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Hyperthermic therapy for HIV infection
Medical Hypotheses Medical Hypotheses (1995) 44, 235-242 © Pearson Professional Ltd 1995
Hyperthermic Therapy for HIV Infection S. D. OWENS and P. W. GASPER Department of Pathology, College of Veterinary and Biomedical Sciences, Colorado State University, Ft Collins, CO 80523, USA. (Correspondence and repnnt requests to Peter W. Gasper).
Abstract m The objective of this paper is to review what is known about the antiviral effects of fever and to highlight the scientific evidence supporting the hypothesis that hyperthermic therapy may prove to be a beneficial treatment modality for persons infected with HIV. Our hyperthermic hypothesis is based upon the mutant escape, quasispecies theory of HIV antigenic diversity. We propose that, if initiated during the asymptomatic stage of HIV infection, hyperthermia may prove to decrease the number of mutant HIV strains arising due to evolutionary pressures created by the patient's immune system, with a resultant prolongation of the asymptomatic period of infection. A review of the literature from three areas of investigation: the immune response to fever, heat as a tumor killing agent, and preliminary studies with fever and retroviral infections, strongly suggests that there is a good scientific basis for the use of hyperthermic therapy in a multimodal treatment approach to HIV infection. Introduction The Centers for Disease Control and Prevention (CDC) estimate that by year end 1994 there will have been a total of 420 000-540 000 persons diagnosed with AIDS in the USA. In addition, a total of more than one million US citizens (14 million persons worldwide) will be infected with HIV (1). Despite 10 years of intensive research, there is still no treatment or procedure that stops or reverses the primary viral disease process involving the depletion and deactivation of T4 lymphocytes, and it has proven to be very difficult to develop a protective vaccine against an infectious organism that can mutate quickly thereby presenting constantly changing antigens to the immune system (2). A review of the literature from three areas of investigation: the immune response induced by fever, heat as a tumor killing agent, and preliminary studies with fever and retroviral infections, strongly suggests
that there is a good scientific basis for the use of hyperthermic therapy in a multimodal treatment approach to HIV infection. While hyperthermic therapy alone may not prove to be a cure for AIDS, it is our tenet that hyperthermia, in combination with current antiretroviral therapies, offers the potential to extend the asymptomatic stage of HIV infection. Hyperthermia has shown unexpected success in the treatment of Kaposi's sarcoma (3--6) for those persons who have progressed from an HIV-positive status to AIDS. Hyperthermic therapy is not a new treatment procedure. The use of heat in the treatment of disease has been practiced for centuries. In India, as early as 3000 BC, the Ayurvedic system employed a monthlong program in the treatment of illness consisting of the feeding of rice and oils, the administration of purgatives and the heating of the body through the use of steam baths (7). Approximately 3200 years later, in the second century AD, Rufus of Ephesus observed that the occurrence of fever could be beneficial in
Date received 16 December 1993 Date accepted7 February 1994 235
236 many diseases. Additionally, he was of the belief that the benefits of fever were such that: I think that you cannot find another drug which heats in a more penetrating manner than fever...and if there were a physician skillful enough to produce a fever, it would be useless to seek any other remedy against disease (8). Fever is one of the oldest and perhaps best known symptoms of disease (9). There is evidence to support the hypothesis that fever has adaptive value and may have survival value through increased immune responsiveness at higher temperatures (10-12). The objective of this paper is to review what is known about the antiviral effects of fever and to highlight the scientific evidence supporting our hypothesis that hyperthermic therapy may prove to be beneficial as a treatment modality for persons infected with HIV. Fever A fever or febrile response is noted in almost all infections caused by pathologic agents (13). Fever may be defined physiologically as a rise in core temperature resulting from either an increase in the set-point around which body temperature is normally centered, or a decrease in the thermal sensitivity of central heat-sensitive neurons (13), with a natural fever being characterized by a rise in core temperature of approximately 2oC over a few hours (11). Fever, as an immune response, is not confined to humans. Almost all endothermic and exothermic vertebrates and invertebrates exhibit a febrile response when challenged with endotoxins or other pyrogenic agents (14). At the onset of infection, blood monocytes become activated by phagocytosis of the invading microorganism resulting in the synthesis and release of interleuken-1 (IL-1) (15). The initiation of fever and the acute phase responses appears to be controlled by IL-1 (16). Interleuken-1, previously described by Beeson and colleagues as endogenous pyrogen (16), is actually a family of polypeptides having retained a common biological property which appears to be lymphocyte activation in the presence of an antigen or mitogen (15). The IL-1 stimulation and activation of lymphocytes is a vital host defense function since this contributes to the initiation of cellular and humoral immune mechanisms directed against the infecting microbe (15). Interleuken-1 has also been shown to induce slow-wave sleep (17). The increased sleep that accompanies many infectious diseases may serve to reduce energy demands and contribute to the overall efficiency of the host's defense and repair mechanisms (18). In vitro experiments have shown that the
MEDICAL HYPOTHESES
