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Toxoplasma gondii: An AIDS enhancing cofactor
Medical Hypotheses I
I Medical tiypothwu W?92) 39,140-142 oLuuamnGImpuKLtd1992
Toxoplasma Gondii: An AIDS Enhancing Cofactor DAH-SHENG LIN’ and D. D. BOWMANt ‘Department of Veterinary Medicine, National Taiwan University, 142 Chou-San Road, Taipei, Taiwan, Republic of China; t Department of Microbiology, Immunology, and Parasitology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA
Abstract-Disseminated toxoplasmosis, one of the most severe acquired immune deficiency syndrome (AIDS)-associated infections in humans, is believed to develop from a latent infection after the cellular immune system is suppressed by human immunodeficiency virus type 1 (HIV-l). However, Toxoplasma gondii may serve as a cofactor in enhancing the immunodeficiency induced by HIV-l. This hypothesis is supported by the facts that: 1) co-infection with other pathogens in humans infected with HIV-1 may enhance the progression of the disease to AIDS; and 2) concomitant infection with T: gondii enhances feline immunodeficiency virus-induced immune dysfunction and is likely to cause a more rapid disease onset than an infection with FIV alone. It is possibe that T: gondii infection induces tumor necrosis factor (TNF) production. TNF then stimulates the induction of T-cell proteins that bind to the long terminal repeat of HIV-l. This binding at the repeat site then leads to increased HIV-1 activation which causes the dysfunction of CD4 cells and a resulting immunodeficiency that allows even greater amounts of T: gondii replication.
Introduction gondii is the most severe acquired immune deficiency syndrome (AIDS)-associated non-viral intracranial infection (1, 2). Clinically apparent toxoplasmic encephalitis has been reported to occur in up to 40% of patients with AIDS (1). The complications of ocular toxoplasmosis in AIDS patients also have been reported (2). Because T. gondii infection is highly prevalent but usually asymptomatic in humans with intact cellular immunity (3), it is believed that severe disseminated toxoplasmosis develops from a latent infection after the cellular immune system is suppressed by human immunodeficiency virus type Toxoplasma
Date received 24 February 1992 Date accepted 1 April 1992
1 (HIV-l) (2, 4). However, the possible effects of on immunodeficiency due to HIV-l are unknown. Immunosuppression induced by T. gondii has been documented both in humans and animals (4). Thus, it is possible that infection with T. gondii may actually enhance the immunodeficiency caused by HIV-l in infected individuals.
T. gondii
Evidence from studies on co-infection and other pathogens
with HIV-l
Epidemiological studies have shown that certain individuals have a greater chance of developing AIDS
140
141
T. GONDII: AN AIDS ENHANCING COFACTOR
than others who have been equally exposed to the risk of HIV-l infection. Some people infected with HIV-l remain asymptomatic, others develop symptomatic disease, and others rapidly progress to AIDS (5,6). One theory is that the co-infection with other pathogens in humans infected with HIV-l may enhance the progression of the disease to AIDS (7). Concurrent infections with other pathogens are not uncommon in AIDS patients (5). Although a long incubation period is required for the development of AIDS, co-infection with other pathogens may cause increased HIV-l replication and more rapid disease onset (7, 8). Also, a correlation has been noted in Africa between antibody titers to HIV-l and malaria (9), and co-infection with Mycoplasma fermentans enhances the ability of HIV-l to induce cytopathic effects on T lymphocytes in vitro (10). Therefore, these pathogens, and possibly T. gondii, by modulating the immune system may indirectly enhance the immunodeficiency induced by HIV-l and thus cause the disease to more rapidly progress to the AIDS phase.
