Leishmania infantum Amastigotes Enhance HIV-1 Production in Cocultures of Human Dendritic Cells and CD4+ T Cells by Inducing Secretion of IL-6 and TNF-α
Abstract:BackgroundVisceral leishmaniasis has emerged as an important opportunistic disease among patients infected with HIV-1. Both HIV-1 and the protozoan parasite Leishmania can productively infect cells of the macrophage-dendritic cell lineage.Methodology/Principal FindingsHere we demonstrate that Leishmania infantum amastigotes increase HIV-1 production when human primary dendritic cells (DCs) are cocultured together with autologous CD4+ T cells. Interestingly, the promastigote form of the parasite does not modula… Show more
“…This is a critical finding in that we have recently reported that HIV replication efficiencies in a wide variety of relevant cell types, including monocytes and macrophages, is directly related to the relative intra-cellular dNTP concentrations [31], [32]. Thus, the finding of elevated dNTP levels in both GM-CSF- and Leishmania -maturated human MDMs, as compared to both freshly isolated monocytes and untreated control cells, offers a novel mechanism to explain both the present results as well as prior in vitro and in vivo studies that demonstrate accelerated HIV-1 replication in both GM-CSF-treated and Leishmania co-infected patients [55], [67], [77], [78]. These results are consistent with the 200–1500 times decrease in replication competence of wild-type HIV-1 in monocytes as compared to the corresponding differentiated MDMs [33].…”
Leishmaniasis is a parasitic disease that is widely prevalent in many tropical and sub-tropical regions of the world. Infection with
Leishmania
has been recognized to induce a striking acceleration of Human Immunodeficiency Virus Type 1 (HIV-1) infection in coinfected individuals through as yet incompletely understood mechanisms. Cells of the monocyte/macrophage lineage are the predominant cell types coinfected by both pathogens. Monocytes and macrophages contain extremely low levels of deoxynucleoside triphosphates (dNTPs) due to their lack of cell cycling and S phase, where dNTP biosynthesis is specifically activated. Lentiviruses, such as HIV-1, are unique among retroviruses in their ability to replicate in these non-dividing cells due, at least in part, to their highly efficient reverse transcriptase (RT). Nonetheless, viral replication progresses more efficiently in the setting of higher intracellular dNTP concentrations related to enhanced enzyme kinetics of the viral RT. In the present study,
in vitro
infection of CD14+ peripheral blood-derived human monocytes with
Leishmania major
was found to induce differentiation, marked elevation of cellular p53R2 ribonucleotide reductase subunit and R2 subunit expression. The R2 subunit is restricted to the S phase of the cell cycle. Our dNTP assay demonstrated significant elevation of intracellular monocyte-derived macrophages (MDMs) dNTP concentrations in
Leishmania
-infected cell populations as compared to control cells. Infection of
Leishmania
-maturated MDMs with a pseudotyped GFP expressing HIV-1 resulted in increased numbers of GFP+ cells in the
Leishmania
-maturated MDMs as compared to control cells. Interestingly, a sub-population of
Leishmania
-maturated MDMs was found to have re-entered the cell cycle, as demonstrated by BrdU labeling. In conclusion,
Leishmania
infection of primary human monocytes promotes the induction of an S phase environment and elevated dNTP levels with notable elevation of HIV-1 expression in the setting of coinfection.
