Insights to the HIV-associated visceral leishmaniasis clinical outcome: lessons learned about immune mediated disorders

Abstract

Most cases of visceral leishmaniasis (VL) and human immunodeficiency virus (HIV) co-infection (VL/HIV) in the Americas occur in Brazil, and the prevalence of VL/HIV has been increasing since 2019, reaching 19% in 2023. This association presents a challenge for the management of VL, since both VL and HIV infection share immunopathogenic characteristics that can reciprocally affect co-infected patients. Thus, VL may contribute to the immunosuppression and other immunological disturbances associated with the rapid progression to acquired immunodeficiency syndrome (AIDS), whereas HIV infection accelerates the development of active VL and reduces the probability of a successful response to anti-Leishmania therapy, resulting in an increase in the relapse and lethality rates of VL. In this synergistic impairment, one of the most critical hallmarks of VL/HIV co-infection is the enhancement of immunosuppression and intense chronic immune activation, caused not only by each infection per se, but also by the cytokine storm and translocation of microbial products. Thus, co-infected patients present with an impaired effector immune response that may result in inefficient parasitic control. In addition, the chronic activation environment in VL/HIV patients may favor progression to early immunosenescence and exhaustion, worsening the patients' clinical condition and increasing the frequency of disease relapse. Herein, we review the immunological parameters associated with the immunopathogenesis of VL/HIV co-infection that could serve as good biomarkers of clinical prognosis in terms of relapse and severity of VL.

Keywords: VL/HIV co-infection; cellular activation; immune response; immunosenescence; relapses; visceral leishmaniasis.

Figure 1

Immunopathogenesis of visceral leishmaniasis in HIV-infected individuals: Chronic immune activation and its implications for the immune impairment of VL/HIV co-infection (1) Co-infection with L. infantum/L. donovani and HIV is characterized by simultaneous systemic involvement of organs such as lymph nodes and thymus, in addition to parasitism of the bone marrow, spleen and liver (2). The intense parasitism of monocytes and macrophages by the protozoan culminates in changes in the production of myeloid and lymphoid progenitors by the bone marrow. In an attempt to recover the parasitized cells, there is a shift in favor of this lineage, which can lead to a laboratorial profile of erythropenia, neutropenia, thrombocytopenia and lymphopenia. In VL/HIV co-infection, the drop in absolute counts of peripheral CD4 T lymphocytes is enhanced by infection and concomitant thymic impairment by HIV and the protozoan. (3a) In parallel with immunosuppression, co-infection occurs with high cellular activation, characterized by activated T lymphocytes, high production of inflammatory cytokines (cytokine storm) and (3b) polyclonal activation of B lymphocytes, which culminates in hyperglobulinemia (4). In addition to parasite and viral antigens, the translocation of microbial products has been identified as an important cofactor for increasing levels of systemic activation (5). As a result of this persistent activation, activation-induced cell death (AICD), worsening of lymphopenia and an impairment of the cellular immune response specific to the parasite is observed, which may favor relapses (6). The maintenance of this scenario can result in the exhaustion of primary immune resources (thymus and bone marrow) and the inability of lymphocytic repopulation. This process results in the deterioration of the responsive capacity to parasitic stimuli, favoring the accumulation of exhausted and/or terminally differentiated cells and the low diversity of the lymphocyte repertoire. SASP, Senescence-Associated Secretory Phenotype. Dashed lines indicate direct damage caused by pathogens. Source: The author. Created with BioRender.com.

Figure 2

Both infections share immunopathogenic characteristics that can reciprocally impair the immune response to pathogens. Visceral leishmaniasis can contribute to the decrease in CD4 T lymphocytes, worsening immunosuppression, increasing viral replication and the cellular activation degree, which in turn may favor progression to AIDS. On the other hand, HIV infection and its consequences for the immune response can increase the parasite load, the resistance to the treatment, dissemination of VL for atypical sites and favor the severity and relapses of the disease. Microbial translocation, immunosenescence and the exhaustion degree may act as key cofactors of the process that culminates in the collapse of the immune response in co-infected patients. Source: The author. BioRender.com.