secretion of intedeuken-1 is defective in patients with HIV infection (19). There are numerous studies showing that cellular functions increase at febrile temperatures (14,15,20,21). Fibroblasts treated with interferon at febrile temperatures proved to be significantly more resistant to viral challenge than those cells treated with interferon at non-febrile temperatures (21). Fever enhances the early inflammatory response by promoting the migration of leukocytes and neutrophils to the site of infection (13). The effects of IL-1 on T cells has been shown to increase at febrile temperatures. In addition, T cell killing of tumor cells and the activity of cytotoxic T cells are also enhanced at febrile temperatures (22). Evidence that fever is beneficial Fever is a metabolically costly host response to infection. Kluger believes it 'improbable that fever would have evolved and been retained throughout the vertebrates and invertebrates without being of benefit to the host' (14). Additionally, Kluger and his associates have discovered, using the desert lizard Dipsosaurus dorsalis that, in lizards who were inoculated with live bacteria (Aeromonas hydrophila), an elevated body temperature resulted in increased survival (10). In humans, an elevation in body temperature after bacterial challenge has also been shown to be beneficial. For example, it is not uncommon for persons undergoing treatment for third-degree burns to develop bacterial infections. Clinical observation has shown that 'as destruction of epithelial layers leads to increased evaporative heat loss, these patients often encounter thermoregulatory difficulties. The prognosis for survival is considered better in patients developing a fever of 1-2oC than in patients who remain at normal or afebrile body temperatures' (10). Cancer patients who exhibit afebrile response have a significantly decreased incidence of metastatic spread of their neoplasms (23). It has also been shown that newborn mammals have a higher survival rate if febrile after exposure to viral challenge (10). Thus, if it can be assumed that fever is a beneficial host response to bacterial or viral infection or in the prevention of metastases of tumors, the question of whether induced elevations of body temperature can be used as therapy, and the automatic administration of antipyretics to reduce the temperatures of patients with fevers should be re-evaluated. When does fever become pathogenic? For most people, fever remains an undesirable and often frightening aspect of illness. Parents of young
237
HYPERTHERMIC THERAPY FOR HIV INFECTION
children are especially cautious of fever and more often than not misunderstand the role of fever in illness to such an extent that it led Schmitt to coin the phrase 'fever phobia' (24). Although there is strong evidence to support the theory and belief that fever does indeed play a beneficial role in the immune response to infection, there are instances when fever becomes pathogenic. It is generally accepted that prolonged fevers above 41oC (hyperpyrexia) can have detrimental effects on the host. Hyperpyrexia stresses the cardiovascular and pulmonary systems due to the dramatic increase in oxygen consumption at high temperatures and cause delirium, dehydration and a negative nutrient balance (13,24,25). Schmitt reports that the two most common complications of fever that can lead to permanent bodily harm are febrile status epilepticus and heat stroke (24). Yet, as research has shown, fever rarely causes any permanent damage to the patient during the course of infection (24).
by syphilis. The treatment involved transfusing blood from a person infected with malaria into the body of a person infected with syphilis. The high fever created by the malarial infection cured the syphilitic paralysis (28). In the last few years, there has been a revival in the use of malarial infection in fever therapy. Dr Henry Heimlich, inventor of the Heimlich manuever, has been giving malaria therapy to sufferers of cancer and Lyme disease who visit a Mexican clinic near the Texas border (29). However, the results of Heimlich's work remain unpublished. Indirectly, fever therapy has continued with the advent of therapeutic cytokines. The use of cloned alpha interferon and interleuken-2 to treat a number of conditions is accompanied by elevated body temperature. Thus, the long-term objective may be to establish the hierarchy of the various cytokines which underlie fever with the future goal of administering 'cytokine cocktails' to treat certain diseases.
Fever as a therapeutic agent
Hyperthermic therapy
Fever therapy has a long history of use as a treatment therapy for a variety of diseases. Before the antibiotic era, fever therapy was the principle form of treatment for neurosyphilis, gonococcal infection and chancroid (11,12,16,21). Louis Pasteur once speculated that the effect of fever was to starve out microbial infection (18). For the purposes of this discussion, fever therapy shall be defined here as the intentional inoculation of a patient with a micro-organism, endotoxin or any other biological agent in order to evoke a febrile response from the patient's immune system. The Hippocratic theory of the vis mediatrix naturae, the healing power of nature, which Hippocrates believed should be assisted rather than hindered by the physician (9), is the operative philosophy of fever therapy. In the late 1800s, W.C. Coley, a New York physician, noticed that in patients who developed postoperative infections after undergoing surgery for cancer, metastatic disease and tumor progression were often delayed and in some cases prevented (7,15). Particularly favorable results were obtained against osteosarcomas and soft tissue sarcomas (26). This observation led Coley to create a mixture of filtrates from erysipelas strains of streptococci and endotoxin producing Serratia m a r c e s c e n s which became known as 'Coley's Toxins'. This mixture was commonly used in the treatment of cancer before the advent of radiation therapy (27). In 1927, Julius Wagner-Jauregg, an Austrian psychiatrist, was awarded the Nobel Prize in Physiology and Medicine for his work on developing a therapy for the relief of the general paralysis brought on
Hyperthermic therapy, in contrast to fever therapy, is herein defined as therapy in which tissue temperature is raised to 41oC or higher by external means (7). The methods used in the administration of clinical hyperthermia can be classified into three broad categories: whole-body, regional and localized hyperthermia. Whole-body hyperthermia (WBHT) introduces thermal energy into the body either through non-invasive means such as hot air, ultrasound and high temperature hydrotherapy or invasively, which involves heating the blood extra-corporally. Whole-body hyperthermia, in which the patient's core temperature is raised and maintainend at up to 42oC for a period of time is the means by which we are hypothesizing HIV infections can be treated. Both invasive and non-invasive methods of WBHT have their own distinct advantages. Hyperthermic cabinets or cocoons enable heating without the risks associated with placing an arterial catheter. However, in situations where the risks of secondary opportunistic infection due to the placement of an arterial catheter are minimal, extra-corporeal WBHT appears to be the thermal delivery method best suited for optimal resuits for several reasons. Extra-corporeal whole-body hyperthermia enables the clinician to raise the temperature of the blood to a higher thermal value than would normally be possible with other thermal delivery methods due to the fact that the blood is removed from the body, heated and then returned to the patient. Additionally, while the blood is outside the patient's body, procedures such as photopheresis can be utilized with the goal of eliminating retrovirus that is