“…This is a critical finding in that we have recently reported that HIV replication efficiencies in a wide variety of relevant cell types, including monocytes and macrophages, is directly related to the relative intra-cellular dNTP concentrations [31], [32]. Thus, the finding of elevated dNTP levels in both GM-CSF- and Leishmania -maturated human MDMs, as compared to both freshly isolated monocytes and untreated control cells, offers a novel mechanism to explain both the present results as well as prior in vitro and in vivo studies that demonstrate accelerated HIV-1 replication in both GM-CSF-treated and Leishmania co-infected patients [55], [67], [77], [78]. These results are consistent with the 200–1500 times decrease in replication competence of wild-type HIV-1 in monocytes as compared to the corresponding differentiated MDMs [33].…”
Leishmaniasis is a parasitic disease that is widely prevalent in many tropical and sub-tropical regions of the world. Infection with
Leishmania
has been recognized to induce a striking acceleration of Human Immunodeficiency Virus Type 1 (HIV-1) infection in coinfected individuals through as yet incompletely understood mechanisms. Cells of the monocyte/macrophage lineage are the predominant cell types coinfected by both pathogens. Monocytes and macrophages contain extremely low levels of deoxynucleoside triphosphates (dNTPs) due to their lack of cell cycling and S phase, where dNTP biosynthesis is specifically activated. Lentiviruses, such as HIV-1, are unique among retroviruses in their ability to replicate in these non-dividing cells due, at least in part, to their highly efficient reverse transcriptase (RT). Nonetheless, viral replication progresses more efficiently in the setting of higher intracellular dNTP concentrations related to enhanced enzyme kinetics of the viral RT. In the present study,
in vitro
infection of CD14+ peripheral blood-derived human monocytes with
Leishmania major
was found to induce differentiation, marked elevation of cellular p53R2 ribonucleotide reductase subunit and R2 subunit expression. The R2 subunit is restricted to the S phase of the cell cycle. Our dNTP assay demonstrated significant elevation of intracellular monocyte-derived macrophages (MDMs) dNTP concentrations in
Leishmania
-infected cell populations as compared to control cells. Infection of
Leishmania
-maturated MDMs with a pseudotyped GFP expressing HIV-1 resulted in increased numbers of GFP+ cells in the
Leishmania
-maturated MDMs as compared to control cells. Interestingly, a sub-population of
Leishmania
-maturated MDMs was found to have re-entered the cell cycle, as demonstrated by BrdU labeling. In conclusion,
Leishmania
infection of primary human monocytes promotes the induction of an S phase environment and elevated dNTP levels with notable elevation of HIV-1 expression in the setting of coinfection.
“…It is estimated that HIV increases the risk of VL development in L. donovani -exposed populations by several hundred-fold [3], through either decreased resistance to a new primary infection or reactivation of a previous subclinical infection [108]. Co-infection studies in primary human monocyte-derived MΦs, DCs, and tonsillar tissue demonstrated that each pathogen has a detrimental effect on containment of the other— Leishmania infection enhances HIV replication via chronic immune activation, and that HIV promotes Leishmania infection by suppressing a protective host defense [109–112]. The latter is corroborated by higher levels of L. donovani parasitemia in HIV co-infected individuals [113] and low CD4 + T cell counts despite suppression of viral load by antiretroviral therapy [114].…”
Section: Spectrum and Immunopathogenesis Of Progressive Vl In Humansmentioning
The outcomes of Leishmania infection are determined by host immune and nutrition status, parasite species, and co-infection with other pathogens. While subclinical infection and self-healing cutaneous leishmaniasis (CL) are common, uncontrolled parasite replication can lead to non-healing local lesions or visceral leishmaniasis (VL). It is known that infection control requires Th1-differentiation cytokines (IL-12, IL-18, and IL-27) and Th1 cell and macrophage activation. However, there is no generalized consensus for the mechanisms of host susceptibility. The recent studies on regulatory T cells and IL-17-producing cells help explain the effector T cell responses that occur independently of the known Th1/Th2 cell signaling pathways. This review focuses on the immunopathogenesis of non-healing American CL and progressive VL. We summarize recent evidence from human and animal studies that reveals the mechanisms of dysregulated, hyper-responses to Leishmania braziliensis, as well as the presence of disease-promoting or the absence of protective responses to Leishmania amazonensis and Leishmania donovani. We highlight immune-mediated parasite growth and immunopathogenesis, with an emphasis on the putative roles of IL-17 and its related cytokines as well as arginase. A better understanding of the quality and regulation of innate immunity and T cell responses triggered by Leishmania will aid in the rational control of pathology and the infection.
The Leishmaniases are a group of diseases transmitted to humans by the bite of a sandfly, caused by protozoan parasites of the genus Leishmania. Various Leishmania species infect humans, producing a spectrum of clinical manifestations. It is estimated that 350 million people are at risk, with a global yearly incidence of 1-1.5 million for cutaneous and 500,000 for visceral Leishmaniasis (VL). VL is a major cause of morbidity and mortality in East Africa, Brazil and the Indian subcontinent. Co-infection with human immunodeficiency virus (HIV) alters the immune response to the disease. Here we review the immune response to Leishmania in the setting of HIV co-infection. Improved understanding of the immunology involved in co-infections may help in designing prophylactic and therapeutic strategies against Leishmaniasis.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.