Visceral leishmaniasis is a severe complication of HIV infection . HAART combined with antileishmanial treatment has been shown to decrease significantly the incidence and improve the prognosis of visceral leishmaniasis in HIV-infected patients . Nevertheless, HIV/Leishmania co-infected patients responding poorly to HAART remain at risk of a relapse of leishmaniasis .
HIV and Leishmania target the same cells, the monocytes/macrophages, and may add their effects in the co-infected host. HIV promotes Leishmania replication in vitro and impairs the ability of macrophages to control the growth of Leishmania[4,5]. In addition, both HIV and Leishmania induce a shift from a T helper 1 to a T helper 2 type cytokine profile, with reduced IL-2 and IFN-γ production [6–8].
The administration of human recombinant IL-2 (rIL-2) concurrently with HAART increased CD4 cell counts and function in patients with HIV infection, including those with advanced disease [9,10]. On the other hand, rIL-2 reduced the local parasite load in human cutaneous leishmaniasis . Furthermore, the restoration of lymphoproliferative responses to Leishmania antigen was achieved in vitro by IL-2 and IFN-γ , and exogenous IL-2 induced a therapeutic effect in a murine model of visceral leishmaniasis . On the basis of the rationale that rIL-2 could be effective by both restoring immunity and directly acting on Leishmania infection, we administered rIL-2 to a patient with HIV/Leishmania co-infection who failed to respond to anti-leishmanial therapy and HAART.
The patient was an Italian, 36-year-old HIV-infected woman diagnosed with visceral leishmaniasis in 1997 by the demonstration of Leishmania amastigotes in Giemsa-stained bone marrow smears. She was receiving zidovudine, didanosine and saquinavir; the CD4 cell count was 98 cells/μl, HIV RNA was 7000 copies/ml. The patient was successfully treated with liposomal amphotericin B at 3 mg/kg for 10 days, but leishmaniasis relapsed on seven distinct occasions over the following 4 years despite antileishmanial treatment, including liposomal amphotericin B, meglumine antimoniate and pentamidine, and monthly 5 mg/kg liposomal amphotericin B between treatment courses. Starting from March 2000, real-time polymerase chain reaction was used to quantify Leishmania DNA in whole peripheral blood . Over a 14-month period, levels remained detectable (range 2.70–6.63 log copies/ml), with the lowest values observed at the end of liposomal amphotericin B treatments.
Recombinant IL-2 was started in July 2001, and was given subcutaneously for seven cycles every 4–8 weeks, at 3 million IU (MIU, first four cycles) or 6 MIU (cycles 5–7) twice a day for 5 days. Starting from the second cycle, liposomal amphotericin B was administered between each rIL-2 cycle (Fig. 1). At the start of rIL-2 the patient had received no antileishmanial drugs for 2 months; she presented with fever up to 37.8°C and splenomegaly, and low white blood cells and haemoglobin levels (Fig. 1). During the one-year period of rIL-2 the patient maintained a slight fever, which increased transiently during each rIL-2 cycle. The parasite burden decreased substantially after the long-term administration of amphotericin B, before the third and sixth rIL-2 cycle. It increased at the end of each rIL-2 cycle, however, with the exception of the third cycle, which was started one day after the end of amphotericin B therapy. White blood cells and haemoglobin levels did not increase substantially during the year of IL-2 treatment, whereas CD4 cell counts decreased progressively.
Not only HIV, but also Leishmania infection is associated with decreased T-cell responses and CD4 cell apoptosis [4,12,15]. It is thus plausible that the dosage of rIL-2 taken by our patient was not sufficient to counter the HIV and Leishmania-related depletion of CD4 cells. Although this hypothesis was not further investigated in our patient, increased expression of the IL-2 receptor has been reported in HIV/Leishmania co-infection compared with HIV infection alone, which might reflect a loss of sensitivity to IL-2 by T cells . On the other hand, each rIL-2 cycle was accompanied by increased Leishmania levels in the blood. Although this may have partly resulted from amphotericin B withdrawal before rIL-2, this was not the explanation in the first two rIL-2 cycles, which were not preceded by anti-leishmanial therapy. T cells and their products are expected to promote resistance to Leishmania infection [12,13]; however, IL-2 may stimulate the growth of Leishmania under certain circumstances, for example under suboptimal culture conditions . Therefore, a direct derimental effect of rIL-2 on Leishmania replication can also be considered.
In conclusion, the use of rIL-2 in HIV/Leishmania co-infection did not show any benefit in the context of low CD4 cell counts and incomplete HIV suppression despite HAART. On the contrary, the observation of increased Leishmania DNA levels after each IL-2 cycle suggests the activation of Leishmania, which might in turn have favoured the progression of HIV infection.
