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Antiviral Therapy 7: 73–80 Editorial Review Using live pathogens to treat infectious diseases: a historical perspective on the relationship between GB virus C and HIV David M Aronoff* Infectious Diseases and Clinical Pharmacology Divisions of the Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tenn., USA *Present address and affiliation: Infectious Diseases Division of the Department of Medicine, University of Michigan Health System, Ann Arbor, Mich., USA. Tel: +1 734 763 9077; Fax: +1 734 764 4556; E-mail: [email protected] Recent reports that co-infection with GB virus C (GBVC) is associated with a reduced mortality in HIV-infected individuals, a slower progression to AIDS, and lower HIV viral loads, suggest a potential role of GBV-C as therapy for HIV infection. Although not known to cause any human disease, GBV-C was only recently discovered and prospective studies assessing long-term consequences of infection have not been completed. Our understanding of the host-viral interactions between humans and GBV-C is in its infancy. Further research into the intriguing relationship between GBV-C and HIV is needed before intentional inoculation of GBV-C into individuals infected with HIV should proceed. This essay explores the history of the once-popular treatment of paretic tertiary syphilis with the blood-borne pathogen Plasmodium vivax, providing a historical perspective on the current state of affairs between GBV-C and HIV. A brief review of GBV-C biology and human infection is followed by a discussion of the current challenges facing the use of this organism to treat HIV. Introduction Recent investigations document that co-infection with GB virus C (GBV-C) is associated with a reduced mortality in HIV-infected individuals, a slower progression to AIDS, and lower HIV viral loads [1–6]. In one study, for example, mortality was 28.5% in patients testing positive for GBV-C RNA, and 56.4% in GBV-C RNA-negative patients when followed over 4.1 years [5]. GBV-C was first described in 1995 [7]. It is an enveloped, positive-strand RNA virus of the Flaviviridae family, related to hepatitis C [8,9]. It is unclear which host cells serve as the predominant reservoir for replicating GBV-C. Multiple genotypes have been described [10], but the clinical importance of these genotypes, with respect to host-viral interactions, remains unknown. As GBV-C is not known to cause any human disease, the idea of using this virus to treat HIV-infected persons has been noted [5,6,11]. The intentional inoculation of patients with improperly screened blood from GBV-C RNA-positive donors is inadvisable, as GBV-C frequently co-exists with other blood-borne pathogens. Although it was only recently characterized, long-term retrospective studies fail to ©2002 International Medical Press 1359-6535/02/$17.00 find important consequences of infection with GBV-C [reviewed in references 9,12]. As future research investigates the therapeutic usefulness of the intriguing relationship between GBVC and HIV, it is of historical interest to examine another situation in which a living pathogen was used as therapy for an infectious disease. The infectious disease was syphilis and the therapeutic microbe was Plasmodium vivax. Reviewing the experience of malaria therapy for tertiary syphilis provides a relevant context for discussing the current challenge of developing GBV-C-based therapy for HIV infection. General paralysis General paralysis (GP) is a tertiary form of Treponema pallidum infection (syphilis) that appears 10–20 years after initial infection when left untreated. Also referred to as general paralysis of the insane, general paresis, dementia paralytica, and progressive paralysis, GP is characterized by both neurological and psychiatric manifestations, including alterations in personality, 73 DM Aronoff affect, sensorium, intellect, insight and judgment [13]. Before the advent of effective therapy it progressed to psychosis and an agonizing death [14]. Although exact figures are unknown, GP presented a major clinical challenge for late-19th- and early-20th-century psychiatrists [14]. Some European asylums reported that up to 45% of their male patients suffered from GP [14]. In the early 1900s nearly 20% of male first admissions to mental hospitals in New York were afflicted [14], and in 1921 approximately 10% of all patients in British asylums were believed to be victims of GP [15]. The condition came to be regarded by some as ‘perhaps the most terrible of all mankind’s diseases’ [15,16]. The same could be said of AIDS in our time. Malaria therapy Towards the end of the 1800s and the early part of the 20th century, the Austrian psychiatrist Julius WagnerJauregg (1857–1940) began studying fever as treatment for mental diseases [15,17]. It is believed his interest was sparked after one of his patients contracted erysipelas and subsequently recovered from a severe mental illness [17]. Further studies on the relationship between pyrexia and recovery from psychosis led to his 1887 publication The Effect of Feverish Diseases on Psychoses [18]. With regards to GP, Wagner-Jauregg noted that, ‘in the rare cases of cure and in the frequent remissions of progressive paralysis, a febrile infectious disease or protracted