Leishmania and HIV-1 interaction : immunopathogenic mechanisms
Author: Wolday, Dawit
Date: 2000-01-17
Location: Föreläsningssalen vid Mikrobiologiskt och Tumörbiologiskt Centrum (MTC), Theorells väg 7
Time: 9.00
Department: Mikrobiologiskt och Tumörbiologiskt Centrum (MTC) / Microbiology and Tumor Biology Center (MTC)
Abstract
Both Leishmania and HIV can infect and multiply in macrophages, and both can dysregulate the T-helper (Th) immune system. This thesis was, therefore, undertaken to unravel some of the underlying immunopathogenic mechanisms of the interaction of the two pathogens.
Clinical findings at presentation in some of our visceral leishmaniasis (VL)-HIV co-infected patients were atypical (i.e. absence of organomegaly) with high parasite load, severe immunosuppression (low CD4/CD8 ratio) and frequent relapse following successful initial response. Heat-inactivated (HI)-HIV-1 inhibited Leishmania-induced cell proliferation, but not IL-6 and TNF-[alpha] secretion, suggesting that the parasite can activate HIV. In addition, both HI and live HIV led to the uncontrolled growth of Leishmania in monocytes.
Stimulation of CD8-depleted peripheral blood mononuclear cells (PBMCs) from asymptomatic HIV-1 infected persons with Leishmania or lipophosphoglycan (LPG), a major membrane constituent of Leishmania, resulted in HIV-1 replication, cellular immune activation CD4+T cell apoptosis. Interestingly, the immunomodulatory compound thalidomide inhibited Leishmania antigen-induced secretion of TNF-[alpha] and virus replication, with no effect on IL-2 or IL-6 production, cellular activation and apoptosis. They suggest that TNF-[alpha] secretion is pivotal in the process of induction of HIV replication. Thalidomide may be of potential use to reduce HIV disease progression in VL co-infected patients.
The in vitro findings were supported by the observations we made in vivo; persistence of parasite and hence active VL in patients who failed anti-leishmanial chemotherapy was associated with high HIV load than in those who had good response to therapy. Moreover, proliferative responses to PHA or Leishmania were lower in VL and/or HIV-infected persons compared to healthy controls. PBMC from healthy donors produced high levels of Th1 cytokine (IFN-[gamma]), Th1-inducing cytokines (IL-12 & IL-18), and low Th2 cytokines (IL-4 & IL-10); HI-HIV abrogated the production of IFN-[gamma] induced by Leishmania and augmented IL-4 and IL- 10. In contrast, VL and/or HIV-infected produced low levels of Th1 or Th1-inducing cyokines, but high levels of IL-10. Data suggest that the inhibitory effect of HIV and VL on the proliferative and IFN-[gamma] production was not only due to IL- 10, but also that the defect induced by HIV and VL probably operate at the level of regulation of IFN-[gamma]-inducing factors.
Clinical findings at presentation in some of our visceral leishmaniasis (VL)-HIV co-infected patients were atypical (i.e. absence of organomegaly) with high parasite load, severe immunosuppression (low CD4/CD8 ratio) and frequent relapse following successful initial response. Heat-inactivated (HI)-HIV-1 inhibited Leishmania-induced cell proliferation, but not IL-6 and TNF-[alpha] secretion, suggesting that the parasite can activate HIV. In addition, both HI and live HIV led to the uncontrolled growth of Leishmania in monocytes.
Stimulation of CD8-depleted peripheral blood mononuclear cells (PBMCs) from asymptomatic HIV-1 infected persons with Leishmania or lipophosphoglycan (LPG), a major membrane constituent of Leishmania, resulted in HIV-1 replication, cellular immune activation CD4+T cell apoptosis. Interestingly, the immunomodulatory compound thalidomide inhibited Leishmania antigen-induced secretion of TNF-[alpha] and virus replication, with no effect on IL-2 or IL-6 production, cellular activation and apoptosis. They suggest that TNF-[alpha] secretion is pivotal in the process of induction of HIV replication. Thalidomide may be of potential use to reduce HIV disease progression in VL co-infected patients.