munodeficiency and cause a more rapid disease progression than infection with HIV-l alone. Proposed mechanisms
It has been found that T cells from AIDS patients undergo enhanced HIV-l proliferation and infection in vitro when exposed to mitogens and other T-cell stimulating factors (19). Also, the immunological stimulation required for interleukin 2 secretion induces viral expression (7). The activation of T cells involves the induction of cellular factors that bind to enhancer elements, kB, in the interleukin 2 gene (20). Interestingly, kB is homologous to a segment of the HIV-I long terminal repeat (20, 21). Thus, the stimulation of T cells during an immune response results in the induction of kB-binding proteins that also bind to the HIV-l long terminal repeat initiating transcription of HIV-l mRNA (20, 21). The possibility of the involvement of cytokines in activating kB-binding proteins has been studied. Tumor necrosis factor (TNF) consistently induces the production of kB-binding proteins white other interleukins, platelet-derived growth factor, and gamma Evidence from studies on a feline model interferon have no such effect (20, 22). In mice with The feline model is appropriate for investigations on toxoplasmosis, death is preceded by an increased lethe possibility of a co-infection with T. gondii en- vel of TNF production, and it is postulated that the hancing the immunodeficiency induced by HIV-l for increased level of TNF in these mice contributes to the following reasons: 1) the feline immune system the wasting-type of disease typical of fatal toxoplasappears similar to those of humans and other ani- mosis (23). Thus, T. gondii may cause a similar promals (11, 12); 2) the feline immunodeficiency virus duction of TNF and, therefore, an increased activation (FIV) is similar to HIV-l in its disease pathogene- of HIV-l within T lymphocytes. This begins a cycle sis, T lymphotropism, protein identity, morphologiwherein T. gondii replication causes increased TNF cal features, and the Mg++ dependency of its rc- production that leads to increased HIV-l activation verse transcriptase activity (13, 14); 3) a high pro- which will cause the dysfunction of CD4 cells and portion of cats with clinical disseminated toxoplas- a resulting immunodcficiency that will allow even mosis are known to have concurrent infections wirh greater amounts of T. gondii replication. FlV (15); and 4) disseminated toxoplasmosis occurs in immunosuppressed cats (16). The studies on the Conclusion effects of concomitant infections with T. gondii and It is hypothesized that AIDS may develop more FIV suggest that FIV infection favors the establish- rapidly in humans who are co-infected with T. gondii. ment of toxoplasmosis and that T. gondii may enhance The evidence from the studies on co-infection with the immune dysfunction caused by FIV in cats (17, HIV-l and other pathogens and studies on a feline 18). Within months after cats are infected with both model supports the above hypothesis. That TNF may pathogens, they develop more clinical signs than cats play a central role in the interactions between T. infected with either pathogen alone. Dually infected gondii and HIV-I is also proposed. cats have lymphocytes with significantly decreased mitogenic responses, delayed T. gondii- specific IgG Acknowledgment! and IgM responses, and significantly more T. gondii This work was supponed, in part, by a gift to DDB from the Aniorganisms in their brains and mesenteric lymph nodes mal Health Division of the CIBA-GEIGY Corporation. We would than cats infected only with T. gondii. If the feline like to thank MS Man-Ling Hung for assistance in the manuscript model does represent similar causes and effects to preparation. those that are occurring in humans with HIV-l and References toxoplasmosis, it is likely that infection with T. gondii 1. Luft B J, Remington J S. Toxoplasmic encephalitis. J Infect in humans may actually enhance HIV-l-induced im-