238 either free or located within infected cells in the blood (30). Like fever therapy, whole-body hyperthermia has also been used in the treatment of neurosyphilis. During the course of treatment, temperatures of 42oC were produced and maintained in patients for 8-10 consecutive hours. The patients were heated using a hyperthermia cabinet set at 54.4oC. It is reported that, although many of the patients experienced disorientation and vomiting, heat stroke was uncommon and the mortality rate was less than 0.5% when appropriate means were used to correct dehydration and hypoxia (24). Hyperthermia and cancer
The clinical application of hyperthermia in oncological therapy has a strong pathophysiologic basis (7,27,31,32,36). The rationale for using hyperthermia in the treatment of malignant disease rests principally on the differences between the vasculature, blood supply and metabolism of tumors and normal tissue (7,33). Additionally, cells undergoing mitosis are extremely heat-sensitive due to the aggregation of globular proteins in the spindle apparatus or the disaggregation of spindles, resulting in an inability to complete the mitotic division (34). Experimental and clinical studies indicate that control of tumor growth rates can be significantly enhanced if radiation therapy is combined with hyperthermia (7,35). Moreover, hyperthermia has shown a synergy with some chemotherapeutic agents against cancer (7,27,36). It is hypothesized that the increased effects of some drugs at elevated temperatures may be related to altered drug pharmacokinetics or pharmacodynamics (7). Thermal therapy was often used in the treatment of cancers in the 1920s and 1930s (7). Since that time, there has been a resurgence in interest in hyperthermic therapy as a viable treatment modality for certain cancers. Most fatal cancers achieve systemic distribution. This may be due to the nature of the disease (i.e. leukemia) or as a result of a metastatic process having spread from what was initially a localized malignancy. The use of whole-body hyperthermia in oncology is an attempt to treat systemic malignant disease. Whole-body hyperthermia and retroviral infections
The usefulness of antiviral agents and biological response modifers alone in the treatment of retroviral disease is likely to be limited because of combined
MEDICAL HYPOTHESES
persistence and latent viral infection, heterogeneity of clinical isolates and single drug resistance. The cat has the widest spectrum of naturallyoccurring retrovirus-associated diseases of all domestic animals, and is an excellent model for the study of human HIV infection (38-40). Both humoral and cellmediated immunity are adversely affected by persistent retrovirus infection in cats. In a study performed using bone marrow transplant therapy for retroviral infection, Gasper and colleagues administered total body irradiation to cats persistently infected with feline leukemia virus (FeLV) followed by bone marrow transplantation from donors previously immunized against FeLV. This approach provided antiviral effector cells to those animals receiving bone marrow transplantation (37). The records of 122 cats which received bone marrow transplants (BMT) for a variety of conditions - controls, certain inherited metabolic diseases, and cats prospectively infected with feline leukemia virus infections or feline immunodeficiency virus infections were analyzed. Cats which engrafted had mean body temperatures which never exceeded normal feline body temperature (101.5oF) by more than 1.0OE A rise in mean body temperatures was noted between day +5 and +15. Cats which failed to engraft had mean body temperatures of 1.0-2.5oF above norreal with much variation about the mean. Cats which developed graft-versus-host disease (GVH) also had mean body temperatures increased by more than 1.0oF, with less variation about the mean than the cats that failed to engraft. 20 out of 30 cats receiving BMTs as therapy for retrovirus infections which were retrovirus negative for between 6 days and 130 days after BMT exhibited the greatest increase in mean body temperature (3.0oF over normal). These fevers were unresponsive to antibiotics and antifungal therapy. Five of the nine cats that remained retrovirusnegative for greater than 40 days post BMT also developed GVH (41). Fever may have played a role in extinguishing the viral infections through a number of potential mechanisms. Immunologically, WBHT mimics fever in cytokine release (42,43). Whole-body hyperthermia experiments were conducted on Rhesus monkeys in a climate-controlled chamber maintained at 45oC until the animal's core temperatures increased 2oC above control levels. The researchers observed an increase in both alpha interferon and non-interferon antiviral factors present in the plasma when these animals were heated. The immunologic changes during hyperthermia were similar to those observed when fever was induced by systemic injection of non-viable E. coli in Rhesus monkeys. The authors of the study suggest
HYPERTI-IERMIC THERAPY FOR HIV INFECTION
that heat augments circulating lymphocyte synthesis of interferon (43). In addition, other studies (20) have shown that at 39ol2 interferon completely blocks the generation of suppressor cells in vitro and in vivo, while it augments both delayed type hypersensitivity and antibody response. Research has also shown interferon's ability to decrease or extinguish retroviral infections (42,44). Whole-body hyperthermia alone may have direct antiviral effects. Macy and colleagues have found that there is a transient but significant drop in viral reverse transcriptase activity and a fall of retroviral infectivity associated with WBHT (45). In in vitro water bath studies, retroviruses including HIV have been shown to be partially inactivated at temperatures equal to or less than 42oC (46). Hyperthermia has been shown to alter the binding of insulin to cellular receptors at elevated temperatures. Heat may play a role in altering membrane surfaces of both viruses and target tissues. There is some evidence that changes in membrane fluidity may alter presentation exposure of proteins from membranes (47--49). These changes in organization of the cell and viral membranes may alter viral pathogenesis, particularly in the stages of attachment, penetration, assembly and release. If viral or host membrane proteins are not sufficiently exposed, viral attachment will be inhibited. In addition, membrane changes might influence viral envelope assembly. A glyeoprotein involved in the maturation of temperature-sensitive vesicular stomatitis virus does not become incorporated into the virus at temperatures above 40oC (50). At this temperature, viral protein reaches the plasma membrane but the virus is not completed because viron formation requires a less fluid host membrane.
