Moore et al., 1996; Whitby et al., 1995). Shortly thereafter, studies were performed to see whether ganciclovir, a specific antiviral agent, could be used to treat KS (Martin et al., 1999). At the present, there have been over 2,000 papers published on KSHV and its role in malignancy. Finding a new pathogen also can benefit other fields. When KSHV was first described, only two other related rhadinoviruses had been described in new world primates. Although we live in North America, humans are still considered old world apes. One was herpesvirus saimiri from squirrel monkeys and the other herpesvirus ateles from spider monkeys. Researchers at the University of Washington began to look for other primate KSHV-like viruses (Rose et al., 1997). Using consensus PCR, two were found in rhesus macaques, and subsequently in all the various branches of the primates, both lower and higher primates. This suggests that the viral ancestor of KSHV evolved with us over time. Even more

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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary interesting, another group found a closely-related but distinctly different virus in rhesus macaques (Desrosiers et al., 1997). It was named rhesus rhadinovirus (RRV) and belongs to a second lineage of rhadinoviruses. RRV was initially only found in the lower primates, but last year an RRV was found in chimps (Greensill et al., 2000; Lacoste et al., 2000; Lacoste et al., 2001). The implication is that there is an ancestral KSHV/RRV-like virus split off in the primate evolution and has followed through with the different primate lineages, probably including humans. Thus, it is almost certain that there is an undiscovered HHV 9. An issue in new pathogen discovery is making the step from finding a new DNA sequence to determining whether or not it causes a specific disease. Applying Koch’s postulates (Koch, 1942) can elucidate the process: The agent occurs in every case of disease. The agent never occurs as a fortuitous or non-pathogenic strain. The agent can be isolated from the lesion, grown in pure culture, induce disease in a susceptible host and can be re-isolated from an infected susceptible host. These were postulates that Koch developed for determining the cause of tuberculosis at a time when not much was known of viruses or the carrier state. This was a brilliant attempt to develop a scientific rationale for determining whether an agent is causal for disease or not. Bradford Hill also developed epidemiologic criteria for causality which are shown here for KSHV and KS (Hill, 1965). Though developed specifically for cigarette smoking, most epidemiologists now use these criteria to determine causality: Is the infection present in cases; do all types of the disease involve infection? Is it reproducible in multiple settings? Does infection precede disease? Is the infection specific to the disease or is it ubiquitous infection among humans? Is the virus localized to the tumor (one interpretation of a biologic gradient)? Do the epidemiologic studies make sense (are they coherent?)? Is it biologically reasonable and do experiments confirm the relationship? With regard to KSHV, the answers to these questions are largely true. KSHV is present in more than 95 percent of KS lesions. It can be said that the remaining negative 5 percent is probably spurious due to technical difficulties in detection or misdiagnosis, and in fact the virus is absolutely necessary for disease. Though this cannot be proven at present, it can be argued that the situation is very similar to that of papillomavirus and cervical cancer 5 years ago. Is it generalizable? Yes. All types of KS are infected as far as is known. It also appears to have the correct

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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary temporal association in that cohort studies show that patients are infected before developing disease, and not afterwards. But specificity is an important question. KSHV is not singly associated with Kaposi’s sarcoma. It is also associated with two other diseases. However, the epidemiology of these two diseases makes some sense in terms of Kaposi’s sarcoma, so multiple outcomes are not too worrisome. Depending on the assay that is used, some researchers suggest that the infection rate in the general population for this virus is much higher than alluded to here, but careful studies suggest that less that 5 percent of Americans are infected with KSHV. Is there a biologic gradient? Yes, there is. Are the epidemiologic findings coherent? Yes, a wide range of epidemiologic studies seem to come to exactly the same set of conclusions. Is it biologically plausible? Yes, there are multiple oncogenes in this virus, related viruses cause cancers, and there are blinded clinical trials which seem to suggest that treatment with ganciclovir prevents the development of Kaposi’s sarcoma. KSHV and KS was a relatively easy case even though it took two years and seven or eight different