142 Dis 157: l-6, 1988. 2. Holliman R E. Toxoplasmosis and the acquired immune deficiency syndrome. J Infect 16: 121-128. 1988. 3. Frenkel J K. Pathophysiology of toxoplasmosis. Parasitol. Today 4: 273-278. 1988. 4. Luft B J. Toxoplasma gondii. ~~179-279 in Parasitic Infections in the Compromised Host. (p D Walzer. R M Genta, eds) Marcel Dekker, Inc. New York City, New York, 1987. 5. Conlar C P Clinical aspects of HIV infection in developing countries. Br Med Bull 44: 101-114. 1988. and sociological aspeas 6. Piot P, Caracl M. Epidemiological of HIV-infection in developing countries. Br Med Bull 44: 68-88, 1988. 7. Zagmy D, Bernard J, Leonard R, Cheynier R, Feldman M, Sarin P S, Gal10 R C. Long term cultures of HTLV-III-infected T cells: a model of cytcpathology of T-c& depletion in AIDS. Science 231: 850-853.1986. 8. Quinn T C, Piot P, McCormick J B. Feinsod F M, Taelman H, Kapita B. Stevens W. Fauci A S. Serologic and immunologic studies in patients with AIDS in North America and Africa. The potential role of infectious agents as cofactors in human immunodeficiency virus infection. J Am Med Assoc 251: 2617-2621, 1987. 9. Biggar R J. Gigase P I. Melbye M, Kesrens L, Sarin P S, Bodner A J, Demedts P, Stevens W J. PaIuku L, Delacollette C, Blattner W A. Elisa HTLV retrovirus antibody reactivity associated with malaria and immune complexes in healthy Africans. Lancet 2: 52&523. 1985. 10. Lo S-C. Tsai S. Benish J R. Shih J W-K. Wear D J. Wang D M. I&hanceanent of HIV-l cytocidal effects in CD4+ lymphocytcs hy the AIDS-associated mycoplasma. Science 251: 1074-1076. 1991. 11. Lin D-S, Bowman D D. Cellular responses of cats with primary toxoplasmosis. J Parasitol 77. 272-279, 1991. 12. Lin D-S. Feline immune system. Comp lmmunol Microbial Infect Dis 15: 1-11. 1992. 13. Pedersen N C. Ho E W, Brown M L, Yamamoto J K. Iso-
MEDICAL HYI’UTHESES
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
lation of a T-lymphctmpic virus from domestic cots with an immunodeficiency-like syndrome. Science 235: 79&793. 1987. Lin D-S, Bowman D D, Jacobson R H, Barr M C, Fevereiro M, Williams J R. Noronha F M 0, Scott F W, Avery R J. Suppression of lymphocyte blastogenesis to mitogens in cats infected with feline immunodeficiency virus. Vet Immunol Immunopathol26: 183-189. 1990. Lappin M R. Greene C E. Winstan S, TolI S L, Epstein M E. Clinical feline toxoplasmosis, serologic diagnosis and therapeutic management of 15 cases. J Vet Int Med 3: 139-143. 1989. Dubey J P, Frenkel J K. Immunity to feline toxoplasmosis: modification by administration of corticosteroids. Vet Path01 11: 350-379. 1974. Lin D-S, Bowman D D, Jacobson R H. Toxoplasma gondii enhances immunosuppression by feline immuncdeficiency virus. FASEB J 5: A1373, 1991. Lin D-S. Bowman D D, Jacobson R H. Immunological changes in cats concurrenlly infected with Toxoplasma gondii and feline immunodeficiency virus. J Clin Microbial 30: 17-24, 1992. Gowda S D, Stein B S, Mohagheghpour N, Benike C J. Engleman E G. Evidence that T celI activation is required for HIV-l entry in CD4+ lymphocytes. J Immunol 142: 773-780. 1989. Rosenberg Z F, Fauci A S. Immunopathogenic mechanisms of HIV infection: cytokine induction of HIV expression. Immunol Today 11: 176180. 1990. Greene W C, Bohnlein E, Ballard D W. HIV-l. HTLV-1 and normal T-cell growth; transcriptional strategies and surprises. Immunol Today 10: 272-278. 1989. Folks TM, Clouse K A, Justement J, Rabson A, Dub E, Kehrl J H, Fauci A S. Tumor necrosis factor alpha induces expression of human immunodeficiency virus in a chronically infected T-cell clone. Proc Nat1 Acad Sci 86: 2365-2368.1989. Chang H R, Grau G E. Pechere J C. Role of TNF and IL-1 in infections with Toxophsma go&ii. Immunol69: 33-37.1990.