Hyperthermia and HIV infection After infection with HIV, and during the incubation period, high levels of virus in the blood are observed for a short but variable period. Soon after this initial spike in virus levels, antibodies become detectable in the blood. However, it becomes increasingly difficult to isolate the virus during the long asymptomatic period of HIV infection. Yet, as the patient progresses from an HIV-positive status to AIDS, the ease of virus isolation increases with the viral level in AIDS patients usually being quite high. Additionally, the antigenie diversity of HIV has been shown to increase during the asymptomatie stage of infection. Our hyperthermic hypothesis is based on the mutant escape theory of HIV antigenic diversity (51). Over the long incubation period of HIV infection,
239 the number of different strains (Quasispecies) of HIV increases. However, most of these are controlled by the immune system. This may explain the significant delay between the initial viral infection and the fatal stage of the disease. As the number of virus strains increases, members of each are present in about the same number. This generation of new strains is kept in check by the immune system. However, as a result of genetic rearrangement, due to selective pressures applied by the host's immune system, there arises a single strain of virus which can evade the immune defenses, replicate unimpeded and mediate the destruction of CD4+ cells. In the AIDS stage of infection, the abundance of the viral mutant increases and the immune system collapses. Thus, it may take a significant incubation period before the virus is able to exhaust the adaptive resources of the host's immune system. The mutant escape theory suggests that viral diversity has a critical threshold below which the immune system can suppress viral replication, however there is a progressive selection for a mutant strain which can evade or escape the immune surveillance. In other words, the development of serious immunodeficiency in HIV-infected patients is a consequence of the ability of the virus to continually produce variants until such time that a mutant escapes that can kill CD4 + cells and replicate unchecked. Moreover, antigenic diversity is the cause, not the consequence, of immunodeficiency (Fig. 1 A). It is our hypothesis that hyperthermic therapy, if initiated during the asymptomatic stage of HIV infection, may prove to decrease the number of mutant HIV strains arising due to evolutionary pressure created by the patient's immune system, with a resultant prolongation of the asymptomatic period. Temperature-sensitive retrovirus mutants have been described (52) and it is known that HIV and other envelope viruses are fragile and temperature sensitive (5). It has also been shown that HIV-infected cells are more sensitive to heat than uninfected cells (53,54). Thus, the research supporting our hypothesis suggests that temperature-sensitive mutants may be the pathogenic variants which arise during the course of persistent HIV infection and may be susceptible to treatment with WBHT, with the ultimate goal of extending the asymptomatic stage of infection in the HIV-positive patient (Fig. 1 B). An interesting point to note is that the onset of AIDS is heralded by the presence of night sweats. Night sweats are thought to be due to a secondary infectious process. Yet, the timing, magnitude and the persistent manifestation of the nightsweat temperatures suggests that perhaps the fevers indicate antiHIV immunity, which unfortunately appears to be too
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little or too late since the pathogenic mutant has escaped.
Hyperthermia and AIDS
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Years After Original Infection Fig. I(A) Hyperthermic therapy for HIV infection. The top line represents numbers of CD4+ lymphocytes. There is an initial decrease in their numbers at the time of establishment of infection followed by a period of no decrease or a subtle decrease in their numbers. The stair-step shaded box represents the number of mutant stralns/quasispecies of retroviruses controlled by the immune system which evolve until a pathogenic mutant which evades (escapes from) the immune system and is pathogenic for CD4+ lymphoeytes emerges. The bottom line represents HIV-measureable antigen. There is an initial peak at the time of establishment of infection followed by a period of no increase in antigen levels. At the time of the emergence of the pathogenic mutant virus, CD4+ lymphocytes are rapidly killed and detectable HIV antigens rapidly increase. The patient will fulfil the definition of AIDS during this phase. Also, the mutant pathogenic virus now predominates and the immune suppressive state stops the selective pressure under which new mutants evolve and therefore the total number of various mutants drops abruptly. (B). Infection with wild type I-IIV occurs as before (initial decrease in CD4 + lymphocytes and initial peak of HIV antigen). The advent of hyperthermia could hypothetically decrease the number of mutant strains/quasispecies of retroviruses by a number of means (e.g. killing temperature-sensitive mutants, increased immune response, increased unveiling and exposure of mutant HIV virions to the immune system, increased cytokines, and increased pharmokineties of antiviral drugs). Periodic administration of the hyperthermic therapy could theoretically delay the emergence of the pathogenic mutant, thereby prolonging the AIDS-free asymptomatic period.
Disseminated Kaposi's sarcoma is an opportunistic infection which has shown little sustained tumor response to common chemotherapy regimens (23,55) and is associated with limited life expectancy in AIDS patients (5). Alonso and colleagues have reported partial tumor regressions, complete tumor remissions and clinical improvement (i.e. weight gain and disappearance of opportunistic infections) as a result of WBHT, in addition to an observed decrease in virus growth. Moreover, patients with an initial CD4+count of 200+ have shown a sustained rise in CD4+ counts after treatments with WBHT (56). Although WBHT alone may only show limited effectiveness in the treatment of AIDS, we feel that WBHT combined with antiviral agents could potentially extend the life expectancy of AIDS patients. Preliminary studies have of the pharmacokinetics of AZT at hyperthermic temperatures suggest that hyperthermia may be expected to increase the serum halflife of AZT, but the increase is small and may not result in changes in efficacy or toxicity itself. The intracellular effects of hyperthermia on AZT metabolism remains unknown (57). AIDS patients treated with WBHT report an increase in the quality of their life without some of the unpleasant side-effects associated with other treatment modalities (53).
Conclusion There is a good scientific basis for the use of hyperthermia in the treatment of retroviral infections. While hyperthermia alone may not prove to be cure for HIV, or consistently prolong the asymptomatic period of infection, hyperthermia, either whole body or extracorporeal, in combination with 'cytokine cocktails', antiviral agents or bone marrow transplants may prove to be the combination of therapies with the potential to treat this difficult viral infection. We envision hyperthermia as part of a multimodal treatment approach, not a sole treatment modality. Preliminary research has shown that hyperthermic therapy can play a role in the management of HIV infection. Further study is necessary to better establish the causal agents underlying hyperthermic therapy, and to clearly define the role that hyperthermia may play in the treatment of HIV infection.
Acknowledgement Supported in part by a grant from the Howard Hughes Medical Institute.