studies before these conclusions could be reached. Nonetheless, the case for causality was relatively easy. Now let’s consider issues where causality is more problematic. First, KSHV has been claimed not only to cause Kaposi’s sarcoma, but also a wide variety of diseases that don’t fit its epidemiologic pattern, such as multiple myeloma and sarcoidosis. Although studies supporting these associations were published in reputable journals, they were based on PCR or had other problems and remain questionable in terms of contemporary epidemiological knowledge. In the age of PCR, it is difficult for the casual observer to sort out what is true and what is not. Assuming that the problem of poor laboratory technique can be solved, there are three more fundamental problems in determining causality. First, causality is relative and should not be thought of as being cast in stone. Causality depends on pathogenic assumptions. That is where Koch’s postulates fall down and also where Hill’s criteria fall down as well. For example, if a virus is associated with autoimmune disorders, it can be assumed that one would have an immune response against that virus. In that case the individual may actually clear the virus, so a reverse association would be seen from what would normally be expected following Hill’s criteria. The criteria simply do not apply in this case, even though it is a reasonable possibility. Second, causality is normative. Researchers can get together and study the data but only a few agree to particular conclusions. When the studies describing KSHV as the cause of KS were completed, it was thought that the issue of causality would be resolved. However, it still required a great deal of interpretation. There were many contradictory studies that were ignored because they were not considered valid. But others might disagree, and this is true for just about any contentious issue. An agent is only considered causal for a disease when a major-

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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary have been directly implicated in the progression of neoplasia. Epstein-Barr virus plays an important role in the evolution of B cell lymphomas in these patients, Kaposi’s sarcoma virus participates in the tumorigenesis of Kaposi’s sarcoma, and human papillomavirus infection contributes to the development of carcinomas of the skin and cervix. A reduction in levels of antigen-specific cytotoxic T cell responses are associated with activation of infection or disease progression in all of these cases, and a reduction in the efficiency of immune surveillance has been proposed as a factor in tumorigenesis. Consistent with this hypothesis, patients on immunosuppressive therapy following transplantation appear to be at increased risk for the same spectrum of malignancies with the exception of a lower incidence of KS; accordingly, KSHV appears to be much less prevalent in transplant patients compared to HIV patients, presumably because of the risk factors associated with the predominantly sexual transmission of KSHV (Chang and Moore, 1996). Hepatitis B Virus Primary infection with hepatitis B virus usually follows an acute and convalescent course in immunocompetent hosts with ultimate resolution of disease. However, in approximately 5 to 10 percent of adults, and in most infants born to infected carrier mothers, primary infection leads to chronic active hepatitis which may progress to cirrhosis of the liver and hepatocellular carcinoma (Kew, 1996). Continuous proliferation of hepatocytes, which may be present for the life of the host, is a prominent feature of chronic active hepatitis; in such patients, the relative risk of developing hepatocelluar carcinoma is increased 20–40 fold. Because of the large number of carriers of hepatitis B virus (HBV), approximately 200 million persons worldwide, hepatocellular carcinoma is one of the most common cancers in the world and is the most common cancer in HBV-endemic areas of the Far East and sub-Saharan Africa. The development of hepatocellular carcinoma probably depends upon direct effects of certain viral determinants along with chronic persistent proliferation of hepatocytes. HBV-related hepatocellular carcinomas often contain defective HBV genomes expressing one or more viral open reading frames; the viral X gene, which is often expressed in malignant tissues, is a transcriptional transactivator of host promoter sequences including those associated with oncogene expression and integrated viral genomes can activate host proto-oncogenes. There is little doubt that continuous proliferation of hepatocytes is also an important contributor to the development of neoplastic disease, since other disorders associated with chronic hepatitis and hepatocyte turnover (such as chronic alcoholism or hereditary hemochromatosis) may also lead to an increased predisposition to liver cancer, and the effects of alcohol ingestion and viral infection may well be synergistic in this regard (Brechot et al., 1996).