1. Alvar J, Canavate C, Gutierrez-Solar B, Jimenez M, Laguna F, Lopez-Velez R, et al
. Leishmania and human immunodeficiency virus co-infection: the first 10 years. Clin Microbiol Rev 1997; 10:298–319.
2. Del Giudice P, Mary-Krause M, Pradier C, Grabar S, Dellamonica P, Marty P, et al
, French Hospital Database on HIV Clinical Epidemiologic Group. Impact of highly active antiretroviral therapy on the incidence of visceral leishmaniasis in a French cohort of patients infected with human immunodeficiency virus. J Infect Dis 2002; 186:1366–1370.
3. Mira JA, Corzo JE, Rivero A, Macias J, De Leon FL, Torre-Cisneros J, et al
. Frequency of visceral leishmaniasis relapses in human immunodeficiency virus-infected patients receiving highly active antiretroviral therapy. Am J Trop Med Hyg 2004; 70:298–301.
4. Wolday D, Berhe N, Akuffo H, Britton S. Leishmania
–HIV interaction: immunopathogenic mechanisms. Parasitol Today 1999; 15:182–187.
5. Barreto-de-Souza V, Pacheco GJ, Silva AR, Castro-Faria-Neto HC, Bozza PT, Saraiva EM, et al
. Increased Leishmania
replication in HIV-1-infected macrophages is mediated by tat protein through cyclooxygenase-2 expression and prostaglandin E2 synthesis. J Infect Dis 2006; 194:846–854.
6. Carvalho EM, Badaro R, Reed SG, Jones TC, Johnson WD Jr. Absence of gamma interferon and interleukin 2 production during active visceral leishmaniasis. J Clin Invest 1985; 76:2066–2069.
7. Cillari E, Liew FY, Lo Campo P, Milano S, Mansueto S, Salerno A. Suppression of IL-2 production by cryopreserved peripheral blood mononuclear cells from patients with active visceral leishmaniasis in Sicily. J Immunol 1988; 140:2721–2726.
8. Nigro L, Cacopardo B, Preiser W, Braner J, Cinatl J, Palermo F, et al
. In vitro production of type 1 and type 2 cytokines by peripheral blood mononuclear cells from subjects coinfected with human immunodeficiency virus and Leishmania
infantum. Am J Trop Med Hyg 1999; 60:142–145.
9. Mitsuyasu RT. The potential role of interleukin-2 in HIV. AIDS 2001; 15(Suppl. 2):22–27.
10. Tambussi G, Ghezzi S, Nozza S, Vallanti G, Magenta L, Guffanti M, et al
. Efficacy of low-dose intermittent subcutaneous interleukin (IL)-2 in antiviral drug-experienced human immunodeficiency virus-infected persons with detectable virus load: a controlled study of 3 IL-2 regimens with antiviral drug therapy. J Infect Dis 2001; 183:1476–1484.
11. Akuffo H, Kaplan G, Kiessling R, Teklemariam S, Dietz M, McElrath J, et al
. Administration of recombinant interleukin-2 reduces the local parasite load of patients with disseminated cutaneous leishmaniasis. J Infect Dis 1990; 161:775–780.
12. Carvalho EM, Bacellar O, Brownell C, Regis T, Coffman RL, Reed SG. Restoration of IFN-gamma production and lymphocyte proliferation in visceral leishmaniasis. J Immunol 1994; 152:5949–5956.
13. Murray HW, Miralles GD, Stoeckle MY, McDermott DF. Role and effect of IL-2 in experimental visceral leishmaniasis. J Immunol 1993; 151:929–938.
14. Bossolasco S, Gaiera G, Olchini D, Gulletta M, Martello L, Bestetti A, Bossi L, et al
. Real-time PCR assay for clinical management of human immunodeficiency virus-infected patients with visceral leishmaniasis. J Clin Microbiol 2003; 41:5080–5084.
15. Potestio M, D’Agostino P, Romano GC, Milano S, Ferlazzo V, Aquino A, et al
. CD4+ CCR5+ and CD4+ CCR3+ lymphocyte subset and monocyte apoptosis in patients with acute visceral leishmaniasis. Immunology 2004; 113:260–268.
16. Mazingue C, Cottrez-Detoeuf F, Louis J, Kweider M, Auriault C, Capron A. In vitro and in vivo effects of interleukin 2 on the protozoan parasite Leishmania
. Eur J Immunol 1989; 19:487–491.