I Medical tiypothwu W?92) 39,140-142 oLuuamnGImpuKLtd1992
Toxoplasma Gondii: An AIDS Enhancing Cofactor DAH-SHENG LIN’ and D. D. BOWMANt ‘Department of Veterinary Medicine, National Taiwan University, 142 Chou-San Road, Taipei, Taiwan, Republic of China; t Department of Microbiology, Immunology, and Parasitology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA
Abstract-Disseminated toxoplasmosis, one of the most severe acquired immune deficiency syndrome (AIDS)-associated infections in humans, is believed to develop from a latent infection after the cellular immune system is suppressed by human immunodeficiency virus type 1 (HIV-l). However, Toxoplasma gondii may serve as a cofactor in enhancing the immunodeficiency induced by HIV-l. This hypothesis is supported by the facts that: 1) co-infection with other pathogens in humans infected with HIV-1 may enhance the progression of the disease to AIDS; and 2) concomitant infection with T: gondii enhances feline immunodeficiency virus-induced immune dysfunction and is likely to cause a more rapid disease onset than an infection with FIV alone. It is possibe that T: gondii infection induces tumor necrosis factor (TNF) production. TNF then stimulates the induction of T-cell proteins that bind to the long terminal repeat of HIV-l. This binding at the repeat site then leads to increased HIV-1 activation which causes the dysfunction of CD4 cells and a resulting immunodeficiency that allows even greater amounts of T: gondii replication.
Introduction gondii is the most severe acquired immune deficiency syndrome (AIDS)-associated non-viral intracranial infection (1, 2). Clinically apparent toxoplasmic encephalitis has been reported to occur in up to 40% of patients with AIDS (1). The complications of ocular toxoplasmosis in AIDS patients also have been reported (2). Because T. gondii infection is highly prevalent but usually asymptomatic in humans with intact cellular immunity (3), it is believed that severe disseminated toxoplasmosis develops from a latent infection after the cellular immune system is suppressed by human immunodeficiency virus type Toxoplasma
Date received 24 February 1992 Date accepted 1 April 1992
1 (HIV-l) (2, 4). However, the possible effects of on immunodeficiency due to HIV-l are unknown. Immunosuppression induced by T. gondii has been documented both in humans and animals (4). Thus, it is possible that infection with T. gondii may actually enhance the immunodeficiency caused by HIV-l in infected individuals.
T. gondii
Evidence from studies on co-infection and other pathogens
with HIV-l
Epidemiological studies have shown that certain individuals have a greater chance of developing AIDS
140
141
T. GONDII: AN AIDS ENHANCING COFACTOR
than others who have been equally exposed to the risk of HIV-l infection. Some people infected with HIV-l remain asymptomatic, others develop symptomatic disease, and others rapidly progress to AIDS (5,6). One theory is that the co-infection with other pathogens in humans infected with HIV-l may enhance the progression of the disease to AIDS (7). Concurrent infections with other pathogens are not uncommon in AIDS patients (5). Although a long incubation period is required for the development of AIDS, co-infection with other pathogens may cause increased HIV-l replication and more rapid disease onset (7, 8). Also, a correlation has been noted in Africa between antibody titers to HIV-l and malaria (9), and co-infection with Mycoplasma fermentans enhances the ability of HIV-l to induce cytopathic effects on T lymphocytes in vitro (10). Therefore, these pathogens, and possibly T. gondii, by modulating the immune system may indirectly enhance the immunodeficiency induced by HIV-l and thus cause the disease to more rapidly progress to the AIDS phase.