suppuration had often preceded the improvement in the state of the disease’ [19]. An early attempt by Wagner-Jauregg to imitate the action of a febrile infectious disease for GP therapy compared paralytic patients treated with tuberculin injection to untreated controls [17]. It was clearly demonstrated that the tuberculin-treated patients had more remissions than untreated subjects [17]. Unfortunately, however, the relapse rates were high. The best results seemed to occur in those cases in which an unintentional infectious disease, such as pneumonia or an abscess, appeared during the course of the treatment [17,19]. From this observation Wagner-Jauregg had the idea of producing a real infectious disease in his paralytic patients. The ideal infection would be one that could be controlled and would not endanger the environment [17]. He chose to study tertian malaria. Wagner-Jauregg’s malaria therapy began in 1917 with the inoculation of two paralytic patients with the blood of a Plasmodium vivax-infected soldier. Seven more patients were soon inoculated with parasitemic blood. Of these nine initial recipients, six showed considerable improvement and two had prolonged remissions [17]. Once infected, paretics became ill 74 following an incubation period of about a week [14]. The onset of chills, nausea and malaise heralded the arrival of pyrexia that peaked at nearly 106°F, lasted several hours, and slowly returned to normal [14]. Patients were permitted to cycle through 10 to 12 ‘febrile convulsions’ before being administered quinine bisulfate to terminate the infection [17,20]. Before receiving quinine, however, 2–6 ml of malarial blood were usually withdrawn in order to inoculate another patient [14]. Malarial strains were maintained by transmitting plasmodia from paretic to paretic [14]. The popularization of malaria therapy By 1925 the number of paralytics treated exceeded 1000 with various degrees of improvement reported in over 60% of patients [17]. During this time malaria therapy was being used all over the world. America’s first patient was inoculated at St Elizabeth’s Hospital in Washington, DC in December 1922 [14]. A 1923 editorial in the American Journal of Psychiatry suggested, ‘It may be that every large hospital for mental disorders may have to maintain one or more malarial patients as source of infectious material’ [21]. The results of malaria therapy worldwide were consistent, with a full remission rate of about 30% and a partial remission rate of nearly an additional 20% [17]. In the USA, complete remission rates ranging from 25–50% were reported in malaria-treated patients, compared with 3–5% for paretic individuals given either arsenicals and heavy metals or no treatment [20,22]. Risks and criticisms Despite the reported results, the risks of malaria therapy were great [22]. Treatment-associated mortality rates of 5–10% were reported and malariainduced morbidities such as splenic rupture, anaemia, cardiovascular collapse, delirium, pneumonia, nephritis, hepatic injury and gastrointestinal haemorrhage also occurred [22]. Perhaps in an effort to reduce these adverse outcomes, hyperthermia induced by artificial (external) means was employed [20,23]. This use of ‘fever cabinets’ demonstrated equivalent efficacy when compared to malaria injection for mild to moderate paresis, and obtained superior results in those with severe GP [23]. Mortality appeared to be reduced by hyperthermia therapy as well [23]. Some questioned the actual effectiveness of malaria therapy. Sir William Osler proclaimed, ‘Prolonged remissions [in GP], which are not uncommon, are often erroneously attributed to the action of remedies’ [24]. Wagner-Jauregg’s studies, along with others from that period, were not randomized controlled trials. Most ©2002 International Medical Press Treating infections with live pathogens were case series without a control group. Thus, although Wagner-Jauregg and other investigators reported remission rates of over 30% for neurosyphilis, the data are difficult to interpret [25]. Confounding variables in these experiments included the lack of a strict case definition, the duration of paresis (better results were consistently reported for early paresis), the aetiology of the neurological illness (GP being a clinical diagnosis), and the general condition of the infected patients [15,25]. Furthermore, there were inconsistent criteria for the definition of remission and no uniform follow-up period was reported [25]. The end of an era Despite the shortcomings of malaria therapy, WagnerJauregg was lauded for his efforts. He received the Nobel Prize in Physiology and Medicine in 1927. In his presentation speech, Professor Wernstedt, Dean of the Royal Karolinska Institute proclaimed: ‘It is now quite clear from this that Wagner-Jauregg has given us a means to a really effective treatment of a terrible disease which was hitherto regarded as resistant to all forms of treatment, and incurable’ [26]. Although granting such a prestigious award for a hazardous therapy supported by insufficient science today seems outlandish, it underscores that we more readily accept interventions of relatively high risk when handicapped by the limits of technology and scientific understanding; particularly when dealing with seemingly