The in vitro findings were supported by the observations we made in vivo; persistence of parasite and hence active VL in patients who failed anti-leishmanial chemotherapy was associated with high HIV load than in those who had good response to therapy. Moreover, proliferative responses to PHA or Leishmania were lower in VL and/or HIV-infected persons compared to healthy controls. PBMC from healthy donors produced high levels of Th1 cytokine (IFN-[gamma]), Th1-inducing cytokines (IL-12 & IL-18), and low Th2 cytokines (IL-4 & IL-10); HI-HIV abrogated the production of IFN-[gamma] induced by Leishmania and augmented IL-4 and IL- 10. In contrast, VL and/or HIV-infected produced low levels of Th1 or Th1-inducing cyokines, but high levels of IL-10. Data suggest that the inhibitory effect of HIV and VL on the proliferative and IFN-[gamma] production was not only due to IL- 10, but also that the defect induced by HIV and VL probably operate at the level of regulation of IFN-[gamma]-inducing factors.
List of papers:
I. Berhe N, Hailu A, Wolday D, Negesse Y, Cenini P, Frommel D (1995). Ethiopian visceral leishmaniasis patients co-infected with human immunodeficiency virus. Trans R Soc Trop Med Hyg. 89(2):205-207.
Pubmed
II. Wolday D, Akuffo H, Britton S, Hathaway A, Sander B (1994). HIV-1 inhibits Leishmania-induced cell proliferation but not production of interleukin-6 and tumour necrosis factor alpha. Scand J Immunol. 39(4):380-386.
Pubmed
III. Wolday D, Akuffo H, Fessahaye G, Valantine A, Britton S. (1998). Live and killed human immunodeficiency virus type-1 increases the intracellular growth of Leishmania donovani in monocyte-derived cells. Scand J Infect Dis. 30(1):29-34.
Pubmed
IV. Wolday D, Akuffo H, Demissie A, Britton S (1999). Role of Leishmania donovani and its lipophosphoglycan in CD4+ T-cell activation-induced human immunodeficiency virus replication. Infect Immun. 67(10):5258-5264.
Pubmed
V. Berhe N, Wolday D, Hailu A, Abraham Y, Ali A, Gebre-Michael T, Desjeux P, Sönnerborg A, Akuffo H, Britton S (1999). HIV viral load and response to antileishmanial chemotherapy in co-infected patients. AIDS. 13(14):1921-1925.
Pubmed
VI. Wolday D, Berhe N, Britton S, Akuffo H (1970). HIV-1 alters T-cell cytokines, IL-12, and IL-18 responses to the protozoan parasite Leishmania donovani. [Manuscript]
I. Berhe N, Hailu A, Wolday D, Negesse Y, Cenini P, Frommel D (1995). Ethiopian visceral leishmaniasis patients co-infected with human immunodeficiency virus. Trans R Soc Trop Med Hyg. 89(2):205-207.
Pubmed
II. Wolday D, Akuffo H, Britton S, Hathaway A, Sander B (1994). HIV-1 inhibits Leishmania-induced cell proliferation but not production of interleukin-6 and tumour necrosis factor alpha. Scand J Immunol. 39(4):380-386.
Pubmed
III. Wolday D, Akuffo H, Fessahaye G, Valantine A, Britton S. (1998). Live and killed human immunodeficiency virus type-1 increases the intracellular growth of Leishmania donovani in monocyte-derived cells. Scand J Infect Dis. 30(1):29-34.
Pubmed
IV. Wolday D, Akuffo H, Demissie A, Britton S (1999). Role of Leishmania donovani and its lipophosphoglycan in CD4+ T-cell activation-induced human immunodeficiency virus replication. Infect Immun. 67(10):5258-5264.
Pubmed
V. Berhe N, Wolday D, Hailu A, Abraham Y, Ali A, Gebre-Michael T, Desjeux P, Sönnerborg A, Akuffo H, Britton S (1999). HIV viral load and response to antileishmanial chemotherapy in co-infected patients. AIDS. 13(14):1921-1925.
Pubmed
VI. Wolday D, Berhe N, Britton S, Akuffo H (1970). HIV-1 alters T-cell cytokines, IL-12, and IL-18 responses to the protozoan parasite Leishmania donovani. [Manuscript]
Issue date: 1999-12-27
Publication year: 1999
ISBN: 91-628-3814-8
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