Visceral Leishmaniasis relapse in HIV patients - A role for Myeloid-Derived Suppressor Cells?

Visceral leishmaniasis (VL) is a disseminated protozoan infection caused by the Leishmania donovani spp. complex and is transmitted by phlebotomine sand flies. Globally, over 200 million people are at risk of contracting VL, and when left untreated, the disease is universally lethal. The human immunodeficiency virus (HIV) pandemic has been one of the main driving forces behind the increased spread of VL over the last 20 years [1]. Sub-Saharan Africa is at the epicentre of this detrimental synergy: in East Africa, the most intense HIV-VL interplay takes place, with HIV prevalence amongst VL cases ranging from 15% to more than 40% in certain areas of Ethiopia and South Sudan. In this region, the highly virulent L. donovani prevails, and a large proportion of VL patients present in advanced stages of HIV infection.

Comorbidities of HIV and other infectious diseases such as tuberculosis, cryptococcosis, or viral hepatitis manifest a number of general characteristics including accelerated disease progression, higher rates of adverse outcomes, and therapy-associated complications like the immune reconstitution inflammatory syndrome (IRIS) [2]. While HIV-VL coinfection is also associated with accelerated HIV and VL progression and a poor prognosis, it appears to be governed by a number of unique and poorly explained features. One of these unique features is that even after virological suppression under antiretroviral therapy (ART), patients often remain clinically and immunologically in a state of immunodeficiency and anergy, with diffuse organ spread of parasites [1], [3]. Such patients are characterised by high rates of anti-VL therapy failure, which can be either primary failure or recurring parasitological relapses. In other patients, the unique entity of "active chronic visceral leishmaniasis" was described, entailing continuous asymptomatic parasite replication under therapy, interspersed with symptomatic secondary VL episodes [4]. The observed therapeutic failure contrasts sharply with, e.g., the IRIS events observed in other coinfections, which--while detrimental--are indicative of a partial and possibly even over-exuberant restoration of pathogen-specific immune responses [2]. This therapeutic failure in HIV-VL poses a major challenge to programmes facing a high burden of the coinfection--however, it remains poorly understood and under-researched