fatal diseases for which no foreseeable effective remedy exists. Malaria therapy was finally abandoned upon the development of penicillin in 1943. Interestingly, inoculation with blood containing Plasmidium vivax has been used recently to treat symptoms attributed to chronic Lyme disease [27,28]. Apropos of the GBV-C findings noted above, eight individuals with HIV infection were given malaria therapy to potentially ‘stimulate’ their immune systems [29]. Malaria therapy has also been proposed as an adjuvant cancer treatment [30]. In these instances, as before, desperate times occasioned the unsubstantiated application of highrisk measures not supported by sound scientific evidence. Perspectives relevant to GBV-C inoculation Given that modern technology affords us the use of organisms cultured and engineered in vitro for preventive and therapeutic measures, the intentional inoculation of patients with blood containing live pathogens may seem anachronistic. Modern examples of such practices are understandably sparse. Antiviral Therapy 7:2 The use of enemas using stool from apparently healthy donors to treat individuals suffering from refractory Clostridium difficile-induced colitis [31–33] provides a controversial example of direct human-tohuman microbial transmission as therapy for an infectious ailment. A more germane example is provided by the recent observation that HIV-positive individuals acutely co-infected with Orientia tsutsugamushi, the causative agent of scrub typhus, exhibit a suppression of HIV viral load [34]. This has led to the exploration of the relationship between these two pathogens [34,35]. Although the therapeutic inoculation of HIV-infected individuals with O. tsutsugamushi has not been attempted, the transfusion of non-infectious plasma donated by acutely infected scrub typhus patients into HIV-positive recipients has been reported [35]. Although a description of that work is beyond the scope of this paper, important issues regarding the screening mechanisms for potential donors reported in the O. tsutsugamushi study are discussed below. GBV-C history, biology and epidemiology of human infection In 1995 the genomes of two novel flaviviruses (GBV-A and GBV-B) were cloned from tamarins inoculated with serum containing an unknown hepatitisproducing agent [36]. The initial serum inoculate was procured from a surgeon (whose initials were GB) suffering from acute hepatitis [7]. Enzyme-linked immunosorbent assays developed from recombinant GBV-A and GBV-B proteins led to the identification of seropositive human subjects [7]. Although subsequent genomic analysis of these seropositive individuals did not reveal evidence for infection with GBV-A or GBVB, the genome of a novel human flavivirus (termed GBV-C) was discovered [7]. The following year, Linnen et al. independently reported the genomic sequence of a hepatitis-associated RNA virus designated hepatitis G virus [37]. Comparisons of the cDNA sequences of GBV-C and hepatitis G virus revealed 96% homology, indicating that the two were separate genotypes of the same virus [9]. GBV-C is an enveloped, positive-strand RNA virus of the Flaviviridae family (reviewed in [8,9]). The viral genome and its organization are somewhat similar to the flavivirus hepatitis C (29% aa homology) [38]. GBV-C RNA encodes a single open reading frame, flanked by non-coding (NC) regions, with structural and nonstructural (NS) proteins being encoded in the 5′- and 3′-ends of the open reading frame, respectively [39]. Transcription of the open reading frame yields a polypeptide predicted to be cleaved into two envelope proteins (E1 and E2), a serine protease-RNA helicase (NS3), and an RNA-dependent RNA polymerase 75 DM Aronoff (NS5) [39,40]. Interestingly, the genetic sequence encoding a nucleocapsid has not been clearly elucidated despite physical evidence for nucleocapsid existence [40–42]. Phylogenetic analyses of GBV-C isolates have demonstrated the presence of at least five genotypes demonstrating significant geographic clustering [10]. Genotype 1 predominates in West Africa, genotype 2 in North America and Europe, genotype 3 in Asia, genotype 4 in Southeast Asia, and genotype 5 in South Africa [10]. These genotypes show a high degree of conservation of polyprotein sequence (94% of identity), and unlike hepatitis C virus, the genome of GBV-C exhibits a low rate of mutation [8]. The distinct geographic distribution of GBV-C variants is consistent with a long co-evolution with human populations during their global spread in palaeolithic times [8]. The clinical significance, if any, of these GBV-C genotypes is not known. Exploring potential differences in host response to different GBV-C strains could be important to the development of live viral strains for therapeutic or preventive purposes (see below). A current research focus has been to determine the cellular targets of GBV-C infection. Initially believed to be largely hepatotropic, GBV-C does not appear to replicate in hepatocytes preferentially. Numerous investigations have failed to implicate the liver as an important site of virion production (reviewed in [12]). However, a recent study of liver biopsy tissue obtained from 15 GBV-C RNA-positive individuals (without hepatitis) revealed evidence of cytoplasmic viral replication