HYPERTHERMIC THERAPY FOR HIV INFECTION
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depletion of cholesterol and effect on viron membrane fluidity and infectivity. J Virology 1978; 27: 320-329. Eigen M. Viral quasispecies. Scientific American 1993, July: 42--49. Linial M, Blair O. Genetics of retrovimses. In: Molecular biology of tumor viruses: RNA Tumor Viruses. New York: Cold Spring Harbor Laboratory, 1972: 653--654. Wong G H W, MeHugh T M, Stites D P, Goeddel D V. HIV infected cells are more susceptible than uninfected cells to killing by irradiation, heat, or tumor necrosis factor. NIH/NY Aead Sci Conf on AIDS (1989), Crystal City, VA. Brenner S. HIV appears to have some susceptibility to heat (Letter). AIDS Res Human Retroviruses 1989; 5: 5-6. Gelrnarm E P, Longo D, Lane H C et al. Combination chemotherapy of disseminated Kaposi's sarcoma in patients with the acquired immunodeficiency syndrome. Am J Med 1987; 82: 456. DeMareo C. Hyperthermia: an effective AIDS treatment. PWA Coalition Newsline 1993; 86: 17-21. Macy D W, Gasper P W, Oulton S Aet al. A comparison of Zidovudine pharmokineties in normothermic and hyperthermic cats (unpublished research).
Hyperthermic Therapy for HIV Infection S. D. OWENS and P. W. GASPER Department of Pathology, College of Veterinary and Biomedical Sciences, Colorado State University, Ft Collins, CO 80523, USA. (Correspondence and repnnt requests to Peter W. Gasper).
Abstract m The objective of this paper is to review what is known about the antiviral effects of fever and to highlight the scientific evidence supporting the hypothesis that hyperthermic therapy may prove to be a beneficial treatment modality for persons infected with HIV. Our hyperthermic hypothesis is based upon the mutant escape, quasispecies theory of HIV antigenic diversity. We propose that, if initiated during the asymptomatic stage of HIV infection, hyperthermia may prove to decrease the number of mutant HIV strains arising due to evolutionary pressures created by the patient's immune system, with a resultant prolongation of the asymptomatic period of infection. A review of the literature from three areas of investigation: the immune response to fever, heat as a tumor killing agent, and preliminary studies with fever and retroviral infections, strongly suggests that there is a good scientific basis for the use of hyperthermic therapy in a multimodal treatment approach to HIV infection. Introduction The Centers for Disease Control and Prevention (CDC) estimate that by year end 1994 there will have been a total of 420 000-540 000 persons diagnosed with AIDS in the USA. In addition, a total of more than one million US citizens (14 million persons worldwide) will be infected with HIV (1). Despite 10 years of intensive research, there is still no treatment or procedure that stops or reverses the primary viral disease process involving the depletion and deactivation of T4 lymphocytes, and it has proven to be very difficult to develop a protective vaccine against an infectious organism that can mutate quickly thereby presenting constantly changing antigens to the immune system (2). A review of the literature from three areas of investigation: the immune response induced by fever, heat as a tumor killing agent, and preliminary studies with fever and retroviral infections, strongly suggests
that there is a good scientific basis for the use of hyperthermic therapy in a multimodal treatment approach to HIV infection. While hyperthermic therapy alone may not prove to be a cure for AIDS, it is our tenet that hyperthermia, in combination with current antiretroviral therapies, offers the potential to extend the asymptomatic stage of HIV infection. Hyperthermia has shown unexpected success in the treatment of Kaposi's sarcoma (3--6) for those persons who have progressed from an HIV-positive status to AIDS. Hyperthermic therapy is not a new treatment procedure. The use of heat in the treatment of disease has been practiced for centuries. In India, as early as 3000 BC, the Ayurvedic system employed a monthlong program in the treatment of illness consisting of the feeding of rice and oils, the administration of purgatives and the heating of the body through the use of steam baths (7). Approximately 3200 years later, in the second century AD, Rufus of Ephesus observed that the occurrence of fever could be beneficial in
Date received 16 December 1993 Date accepted7 February 1994 235
236 many diseases. Additionally, he was of the belief that the benefits of fever were such that: I think that you cannot find another drug which heats in a more penetrating manner than fever...and if there were a physician skillful enough to produce a fever, it would be useless to seek any other remedy against disease (8). Fever is one of the oldest and perhaps best known symptoms of disease (9). There is evidence to support the hypothesis that fever has adaptive value and may have survival value through increased immune responsiveness at higher temperatures (10-12). The objective of this paper is to review what is known about the antiviral effects of fever and to highlight the scientific evidence supporting our hypothesis that hyperthermic therapy may prove to be beneficial as a treatment modality for persons infected with HIV. Fever A fever or febrile response is noted in almost all infections caused by pathologic agents (13). Fever may be defined physiologically as a rise in core temperature resulting from either an increase in the set-point around which body temperature is normally centered, or a decrease in the thermal sensitivity of central heat-sensitive neurons (13), with a natural fever being characterized by a rise in core temperature of approximately 2oC over a few hours (11). Fever, as an immune response, is not confined to humans. Almost all endothermic and exothermic vertebrates and invertebrates exhibit a febrile response when challenged with endotoxins or other pyrogenic agents (14). At the onset of infection, blood monocytes become activated by phagocytosis of the invading microorganism resulting in the synthesis and release of interleuken-1 (IL-1) (15). The initiation of fever and the acute phase responses appears to be controlled by IL-1 (16). Interleuken-1, previously described by Beeson and colleagues as endogenous pyrogen (16), is actually a family of polypeptides having retained a common biological property which appears to be lymphocyte activation in the presence of an antigen or mitogen (15). The IL-1 stimulation and activation of lymphocytes is a vital host defense function since this contributes to the initiation of cellular and humoral immune mechanisms directed against the infecting microbe (15). Interleuken-1 has also been shown to induce slow-wave sleep (17). The increased sleep that accompanies many infectious diseases may serve to reduce energy demands and contribute to the overall efficiency of the host's defense and repair mechanisms (18). In vitro experiments have shown that the
MEDICAL HYPOTHESES
