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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,
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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
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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
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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
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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
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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. Comprehension of the molecular and
cellular responses conferring protection from the
immunosuppressing effects of HIV in co-infected individuals could unlock myriad pharmacological
approaches to treating HIV disease, and should remain
our focus. As the story of GBV-C and HIV unfolds, we
need to avoid resorting to desperate measures and
questionable science.
Acknowledgements
The author wishes to acknowledge Richard
D’Aquila for his careful reading of an earlier version
of this manuscript and John Oates for his informative
discussions.
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