within hepatocytes in 67% of patients [43]. Notably, only a minority of liver cells had detectable viral replication, a finding that may explain the lack of evidence for hepatocyte replication reported in earlier studies. Although some research groups have identified GBV-C replication in peripheral blood mononuclear cells (PBMCs), endothelial cells, splenic tissue and bone marrow, clinically relevant sites of viral propagation are uncertain at present (reviewed in [9,12]). Recent data suggest that, similar to hepatitis C virus, GBV-C may be able to enter cells via low density lipoprotein receptors [44]. GBV-C may be transmitted via blood (or blood products), vertically/perinatally from mother to child, and probably sexually (reviewed in [12]). GBV-C RNA is detectable in serum as early as 2–3 weeks following infection and may persist for many years. It is estimated that 50–75% of newly infected individuals will clear their GBV-C infection, as evidenced by the disappearance of viral RNA and the appearance of anti-E2 serum antibodies [12]. Clearance tends to occur within the first 2 years of infection but can occur after many years. The host and/or viral factors 76 critical in determining when (or if) viral clearance occurs are unknown – an important point when planning to use GBV-C infection therapeutically. An estimated 1–4% of blood donors worldwide are GBV-C RNA-positive [9,12]. RNA-positive rates as high as 10–33% have been noted in South American and African populations [9]. Seroprevalence, as assessed by measuring anti-E2 antibodies, allows for an estimation of the number of individuals previously infected with GBV-C. Resolved infections appear to be more prevalent than ‘viraemic’ infections (as determined by RNA measurement) [9]. Global seropositivity has been estimated between 3% and 20%, depending upon geographic regions [9]. Consequences of GBV-C infection At present, most GBV-C infections appear to be asymptomatic and pathologically inconsequential (reviewed extensively in [9,12]). The abundance of clinical data accrued at present does not implicate GBV-C as a causative agent in any disease [45]. There are, however, some limitations to our current understanding of the natural history of GBV-C infection that warrant consideration. The risks of long-term GBV-C infection have been assessed retrospectively in individuals infected with GBV-C for up to 16 years [46–51] (reviewed in [9,12]). GBV-C does not appear to cause any type of liver disease, either acute or chronic. Because the major endpoints reported by these and other studies have centred on the development of liver disease, the risk of occurrence of extrahepatic ailments has not been adequately assessed. Retrospective studies of GBV-C-infected cohorts examining a broader range of non liver-related illnesses might be useful, although it may be difficult to identify (a priori) diseases for which GBV-C might exhibit a biologically plausible role. Prospective studies may provide the best mechanism for detecting an involvement of GBV-C in human pathology but they have so far failed to link GBV-C to hepatic or extrahepatic diseases, although the duration of these studies is under 10 years at present [52,53]. A small but cautionary study by Ellenrieder et al. [54] documents a 16.3% prevalence of GBV-C infection in patients suffering from low-grade lymphomas, in the absence of hepatitis C infection. There were no cases of GBV-C infection in their cohort of patients with high-grade lymphoma, despite the fact (as the authors postulate) that both groups received blood transfusions [54]. A limitation of this study, in addition to its small sample size, was the lack of in situ data assessing the presence or absence of GBV-C in neoplastic lymph nodes. Although ruling out any potentially causative asso©2002 International Medical Press Treating infections with live pathogens ciation between GBV-C infection and clinical disease is not currently possible, if such an association exists, it is probably quite infrequent, or it would have been recognized during this recent period of intense surveillance [12]. The finding that an immunosuppressed population (HIV-positive individuals) may benefit from GBV-C infection supports this notion. In this light, it has been recommended that GBV-C not be screened for in blood donors [12,55]. Developing a therapeutic strain of GBV-C Important issues regarding the development of a therapeutic supply of GBV-C need to be addressed more fully before clinical trials commence employing the intentional infection of HIV-positive patients with GBV-C. Most notably, GBV-C infection has not been proven to directly cause the beneficial virological and/or immunological effects reported in HIV/GBV-C co-infected patients. It has been postulated that GBV-C infection may be a marker for separate immune mechanisms underlying the maintenance of health in HIV-infected patients [56]. However, recent in vitro findings that GBV-C infection can be supported in CD4 T-cells [40] and that GBV-C infection suppresses HIV replication [5] suggest that a direct effect of GBVC may exist. Further research underlying these interactions must continue. The risk of inoculating individuals with GBV-Cinfected blood can be reduced if the donor serum has been adequately screened for