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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary Hepatitis C Virus A rapidly emerging association of chronic viral infection with malignancy is the development of hepatocellular carcinoma associated with chronic hepatitis C virus infection. In the United States, HCV infection is projected to become the major cause of liver cancer, due in part the large number of chronic carriers in this country, currently estimated at 3.5 million persons. In the case of HCV infection, a major determinant of development of hepatocellular cancer appears to be duration of infection and the degree of persistent liver injury (Zein and Persing, 1996). Several studies have associated certain HCV subtypes with differences in liver disease severity, interferon responsiveness, and duration of infection. Viral subtypes that appear to have been in the U.S. population for longer periods of time are dramatically overrepresented among patients with liver cancer. Specifically, subtype 1b, which is present in 15–20 percent of cases nationwide, is present in 90 percent or more of liver cancer patients in several studies conducted at different centers (Zein et al., 1996). Since presence of genotype 1b appears to be a marker of longer duration of infection in U.S. patients, it is possible that other genotypes will be more commonly implicated in cases of hepatocellular carcinoma in other countries, and that the overrepresentation of genotype 1b in the United States will decline over time. Additional factors such as alcohol consumption may contribute independently to risk of neoplasia, even in patients with more recent infections (Brechot et al., 1996). As for HPV infection, host immunogenetic or other factors may play a role in susceptibility to viral infection as well as in determining the severity of infection (see below). Recently, chronic HCV infection has been associated with the development of B-cell non-Hodgkin’s lymphomas in an Italian population (Mele et al., 2003) and with the development of cryoglobulinemia and monoclonal gammopathy in the United States (Cacoub et al., 1994). The development monoclonal gammopathy is thought to presage the development of hematologic malignancies in a significant subset of cases; it is not yet known whether HCV-associated monoclonal gammopathy or mixed cryoglobulinemia is a predisposing variable for the development of such malignancies in the United States. One recent study suggests that HCV infection-associated lymphoproliferative disease might include multiple myeloma (Montella et al. 2001). It is possible that MGUS is a marker of an underlying benign, perhaps antigen driven lymphoproliferative process, which may after many years convert to a malignant process via somatic mutation. In this respect, the genesis of neoplasia may be similar to that described for Helicobacter pylori-related MALT lymphoma. The relative disparity in the frequency of non-Hodgkin’s lymphoma associated with HCV infection in the United States compared to that in Europe may conceivably reflect differences in duration of infection within the population, immunogenetic differences, or exposure to other oncoviruses including KHSV.

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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary Human Papillomavirus Infection In the past decade, human papillomavirus (HPV) has emerged as the single most important risk factor for development of cervical carcinoma, and it may be associated with neoplasia in other tissues as well. To date, more than 80 HPV subtypes have been described in a wide variety of epithelial tissues, with some viral subtypes found exclusively in certain tissues; partial sequences of novel subtypes indicate that over 100 subtypes may exist in humans. It is estimated that approximately 95 percent of cervical cancers worldwide are associated with infection by certain human papillomavirus subtypes, usually types 16 or 18 but occasionally other types. HPV-associated cervical cancers typically harbor at least remnants of the HPV genome in the form of two viral oncogenes which are consistently expressed in malignant tissues. The viral E6 gene product binds to tumor suppressor protein p53, promoting its degradation, and the viral E7 product binds to the retinoblastoma gene product, resulting in a functional inactivation. In addition, the E6 and E7 oncoproteins stimulate cell proliferation by activating cyclins E and A. The combination of these effects is to immortalize keratinocytes in vitro. However, additional mutational events are apparently needed to provide the fully transformed phenotype, since immortalized keratinocytes do not form tumors in vivo (zur Hausen and Rosl, 1994). Nonetheless, the viral E6 and E7 genes and their products may become attractive diagnostic targets for monitoring metastatic disease and for the development of