munodeficiency and cause a more rapid disease progression than infection with HIV-l alone. Proposed mechanisms
It has been found that T cells from AIDS patients undergo enhanced HIV-l proliferation and infection in vitro when exposed to mitogens and other T-cell stimulating factors (19). Also, the immunological stimulation required for interleukin 2 secretion induces viral expression (7). The activation of T cells involves the induction of cellular factors that bind to enhancer elements, kB, in the interleukin 2 gene (20). Interestingly, kB is homologous to a segment of the HIV-I long terminal repeat (20, 21). Thus, the stimulation of T cells during an immune response results in the induction of kB-binding proteins that also bind to the HIV-l long terminal repeat initiating transcription of HIV-l mRNA (20, 21). The possibility of the involvement of cytokines in activating kB-binding proteins has been studied. Tumor necrosis factor (TNF) consistently induces the production of kB-binding proteins white other interleukins, platelet-derived growth factor, and gamma Evidence from studies on a feline model interferon have no such effect (20, 22). In mice with The feline model is appropriate for investigations on toxoplasmosis, death is preceded by an increased lethe possibility of a co-infection with T. gondii en- vel of TNF production, and it is postulated that the hancing the immunodeficiency induced by HIV-l for increased level of TNF in these mice contributes to the following reasons: 1) the feline immune system the wasting-type of disease typical of fatal toxoplasappears similar to those of humans and other ani- mosis (23). Thus, T. gondii may cause a similar promals (11, 12); 2) the feline immunodeficiency virus duction of TNF and, therefore, an increased activation (FIV) is similar to HIV-l in its disease pathogene- of HIV-l within T lymphocytes. This begins a cycle sis, T lymphotropism, protein identity, morphologiwherein T. gondii replication causes increased TNF cal features, and the Mg++ dependency of its rc- production that leads to increased HIV-l activation verse transcriptase activity (13, 14); 3) a high pro- which will cause the dysfunction of CD4 cells and portion of cats with clinical disseminated toxoplas- a resulting immunodcficiency that will allow even mosis are known to have concurrent infections wirh greater amounts of T. gondii replication. FlV (15); and 4) disseminated toxoplasmosis occurs in immunosuppressed cats (16). The studies on the Conclusion effects of concomitant infections with T. gondii and It is hypothesized that AIDS may develop more FIV suggest that FIV infection favors the establish- rapidly in humans who are co-infected with T. gondii. ment of toxoplasmosis and that T. gondii may enhance The evidence from the studies on co-infection with the immune dysfunction caused by FIV in cats (17, HIV-l and other pathogens and studies on a feline 18). Within months after cats are infected with both model supports the above hypothesis. That TNF may pathogens, they develop more clinical signs than cats play a central role in the interactions between T. infected with either pathogen alone. Dually infected gondii and HIV-I is also proposed. cats have lymphocytes with significantly decreased mitogenic responses, delayed T. gondii- specific IgG Acknowledgment! and IgM responses, and significantly more T. gondii This work was supponed, in part, by a gift to DDB from the Aniorganisms in their brains and mesenteric lymph nodes mal Health Division of the CIBA-GEIGY Corporation. We would than cats infected only with T. gondii. If the feline like to thank MS Man-Ling Hung for assistance in the manuscript model does represent similar causes and effects to preparation. those that are occurring in humans with HIV-l and References toxoplasmosis, it is likely that infection with T. gondii 1. Luft B J, Remington J S. Toxoplasmic encephalitis. J Infect in humans may actually enhance HIV-l-induced im-