secretion of intedeuken-1 is defective in patients with HIV infection (19). There are numerous studies showing that cellular functions increase at febrile temperatures (14,15,20,21). Fibroblasts treated with interferon at febrile temperatures proved to be significantly more resistant to viral challenge than those cells treated with interferon at non-febrile temperatures (21). Fever enhances the early inflammatory response by promoting the migration of leukocytes and neutrophils to the site of infection (13). The effects of IL-1 on T cells has been shown to increase at febrile temperatures. In addition, T cell killing of tumor cells and the activity of cytotoxic T cells are also enhanced at febrile temperatures (22). Evidence that fever is beneficial Fever is a metabolically costly host response to infection. Kluger believes it 'improbable that fever would have evolved and been retained throughout the vertebrates and invertebrates without being of benefit to the host' (14). Additionally, Kluger and his associates have discovered, using the desert lizard Dipsosaurus dorsalis that, in lizards who were inoculated with live bacteria (Aeromonas hydrophila), an elevated body temperature resulted in increased survival (10). In humans, an elevation in body temperature after bacterial challenge has also been shown to be beneficial. For example, it is not uncommon for persons undergoing treatment for third-degree burns to develop bacterial infections. Clinical observation has shown that 'as destruction of epithelial layers leads to increased evaporative heat loss, these patients often encounter thermoregulatory difficulties. The prognosis for survival is considered better in patients developing a fever of 1-2oC than in patients who remain at normal or afebrile body temperatures' (10). Cancer patients who exhibit afebrile response have a significantly decreased incidence of metastatic spread of their neoplasms (23). It has also been shown that newborn mammals have a higher survival rate if febrile after exposure to viral challenge (10). Thus, if it can be assumed that fever is a beneficial host response to bacterial or viral infection or in the prevention of metastases of tumors, the question of whether induced elevations of body temperature can be used as therapy, and the automatic administration of antipyretics to reduce the temperatures of patients with fevers should be re-evaluated. When does fever become pathogenic? For most people, fever remains an undesirable and often frightening aspect of illness. Parents of young
237
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children are especially cautious of fever and more often than not misunderstand the role of fever in illness to such an extent that it led Schmitt to coin the phrase 'fever phobia' (24). Although there is strong evidence to support the theory and belief that fever does indeed play a beneficial role in the immune response to infection, there are instances when fever becomes pathogenic. It is generally accepted that prolonged fevers above 41oC (hyperpyrexia) can have detrimental effects on the host. Hyperpyrexia stresses the cardiovascular and pulmonary systems due to the dramatic increase in oxygen consumption at high temperatures and cause delirium, dehydration and a negative nutrient balance (13,24,25). Schmitt reports that the two most common complications of fever that can lead to permanent bodily harm are febrile status epilepticus and heat stroke (24). Yet, as research has shown, fever rarely causes any permanent damage to the patient during the course of infection (24).
by syphilis. The treatment involved transfusing blood from a person infected with malaria into the body of a person infected with syphilis. The high fever created by the malarial infection cured the syphilitic paralysis (28). In the last few years, there has been a revival in the use of malarial infection in fever therapy. Dr Henry Heimlich, inventor of the Heimlich manuever, has been giving malaria therapy to sufferers of cancer and Lyme disease who visit a Mexican clinic near the Texas border (29). However, the results of Heimlich's work remain unpublished. Indirectly, fever therapy has continued with the advent of therapeutic cytokines. The use of cloned alpha interferon and interleuken-2 to treat a number of conditions is accompanied by elevated body temperature. Thus, the long-term objective may be to establish the hierarchy of the various cytokines which underlie fever with the future goal of administering 'cytokine cocktails' to treat certain diseases.
Fever as a therapeutic agent
Hyperthermic therapy
Fever therapy has a long history of use as a treatment therapy for a variety of diseases. Before the antibiotic era, fever therapy was the principle form of treatment for neurosyphilis, gonococcal infection and chancroid (11,12,16,21). Louis Pasteur once speculated that the effect of fever was to starve out microbial infection (18). For the purposes of this discussion, fever therapy shall be defined here as the intentional inoculation of a patient with a micro-organism, endotoxin or any other biological agent in order to evoke a febrile response from the patient's immune system. The Hippocratic theory of the vis mediatrix naturae, the healing power of nature, which Hippocrates believed should be assisted rather than hindered by the physician (9), is the operative philosophy of fever therapy. In the late 1800s, W.C. Coley, a New York physician, noticed that in patients who developed postoperative infections after undergoing surgery for cancer, metastatic disease and tumor progression were often delayed and in some cases prevented (7,15). Particularly favorable results were obtained against osteosarcomas and soft tissue sarcomas (26). This observation led Coley to create a mixture of filtrates from erysipelas strains of streptococci and endotoxin producing Serratia m a r c e s c e n s which became known as 'Coley's Toxins'. This mixture was commonly used in the treatment of cancer before the advent of radiation therapy (27). In 1927, Julius Wagner-Jauregg, an Austrian psychiatrist, was awarded the Nobel Prize in Physiology and Medicine for his work on developing a therapy for the relief of the general paralysis brought on
Hyperthermic therapy, in contrast to fever therapy, is herein defined as therapy in which tissue temperature is raised to 41oC or higher by external means (7). The methods used in the administration of clinical hyperthermia can be classified into three broad categories: whole-body, regional and localized hyperthermia. Whole-body hyperthermia (WBHT) introduces thermal energy into the body either through non-invasive means such as hot air, ultrasound and high temperature hydrotherapy or invasively, which involves heating the blood extra-corporally. Whole-body hyperthermia, in which the patient's core temperature is raised and maintainend at up to 42oC for a period of time is the means by which we are hypothesizing HIV infections can be treated. Both invasive and non-invasive methods of WBHT have their own distinct advantages. Hyperthermic cabinets or cocoons enable heating without the risks associated with placing an arterial catheter. However, in situations where the risks of secondary opportunistic infection due to the placement of an arterial catheter are minimal, extra-corporeal WBHT appears to be the thermal delivery method best suited for optimal resuits for several reasons. Extra-corporeal whole-body hyperthermia enables the clinician to raise the temperature of the blood to a higher thermal value than would normally be possible with other thermal delivery methods due to the fact that the blood is removed from the body, heated and then returned to the patient. Additionally, while the blood is outside the patient's body, procedures such as photopheresis can be utilized with the goal of eliminating retrovirus that is