tumor-specific immunotherapeutic protocols. The association of HPV infection with carcinomas of other tissues has been less clear cut, but is somewhat reminiscent of the early days of research on the association of HPV with cervical cancer in which a fundamental limitation in the detection of the large variety of HPV types led initially to great controversy. On the other hand, the inherent proneness of PCR technology to contamination problems, coupled with its ability to detect extremely small numbers of possibly incidental HPV contaminants, warrants a careful interpretation of the growing number of reports implicating this virus in malignancies of many types. Archetypal “oncogenic” subtypes of HPV appear capable of infecting different anatomical sites, and associations of HPV infection with squamous cell carcinomas of the head and neck are reasonably well established. The involvement of HPV in the pathogenesis of skin cancer, the most common malignancy in the world, was suggested recently and a new family of HPV types has now been described in recurrent squamous cell carcinomas of the skin in transplant patients (Shamanin et al., 1996). This finding seems consistent with the clinical experience in patients who are immunosuppressed by HIV infection, in which cervical dysplasia is highly prevalent (Sun et al., 1995). The role of HPV infection in epithelial carcinomas of the bladder and lung are also being investigated. Studies of the bovine papilloma virus (BPV) have been shown to have an association with cancer of the bladder in cattle (Olson et

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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary al., 1965). Inoculation of BPV into newborn hamsters or mice has also been demonstrated to induce tumors (zur Hausen, 1996). Some human studies in recent years have suggested that relatively common HPV types can be detected in human transitional cell carcinoma (TCC) of the bladder in up to 34 percent of cases in certain patient populations (Smetana et al., 1995), but the presence of HPV in the neoplastic tissue has been difficult to demonstrate with consistency (Chetsanga et al., 1992). Interestingly, cases of rapidly progressive multifocal TCC of the bladder have been reported in patients following renal and cardiac transplantation, suggesting that HPV may play a more significant role in TCC of the bladder in immunosuppressed patients (Noel et al., 1994). Although smoking history is the leading risk factor in the development of squamous cell carcinoma of the lung, a recent study implicated the presence of HPV type 16 in an unexpectedly high number of cases of well-differentiated squamous cell carcinoma of the lung on the island of Okinawa (Kinoshita et al., 1995). However, although some studies have supported this finding (Hirayasu et al., 1996), others have failed to implicate HPV in lung cancer (Szabo et al., 1994). In this regard, it is interesting to note that risk of cervical cancer is linked epidemiologically to risk of carcinoma of the lung but not uterine or ovarian cancers, and that both of the former are linked to smoking (Anderson et al., 1997). Clearly, additional studies will be necessary which are designed to rule out the effects of incidental virus and DNA contamination, yet also designed to be capable of detection of the widest range of HPV types. Recent studies of the natural history of HPV infection have suggested that the ability of the genetically heterogeneous papillomaviruses to exploit relative deficiencies in the immune response may represent an important determinant of the risk of developing chronic infection and subsequent neoplastic disease. Attention has focused recently on cytokine production in HPV-specific helper T lymphocyte populations in women with cervical cancer compared to women in whom the disease regresses spontaneously. Several studies have now indicated that failure to mount cytotoxic T cell (CTL) responses to human papillomavirus-infected cells may significantly predispose to the development of cervical cancer (Tsukui et al., 1996); this failure may be virus type-specific, such that the types represented most often in cervical cancer are those most successful at avoidance of CTL activity (Ellis et al., 1995). Conditions associated with reduced CTL activity, such as HIV and HTLV infection, oral contraceptive use, pregnancy, and immune suppression associated with transplantation have likewise been associated with increased HPV viral burden and acceleration of disease progression (Sun et al., 1995). Twin studies have suggested that risk factors for cervical cancer, as for another HPV-associated lesion, epidermoplasia verruciformis, may be inherited (Ahlbom et al., 1997). More recent studies have failed to detect an association with somatic mutations in the gene encoding p53, and have further explored associations with the immunoglobulin gene cluster (Cuzick et al., 2000). Understanding the contribution of the environmental, host somatic, and host im-