known human pathogens, in a manner similar to that currently outlined by the American Association of Blood Banks (http://www.aabb.org). The extent of screening required (at minimum) is illustrated by a recent experiment conducted in Thailand, designed to inoculate HIV-infected individuals with pathogen-free plasma collected from individuals suffering from acute scrub typhus infection (see above) [35]. Potential donors completed an extensive history questionnaire (following American Association of Blood Banks guidelines) and were excluded if they had tattoos, a history of drug use, exposure to blood or blood products, non-sterile skin penetration or contact with persons infected with viral hepatitis or HIV [35]. Donor blood was tested prior to plasma donation (and 1 month later) for anti-HIV antibody, T. pallidum antigen, anti-hepatitis C antibody, dengue infection, hepatitis B surface antigen, malaria and for biochemical evidence of hepatitis [35]. Obtained plasma was cultured for aerobic and anaerobic bacteria, tested by RT-PCR for HIV RNA, and by PCR for HCV RNA. Prior to use the plasma was frozen at –70°C and then sequentially thawed, transferred to a sterile blood bag and heated at 50°C for 3 h to inactivate transmissible viruses [35]. Although the large-scale Antiviral Therapy 7:2 application of a similar process for use of GBV-Cinfected blood is possible, it would amount to a major undertaking. In addition, selection of donors could be further complicated if important differences among the various GBV-C genotypes on HIV pathogenesis are discovered [57]. The development and mass cultivation of pathogenfree GBV-C in vitro may present a more tenable goal. Again, studies of the importance of GBV-C genotypes may impact on this prospect. Drawing from the experience of vaccine development, it might be possible to develop therapeutic GBV-C products utilizing recombinant technologies. Hepatitis B surface antigen vaccine, for instance, has been accomplished by cloning the surface antigen gene into yeast cells [58]. Insertion of GBV-C genes into viral vectors such as pox viruses (vaccinia or canarypox) or bacteria such as salmonella or bacillus Calmette-Guerin might also be possible, as may the direct inoculation of patients with all or part of the GBV-C RNA genome [58]. Prior to exploring these alternatives, a better understanding of the host immune response to GBV-C is imperative. In addition, it is not clear if the immune response to GBV-C or the direct effects of the virus itself protect the host against HIV pathogenesis. Development of pathogen-free GBV-C for human use will require stable sources of virus cultivated in vitro. Efforts to propagate GBV-C have met with mixed results. Successful replication was initially reported by co-incubating hepatitis C virus and GBV-C with either MT-2C (a human T-cell leukaemia virus type I-infected human T-cell line) or PH5CH (a nonneoplastic human hepatocyte cell line immortalized with simian virus 40 large T antigen) cells [59]. Dual infection was also successful using H-903 (a Burkitt lymphoma-derived interferon-resistant Daudi cell line) cells [60]. A therapeutic or preventive supply of GBVC would obviously need to be free of known human pathogens however. Efforts to grow GBV-C in the absence of hepatitis C virus have succeeded, using human PBMCs, but viral replication varied among PBMC donor cell lines [39]. In each of these studies initial inoculums of GBV-C were obtained from clinical specimens, a potential limitation with regards to the standardization of GBV-C strains propagated for medical use. An important recent advance in this regard was the successful growth of GBV-C in human CD4 T-cells transfected with full-length RNA transcripts derived from a GBV-C cDNA clone [40]. Conclusions Today HIV infection and the consequential development of AIDS pose an enormous threat to the social, political and economic landscape of the entire global 77 DM Aronoff population [61]. The impact of AIDS on world civilizations certainly humbles any prior infectious disease threat in our history. Current antiretroviral therapeutics may someday be looked upon as temporizing measures that provided some benefit until extremely potent treatments could be devised. Certainly this is how we view the application of malaria therapy to paretic syphilis. Prior to the development of penicillin, malaria therapy was embraced as a highly successful treatment for a largely incurable disease. To this day there is uncertainty if the association between malaria therapy and the resolution of paretic syphilis was one of cause and effect; an uncertainty largely resulting from a lack of well-designed studies of malaria therapy, coupled with a poor understanding of both the pathogenesis of tertiary syphilis and the host response to tertian malaria. The prospect of treating HIV-infected patients with in vitro-cultivated or recombinant GBV-C may be on the horizon. Perhaps more important, however, are the newfound scientific avenues illuminated by the significant observation that GBV-C infection is associated with clinical benefits for HIV-infected individuals. Investigations into this phenomenon might facilitate our understanding of HIV pathogenesis and host immunity. 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