238 either free or located within infected cells in the blood (30). Like fever therapy, whole-body hyperthermia has also been used in the treatment of neurosyphilis. During the course of treatment, temperatures of 42oC were produced and maintained in patients for 8-10 consecutive hours. The patients were heated using a hyperthermia cabinet set at 54.4oC. It is reported that, although many of the patients experienced disorientation and vomiting, heat stroke was uncommon and the mortality rate was less than 0.5% when appropriate means were used to correct dehydration and hypoxia (24). Hyperthermia and cancer
The clinical application of hyperthermia in oncological therapy has a strong pathophysiologic basis (7,27,31,32,36). The rationale for using hyperthermia in the treatment of malignant disease rests principally on the differences between the vasculature, blood supply and metabolism of tumors and normal tissue (7,33). Additionally, cells undergoing mitosis are extremely heat-sensitive due to the aggregation of globular proteins in the spindle apparatus or the disaggregation of spindles, resulting in an inability to complete the mitotic division (34). Experimental and clinical studies indicate that control of tumor growth rates can be significantly enhanced if radiation therapy is combined with hyperthermia (7,35). Moreover, hyperthermia has shown a synergy with some chemotherapeutic agents against cancer (7,27,36). It is hypothesized that the increased effects of some drugs at elevated temperatures may be related to altered drug pharmacokinetics or pharmacodynamics (7). Thermal therapy was often used in the treatment of cancers in the 1920s and 1930s (7). Since that time, there has been a resurgence in interest in hyperthermic therapy as a viable treatment modality for certain cancers. Most fatal cancers achieve systemic distribution. This may be due to the nature of the disease (i.e. leukemia) or as a result of a metastatic process having spread from what was initially a localized malignancy. The use of whole-body hyperthermia in oncology is an attempt to treat systemic malignant disease. Whole-body hyperthermia and retroviral infections
The usefulness of antiviral agents and biological response modifers alone in the treatment of retroviral disease is likely to be limited because of combined
MEDICAL HYPOTHESES
persistence and latent viral infection, heterogeneity of clinical isolates and single drug resistance. The cat has the widest spectrum of naturallyoccurring retrovirus-associated diseases of all domestic animals, and is an excellent model for the study of human HIV infection (38-40). Both humoral and cellmediated immunity are adversely affected by persistent retrovirus infection in cats. In a study performed using bone marrow transplant therapy for retroviral infection, Gasper and colleagues administered total body irradiation to cats persistently infected with feline leukemia virus (FeLV) followed by bone marrow transplantation from donors previously immunized against FeLV. This approach provided antiviral effector cells to those animals receiving bone marrow transplantation (37). The records of 122 cats which received bone marrow transplants (BMT) for a variety of conditions - controls, certain inherited metabolic diseases, and cats prospectively infected with feline leukemia virus infections or feline immunodeficiency virus infections were analyzed. Cats which engrafted had mean body temperatures which never exceeded normal feline body temperature (101.5oF) by more than 1.0OE A rise in mean body temperatures was noted between day +5 and +15. Cats which failed to engraft had mean body temperatures of 1.0-2.5oF above norreal with much variation about the mean. Cats which developed graft-versus-host disease (GVH) also had mean body temperatures increased by more than 1.0oF, with less variation about the mean than the cats that failed to engraft. 20 out of 30 cats receiving BMTs as therapy for retrovirus infections which were retrovirus negative for between 6 days and 130 days after BMT exhibited the greatest increase in mean body temperature (3.0oF over normal). These fevers were unresponsive to antibiotics and antifungal therapy. Five of the nine cats that remained retrovirusnegative for greater than 40 days post BMT also developed GVH (41). Fever may have played a role in extinguishing the viral infections through a number of potential mechanisms. Immunologically, WBHT mimics fever in cytokine release (42,43). Whole-body hyperthermia experiments were conducted on Rhesus monkeys in a climate-controlled chamber maintained at 45oC until the animal's core temperatures increased 2oC above control levels. The researchers observed an increase in both alpha interferon and non-interferon antiviral factors present in the plasma when these animals were heated. The immunologic changes during hyperthermia were similar to those observed when fever was induced by systemic injection of non-viable E. coli in Rhesus monkeys. The authors of the study suggest
HYPERTI-IERMIC THERAPY FOR HIV INFECTION
that heat augments circulating lymphocyte synthesis of interferon (43). In addition, other studies (20) have shown that at 39ol2 interferon completely blocks the generation of suppressor cells in vitro and in vivo, while it augments both delayed type hypersensitivity and antibody response. Research has also shown interferon's ability to decrease or extinguish retroviral infections (42,44). Whole-body hyperthermia alone may have direct antiviral effects. Macy and colleagues have found that there is a transient but significant drop in viral reverse transcriptase activity and a fall of retroviral infectivity associated with WBHT (45). In in vitro water bath studies, retroviruses including HIV have been shown to be partially inactivated at temperatures equal to or less than 42oC (46). Hyperthermia has been shown to alter the binding of insulin to cellular receptors at elevated temperatures. Heat may play a role in altering membrane surfaces of both viruses and target tissues. There is some evidence that changes in membrane fluidity may alter presentation exposure of proteins from membranes (47--49). These changes in organization of the cell and viral membranes may alter viral pathogenesis, particularly in the stages of attachment, penetration, assembly and release. If viral or host membrane proteins are not sufficiently exposed, viral attachment will be inhibited. In addition, membrane changes might influence viral envelope assembly. A glyeoprotein involved in the maturation of temperature-sensitive vesicular stomatitis virus does not become incorporated into the virus at temperatures above 40oC (50). At this temperature, viral protein reaches the plasma membrane but the virus is not completed because viron formation requires a less fluid host membrane.