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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary munogenetic factors to the development of HPV-related dysplasia is an area of intense research activity which may lead to direct practical benefits to patients in the form of improved immunomodulatory approaches to early and late stage lesions. Since the prevalence of HPV infection is so high, the use of routine testing for HPV is of questionable value (Stoler, 2001), except in patients with Pap smears containing atypical features (ASCUS). Clearly, if additional immunogenetic and other host susceptibility factors can be identified, the positive predictive power of HPV testing in cervical cancer screening programs may increase to acceptable levels (Klug et al., 2001). The Role of Humoral and Cellular Immune Responses As illustrated vividly by HIV infection, infection with one pathogen may lead to a predisposition toward other infectious processes as well as cancer; a key feature of the immune suppression associated with HIV infection and pharmacologically-produced immunosuppression following transplantation is a reduction of cytotoxic T-cell (CTL) and related T-helper type 1 responses (Spina and Tirelli, 1992). One important theme that recurs among the above mentioned programs, and in cancer research in general, is the relationship of T cell responses to the evolving tumor. A decline in cytotoxic immunity has been associated with virus-associated tumors in immunosuppressed patients, and relative deficits in the establishment of CTL responses during the initial stages of infection are associated with progression of infection in otherwise immunocompetent hosts. Relative differences in the ability to mount cytotoxic T-cell responses have been noted among mouse strains for several years, and recent evidence suggests that immunogenetic determinants in humans may play similar roles. From a teleological perspective, it is likely that viruses and other pathogens associated with chronic infections in humans have evolved means of avoiding CTL responses in at least some hosts in order to maximize reservoir capacity. An example is the recent documentation of point mutations within a dominant HLA B7-associated CTL epitope of the human papillomavirus E6 gene product; the presence of sequence variation has implications for vaccine design and immunotherapy, and overall, viral diversity must be taken into account in the design of therapeutic strategies. Just as the suppression of cellular immune responses may relate to development of cancer, the development of humoral immune responses may be extremely useful for determining the history of exposure to the pathogen and for the serologic surveillance necessary to establish the etiologic role of a given pathogen. Serologic studies have been critical to the understanding of the role of H. pylori as an etiologic cofactor in various malignancies; when no such assays are available for a novel infectious agent, surrogate serologic assays can be used as proposed previously (Persing, 1997). Furthermore, since IgG antibody subclasses are generated on the basis of T-cell help, measurement of IgG subclasses may lead to an understanding of the role of T-cell responses (i.e., the proportional Th1

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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary and Th2-type responses) in determining the resolution or persistence of a particular infection (Moro et al., 2001). Role Reversal: The Cancer Cell as the Ultimate Eukaroytic Parasite Independent of the etiologic roles of infectious agents in the development of human cancer, in more than one sense, the cancer cell itself represents the ultimate eukaryotic parasite. Cancer cells, like parasitic protozoa, use a variety of mechanisms to avoid immune surveillance including persistence in small numbers, active secretion of immunosuppressive substances, downregulation of MHC class 1-based recognition, and antigenic variation (Buchanan and Nieland-Fisher, 2001). Humoral immune responses to cancer-specific antigens often occur in cancer patients and are undetectable in patients without cancer (Disis et al., 1997), suggesting that immunologic tolerance can be broken and that many types of cancer-specific immune responses, in the form of tissue-specific autoimmune phenomena, can be tolerated in humans. Antibody responses in cancer patients have led to the discovery of many important cancer-specific antigens (Chen, 2000). At the same time, these studies point to the relative lack of efficacy of humoral immune responses in the control of a developing malignancy, much the same way that in chronic carriers of protozoan parasites, immune responses to pathogen-specific antigens happily coexist with the pathogens