Over 850 Leishmania-human immunodeficiency virus (HIV) coinfection cases have been recorded, the majority in Europe, where 7 to 17% of HIV-positive individuals with fever have amastigotes, suggesting that Leishmania-infected individuals without symptoms will express symptoms of leishmaniasis if they become immunosuppressed. However, there are indirect reasons and statistical data demonstrating that intravenous drug addiction plays a specific role in Leishmania infantum transmission: an anthroponotic cycle complementary to the zoonotic one has been suggested. Due to anergy in patients with coinfection, L. infantum dermotropic zymodemes are isolated from patient viscera and a higher L. infantum phenotypic variability is seen. Moreover, insect trypanosomatids that are currently considered nonpathogenic have been isolated from coinfected patients. HIV infection and Leishmania infection each induce important analogous immunological changes whose effects are multiplied if they occur concomitantly, such as a Th1-to-Th2 response switch; however, the consequences of the viral infection predominate. In fact, a large proportion of coinfected patients have no detectable anti-Leishmania antibodies. The microorganisms share target cells, and it has been demonstrated in vitro how L. infantum induces the expression of latent HIV-1. Bone marrow culture is the most useful diagnostic technique, but it is invasive. Blood smears and culture are good alternatives. PCR, xenodiagnosis, and circulating-antigen detection are available only in specialized laboratories. The relationship with low levels of CD4+ cells conditions the clinical presentation and evolution of disease. Most patients have visceral leishmaniasis, but asymptomatic, cutaneous, mucocutaneous, diffuse cutaneous, and post-kala-azar dermal leishmaniasis can be produced by L. infantum. The digestive and respiratory tracts are frequently parasitized. The course of coinfection is marked by a high relapse rate. There is a lack of randomized prospective treatment trials; therefore, coinfected patients are treated by conventional regimens. Prophylactic therapy is suggested to be helpful in preventing relapses.

Leishmania and human immunodeficiency virus coinfection: the first 10 years.

Recent epidemiologic studies indicate that leishmaniasis in the Americas is far more abundant and of greater public health importance than was previously recognized. The disease in the New World is caused by a number of different parasite species that are capable of producing a wide variety of clinical manifestations. The outcome of leishmanial infection in humans is largely dependent on the immune responsiveness of the host and the virulence of the infecting parasite strain. This article reviews current concepts of the clinical forms, immunology, pathology, laboratory diagnosis, and treatment of the disease as well as aspects of its epidemiology and control. Recommendations for future research on the disease and its control are made.

Leishmaniases of the New World: current concepts and implications for future research.

The clinical manifestations of leishmaniasis depend on com­ plex interactions between the virulence characteristics of the infecting Leishmania species and the immune responses of its host. The result is a spectrum of disease ranging from localized skin lesions to diffuse involvement of the reticuloendothelial system. Human disease has traditionally been divided into three major clinical syndromes: visceral, cutaneous, and mucosal leishmaniasis; however, a number of variants exist. Further­ more, a single Leishmania species can produce more than one clinical syndrome, and each syndrome is caused by multiple species. The true incidence and prevalence of leishmaniasis is uncer­ tain because many cases go undiagnosed or unreported in areas where the infection is endemic. In 1993, the World Health Organization estimated that 350 million people worldwide were at risk for infection. The incidence of cutaneous leishmaniasis has been estimated to be 1.0-1.5 million cases per year, and

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Clinical Spectrum of Leishmaniasis

Human and parasitic papain-like cysteine proteases: their role in physiology and pathology and recent developments in inhibitor design.

Saccharomyces cerevisiae has two independent transport systems for the removal of arsenite from the cytosol. Acr3p is a plasma membrane transporter that confers resistance to arsenite, presumably by arsenite extrusion from the cells. Ycf1p, a member of the ABC transporter superfamily, catalyzes the ATP-driven uptake of As(III) into the vacuole, also producing resistance to arsenite. Vacuolar accumulation requires a reductant such as glutathione, suggesting that the substrate is the glutathione conjugate, As(GS)3. Disruption of either the ACR3 or YCF1 gene results in sensitivity to arsenite and disruption of both genes produces additive hypersensitivity. Thus, Acr3p and Ycf1p represent separate pathways for the detoxification of arsenite in yeast.

https://www.pnas.org/content/pnas/96/9/5001.full.pdf

Pathways of As(III) detoxification in Saccharomyces cerevisiae

We report that in vitro sensitivity to pentavalent antimony (Sb5) of 35 Leishmania isolates as determined by the semiautomated microdilution technique (SAMT) showed an 89% and 86% correlation with clinical outcome after Pentostam and Glucantime treatment, respectively. These results suggest that in over 85% of the cases, the clinical outcome of treatment (cure or failure) could have been predicted by using the SAMT technique. Furthermore, the results clearly indicate that drug resistance is a problem, and that at least in some instances, failure to respond to treatment is due to the parasite as well as patient factors. Strains from Sb5-treated patients with American cutaneous and mucocutaneous disease who fail at least one complete course of Pentostam are as highly nonresponsive to this drug as laboratory-proven drug-resistant Leishmania strains. It was determined that some Leishmania isolates are innately less susceptible to Sb5 than others, and that moderate resistance to Sb5 exists in nature. A 10- and 17-fold increase was detected in the 50% inhibitory concentration (IC50) of Sb5 for L. mexicana and L. braziliensis isolates after subcurative treatment of the patients, when compared with the mean IC50 of seven and six isolates from the same endemic areas in Guatemala and Peru, respectively. Thus, we have correlated subcurative treatment to a decrease in drug sensitivity in at least these two cases. Collectively, these results indicate that under Sb5 pressure from undermedication, the parasites inherently most drug resistant are favored. The degree of resistance of a strain to antimony in association with host-specific factors will determine whether the clinical response to treatment with this drug is a total cure or a partial response followed by relapse(s), and possibly secondary unresponsiveness resulting in total resistance to antimony. It is evident from our in vitro test data that the SAMT is an extremely powerful and highly accurate technique for the prediction and determination of drug sensitivity of leishmanial isolates, as well as a means to screen for anti-leishmanial agents.

E D Franke

Papers

Drug resistance in leishmaniasis : its implication in systemic chemotherapy of cutaneous and mucocutaneous disease