Hyperthermia and HIV infection After infection with HIV, and during the incubation period, high levels of virus in the blood are observed for a short but variable period. Soon after this initial spike in virus levels, antibodies become detectable in the blood. However, it becomes increasingly difficult to isolate the virus during the long asymptomatic period of HIV infection. Yet, as the patient progresses from an HIV-positive status to AIDS, the ease of virus isolation increases with the viral level in AIDS patients usually being quite high. Additionally, the antigenie diversity of HIV has been shown to increase during the asymptomatie stage of infection. Our hyperthermic hypothesis is based on the mutant escape theory of HIV antigenic diversity (51). Over the long incubation period of HIV infection,
239 the number of different strains (Quasispecies) of HIV increases. However, most of these are controlled by the immune system. This may explain the significant delay between the initial viral infection and the fatal stage of the disease. As the number of virus strains increases, members of each are present in about the same number. This generation of new strains is kept in check by the immune system. However, as a result of genetic rearrangement, due to selective pressures applied by the host's immune system, there arises a single strain of virus which can evade the immune defenses, replicate unimpeded and mediate the destruction of CD4+ cells. In the AIDS stage of infection, the abundance of the viral mutant increases and the immune system collapses. Thus, it may take a significant incubation period before the virus is able to exhaust the adaptive resources of the host's immune system. The mutant escape theory suggests that viral diversity has a critical threshold below which the immune system can suppress viral replication, however there is a progressive selection for a mutant strain which can evade or escape the immune surveillance. In other words, the development of serious immunodeficiency in HIV-infected patients is a consequence of the ability of the virus to continually produce variants until such time that a mutant escapes that can kill CD4 + cells and replicate unchecked. Moreover, antigenic diversity is the cause, not the consequence, of immunodeficiency (Fig. 1 A). It is our hypothesis that hyperthermic therapy, if initiated during the asymptomatic stage of HIV infection, may prove to decrease the number of mutant HIV strains arising due to evolutionary pressure created by the patient's immune system, with a resultant prolongation of the asymptomatic period. Temperature-sensitive retrovirus mutants have been described (52) and it is known that HIV and other envelope viruses are fragile and temperature sensitive (5). It has also been shown that HIV-infected cells are more sensitive to heat than uninfected cells (53,54). Thus, the research supporting our hypothesis suggests that temperature-sensitive mutants may be the pathogenic variants which arise during the course of persistent HIV infection and may be susceptible to treatment with WBHT, with the ultimate goal of extending the asymptomatic stage of infection in the HIV-positive patient (Fig. 1 B). An interesting point to note is that the onset of AIDS is heralded by the presence of night sweats. Night sweats are thought to be due to a secondary infectious process. Yet, the timing, magnitude and the persistent manifestation of the nightsweat temperatures suggests that perhaps the fevers indicate antiHIV immunity, which unfortunately appears to be too
240
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little or too late since the pathogenic mutant has escaped.
Hyperthermia and AIDS
A
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Years After Original Infection Fig. I(A) Hyperthermic therapy for HIV infection. The top line represents numbers of CD4+ lymphocytes. There is an initial decrease in their numbers at the time of establishment of infection followed by a period of no decrease or a subtle decrease in their numbers. The stair-step shaded box represents the number of mutant stralns/quasispecies of retroviruses controlled by the immune system which evolve until a pathogenic mutant which evades (escapes from) the immune system and is pathogenic for CD4+ lymphoeytes emerges. The bottom line represents HIV-measureable antigen. There is an initial peak at the time of establishment of infection followed by a period of no increase in antigen levels. At the time of the emergence of the pathogenic mutant virus, CD4+ lymphocytes are rapidly killed and detectable HIV antigens rapidly increase. The patient will fulfil the definition of AIDS during this phase. Also, the mutant pathogenic virus now predominates and the immune suppressive state stops the selective pressure under which new mutants evolve and therefore the total number of various mutants drops abruptly. (B). Infection with wild type I-IIV occurs as before (initial decrease in CD4 + lymphocytes and initial peak of HIV antigen). The advent of hyperthermia could hypothetically decrease the number of mutant strains/quasispecies of retroviruses by a number of means (e.g. killing temperature-sensitive mutants, increased immune response, increased unveiling and exposure of mutant HIV virions to the immune system, increased cytokines, and increased pharmokineties of antiviral drugs). Periodic administration of the hyperthermic therapy could theoretically delay the emergence of the pathogenic mutant, thereby prolonging the AIDS-free asymptomatic period.
Disseminated Kaposi's sarcoma is an opportunistic infection which has shown little sustained tumor response to common chemotherapy regimens (23,55) and is associated with limited life expectancy in AIDS patients (5). Alonso and colleagues have reported partial tumor regressions, complete tumor remissions and clinical improvement (i.e. weight gain and disappearance of opportunistic infections) as a result of WBHT, in addition to an observed decrease in virus growth. Moreover, patients with an initial CD4+count of 200+ have shown a sustained rise in CD4+ counts after treatments with WBHT (56). Although WBHT alone may only show limited effectiveness in the treatment of AIDS, we feel that WBHT combined with antiviral agents could potentially extend the life expectancy of AIDS patients. Preliminary studies have of the pharmacokinetics of AZT at hyperthermic temperatures suggest that hyperthermia may be expected to increase the serum halflife of AZT, but the increase is small and may not result in changes in efficacy or toxicity itself. The intracellular effects of hyperthermia on AZT metabolism remains unknown (57). AIDS patients treated with WBHT report an increase in the quality of their life without some of the unpleasant side-effects associated with other treatment modalities (53).
Conclusion There is a good scientific basis for the use of hyperthermia in the treatment of retroviral infections. While hyperthermia alone may not prove to be cure for HIV, or consistently prolong the asymptomatic period of infection, hyperthermia, either whole body or extracorporeal, in combination with 'cytokine cocktails', antiviral agents or bone marrow transplants may prove to be the combination of therapies with the potential to treat this difficult viral infection. We envision hyperthermia as part of a multimodal treatment approach, not a sole treatment modality. Preliminary research has shown that hyperthermic therapy can play a role in the management of HIV infection. Further study is necessary to better establish the causal agents underlying hyperthermic therapy, and to clearly define the role that hyperthermia may play in the treatment of HIV infection.
Acknowledgement Supported in part by a grant from the Howard Hughes Medical Institute.
HYPERTHERMIC THERAPY FOR HIV INFECTION
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