themselves. Indeed, many of the lessons learned from parasite immunology can be extrapolated to human cancer, especially in the development of new vaccine-based approaches to the treatment of both diseases. Conclusions In purely reductionistic terms, infectious diseases can be viewed as horizontally acquired genetic disorders, in which exogenously acquired nucleic acids of a pathogen integrate, either chromosomally, episomally, or extracellularly, with those of the host to disrupt normal cellular processes or produce inflammation. Developing a better understanding of the interactions of human microbial flora with their hosts, along with an understanding of other host and environmental determinants of pathogenicity, represents an increasingly important intersection of infectious disease research with the Human Genome Project. Illustrations of the latter concept are provided by the discovery of resistance to HIV infection by virtue of mutations within a gene encoding an HIV coreceptor (CCR-5) (Samson et al., 1996). Another important example is the inherited susceptibility to Mycobacterium avium-intracellulare infections in families carrying a mutant allele of the interferon-gamma (IFN-γ) receptor (Newport et al., 1996). The identification of such an allele within the human population has far-reaching implications, since it may be associated with a general reduction in the ability to mount cytotoxic T-cell responses during infections of many types. Genetic predisposition to

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The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects - Workshop Summary papillomavirus infection appears to underlie the inherited skin disorder epideromodysplasia verruciformis (Majewski and Jablonska, 1995), in which cytotoxic T-cell responses apparently fail to develop against certain papillomavirus subtypes. Since early generation of such responses appears to be a critical step in the resolution of human papillomavirus infections, patients harboring functionally similar mutations may be uniquely predisposed to the development of cervical and other cancers linked to HPV infection. By focusing on unusually severe outcomes of relatively common infectious diseases, we may be able to identify critical immunogenetic factors in the formation of protective immune responses, and to tailor patient management and cancer chemoprevention efforts (in some cases directed against the pathogens themselves) in appropriate ways. REFERENCES Ablashi DV, Chatlynne L, Thomas D, Bourboulia D, Rettig MB, Vescio RA, Viza D, Gill P, Kyle RA, Berenson JR, Whitman JE. 2000. Lack of serologic association of human herpesvirus-8 (KSHV) in patients with monoclonal gammopathy of undetermined significance with and without progression to multiple myeloma. Blood 96:2304–2306. Ahlbom A, Lichtenstein P, Malmstrom H, Feychting M, Hemminki K, Pedersen NL. 1997. Cancer in twins: genetic and nongenetic familial risk factors. Journal of the National Cancer Institute 89:287–293. Ambinder RF. 1990. Human lymphotropic viruses associated with lymphoid malignancy: EpsteinBarr and HTLV-1. Hematology Oncology Clinics of North America 4:821–833. Anderson KE, Woo C, Olson JE, Sellers TA, Zheng W, Kushi LH, Folsom AR. 1997. Association of family history of cervical, ovarian, and uterine cancer with histological categories of lung cancer—the Iowa women’s health study. Cancer Epidemiology, Biomarkers & Prevention 6:401–405. Beksac M, Ma M, Akyerli C, DerDanielian M, Zhang L, Liu J, Arat M, Konuk N, Koc H, Ozcelik T, Vescio R, Berenson JR. 2001. Frequent demonstration of human herpesvirus 8 (HHV-8) in bone marrow biopsy samples from Turkish patients with multiple myeloma (MM). Leukemia 15:1268–1273. Brechot C, Nalpas B, Feitelson MA. 1996. Interactions between alcohol and hepatitis viruses in the liver. Clinics in Laboratory Medicine 16:273–287. Buchanan J and Nieland-Fisher NS. 2001. Role of immune function in human papillomavirus infection. Journal of the American Medical Association 286:1173–1174. Cacoub P, Fabiani FL, Musset L, Perrin M, Frangeul L, Leger JM, Huraux JM, Piette JC, Godeau P. 1994. Mixed cryoglobulinemia and hepatitis C virus. American Journal of Medicine 96:124–132. Chang Y and Moore PS. 1996. Kaposi’s Sarcoma (KS)-associated herpesvirus and its role in KS. Infectious Agents & Disease 5:215–222. Chen YT. 2000. Cancer vaccine: identification of human tumor antigens by SEREX. Cancer Journal 6 (Suppl 3):S208–217. Chetsanga C, Malmstrom PU, Gyllensten U, Morenolopez J, Dinter Z, Peterson U. 1992. Low incidence of human papillomavirus type 16 DNA in bladder tumour detected by polymerase chain reaction. Cancer 69:1208–1211. Chu PG, Chang KL, Chen YY, Chen WG, Weiss LM. 2001. No significant association of EpsteinBarr virus infection with invasive breast carcinoma. American Journal of Pathology 159:571–578.

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