142 Dis 157: l-6, 1988. 2. Holliman R E. Toxoplasmosis and the acquired immune deficiency syndrome. J Infect 16: 121-128. 1988. 3. Frenkel J K. Pathophysiology of toxoplasmosis. Parasitol. Today 4: 273-278. 1988. 4. Luft B J. Toxoplasma gondii. ~~179-279 in Parasitic Infections in the Compromised Host. (p D Walzer. R M Genta, eds) Marcel Dekker, Inc. New York City, New York, 1987. 5. Conlar C P Clinical aspects of HIV infection in developing countries. Br Med Bull 44: 101-114. 1988. and sociological aspeas 6. Piot P, Caracl M. Epidemiological of HIV-infection in developing countries. Br Med Bull 44: 68-88, 1988. 7. Zagmy D, Bernard J, Leonard R, Cheynier R, Feldman M, Sarin P S, Gal10 R C. Long term cultures of HTLV-III-infected T cells: a model of cytcpathology of T-c& depletion in AIDS. Science 231: 850-853.1986. 8. Quinn T C, Piot P, McCormick J B. Feinsod F M, Taelman H, Kapita B. Stevens W. Fauci A S. Serologic and immunologic studies in patients with AIDS in North America and Africa. The potential role of infectious agents as cofactors in human immunodeficiency virus infection. J Am Med Assoc 251: 2617-2621, 1987. 9. Biggar R J. Gigase P I. Melbye M, Kesrens L, Sarin P S, Bodner A J, Demedts P, Stevens W J. PaIuku L, Delacollette C, Blattner W A. Elisa HTLV retrovirus antibody reactivity associated with malaria and immune complexes in healthy Africans. Lancet 2: 52&523. 1985. 10. Lo S-C. Tsai S. Benish J R. Shih J W-K. Wear D J. Wang D M. I&hanceanent of HIV-l cytocidal effects in CD4+ lymphocytcs hy the AIDS-associated mycoplasma. Science 251: 1074-1076. 1991. 11. Lin D-S, Bowman D D. Cellular responses of cats with primary toxoplasmosis. J Parasitol 77. 272-279, 1991. 12. Lin D-S. Feline immune system. Comp lmmunol Microbial Infect Dis 15: 1-11. 1992. 13. Pedersen N C. Ho E W, Brown M L, Yamamoto J K. Iso-
MEDICAL HYI’UTHESES
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
lation of a T-lymphctmpic virus from domestic cots with an immunodeficiency-like syndrome. Science 235: 79&793. 1987. Lin D-S, Bowman D D, Jacobson R H, Barr M C, Fevereiro M, Williams J R. Noronha F M 0, Scott F W, Avery R J. Suppression of lymphocyte blastogenesis to mitogens in cats infected with feline immunodeficiency virus. Vet Immunol Immunopathol26: 183-189. 1990. Lappin M R. Greene C E. Winstan S, TolI S L, Epstein M E. Clinical feline toxoplasmosis, serologic diagnosis and therapeutic management of 15 cases. J Vet Int Med 3: 139-143. 1989. Dubey J P, Frenkel J K. Immunity to feline toxoplasmosis: modification by administration of corticosteroids. Vet Path01 11: 350-379. 1974. Lin D-S, Bowman D D, Jacobson R H. Toxoplasma gondii enhances immunosuppression by feline immuncdeficiency virus. FASEB J 5: A1373, 1991. Lin D-S. Bowman D D, Jacobson R H. Immunological changes in cats concurrenlly infected with Toxoplasma gondii and feline immunodeficiency virus. J Clin Microbial 30: 17-24, 1992. Gowda S D, Stein B S, Mohagheghpour N, Benike C J. Engleman E G. Evidence that T celI activation is required for HIV-l entry in CD4+ lymphocytes. J Immunol 142: 773-780. 1989. Rosenberg Z F, Fauci A S. Immunopathogenic mechanisms of HIV infection: cytokine induction of HIV expression. Immunol Today 11: 176180. 1990. Greene W C, Bohnlein E, Ballard D W. HIV-l. HTLV-1 and normal T-cell growth; transcriptional strategies and surprises. Immunol Today 10: 272-278. 1989. Folks TM, Clouse K A, Justement J, Rabson A, Dub E, Kehrl J H, Fauci A S. Tumor necrosis factor alpha induces expression of human immunodeficiency virus in a chronically infected T-cell clone. Proc Nat1 Acad Sci 86: 2365-2368.1989. Chang H R, Grau G E. Pechere J C. Role of TNF and IL-1 in infections with Toxophsma go&ii. Immunol69: 33-37.1990.