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Abstract: Miltefosine (Milt) was originally synthesized as an antineoplastic agent but this phospholipid drug is now clinically used as an antiprotozoal compound. We demonstrate here that Milt reduces replication of HIV-1 in cocultures of human dendritic cells (DCs) and CD4+ T cells. This phenomenon is due to a rapid secretion of soluble factors by DCs. We present evidence that the Milt-mediated repression in virus production is associated with induction of type-I interferon (IFN) in DCs. The Milt-dependent diminution in HIV-1 production was not totally abrogated by B18R, a vaccinia virus-encoded neutralizing type-I IFN receptor, which suggests the involvement of another yet to be identified soluble factor. Altogether, these results suggest that a therapy with Milt when used to control protozoan infections in individuals also carrying HIV-1 might also help to limit viral load. Additional studies are warranted to estimate the exact therapeutic potential of Milt as an anti-HIV-1 agent. [Copyright &y& Elsevier]

Background: Visceral 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 Findings: Here 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 modulate virus replication. Moreover, we report that amastigotes promote virus replication in both cell types. Our results indicate that this process is due to secretion of parasite-induced soluble factors by DCs. Luminex micro-beads array system analyses indicate that Leishmania infantum amastigotes induce a higher secretion of several cytokines (i.e. IL-1α, IL-2, IL-6, IL-10 and TNF-α) and chemokines (i.e. MIP-1α, MIP-1β and RANTES) in these cells. Studies conducted with pentoxifylline and neutralizing antibodies revealed that the Leishmania-dependent augmentation in HIV-1 replication is due to a higher secretion of IL-6 and TNF-α. Conclusions/Significance: Altogether these findings suggest that the presence of Leishmania within DC/T-cell conjugates leads to an enhancement of virus production and demonstrate that HIV-1 and Leishmania can establish complex interactions in such a cellular microenvironment. Author Summary: Visceral leishmaniasis (VL) is a potentially deadly parasitic disease afflicting millions worldwide. Although itself an important infectious illness, VL has also emerged as an opportunistic disease among patients infected with HIV-1. This is partly due to the increasing overlap between urban regions of high HIV-1 transmission and areas where Leishmania is endemic. Furthermore, VL increases the development and clinical progression of AIDS-related diseases. Conversely, HIV-1-infected individuals are at greater risk of developing VL or suffering relapse. Finally, HIV-1 and Leishmania can both productively infect cells of the macrophage-dendritic cell lineage, resulting in a cumulative deficiency of the immune response. We therefore studied the effect of Leishmania infantum on HIV-1 production when dendritic cells (DCs) are cocultured with autologous CD4+ T cells. We show that amastigotes promote virus replication in both DCs and lymphocytes, due to a parasite-mediated production of soluble factors by DCs. Micro-beads array analyses indicate that Leishmania infantum amastigotes infection induces a higher secretion of several cytokines in these cells, and use of specific neutralizing antibodies revealed that the Leishmania-induced increase in HIV-1 replication is due to IL-6 and TNF-α. These findings suggest that Leishmania's presence within DC/T-cell conjugates leads to an enhanced HIV-1 production. [ABSTRACT FROM AUTHOR]

Visceral leishmaniasis is now recognized as an opportunistic disease in individuals infected with human immunodeficiency virus type 1 (HIV-1). Although the usefulness of HIV-1 protease inhibitors (PIs) in antiretroviral regimens is well documented, little is known about their potential impact in the setting of Leishmania/HIV-1 coinfections. We now report that, although selected PIs do not inhibit the growth of Leishmania infantum promastigotes alone in culture, these drugs significantly inhibit the intracellular survival of parasites in phorbol myristate acetate-differentiated THP-1 macrophages and human primary monocyte-derived macrophages (MDMs). Furthermore, a field isolate of Leishmania donovani resistant to sodium stibogluconate (SbV), one of the drugs most commonly used to treat leishmaniasis, is equally susceptible to the tested PIs compared with a sensitive strain, thus suggesting that resistance to SbV does not result in cross-resistance to PIs. Importantly, the efficacy of PIs to reduce the intracellular growth of Leishmania parasites is also observed in MDMs coinfected with HIV-1. [ABSTRACT FROM AUTHOR]

Visceral leishmaniasis is now recognized as an opportunistic disease in patients infected with human immunodeficiency virus type 1 (HIV-1). We report here that Leishmania infantum promastigotes enhance HIV-1 replication in monocyte-derived macrophages (MDMs) at late time points in the virus growth curve but also that, surprisingly, a reduction in HIV-1 production is seen during the initial days after infection. This early effect is caused by a Leishmania-mediated inhibition of virus entry into MDMs through the action of lipophosphoglycan (LPG), the major promastigote surface glycolipid. The impact of LPG in the observed phenomenon was confirmed using LPG-defective lpg1-1- knockout mutant promastigotes. Our results suggest that the LPG-mediated effect results from the disruption of lipid rafts. Altogether, these findings suggest that the presence of Leishmania within the same cellular microenvironment leads to 2 opposite, time-dependent effects on HIV-1 replication. Leishmania and HIV-1 can thus establish complex interactions in their common natural host cells. [ABSTRACT FROM AUTHOR]

Recent studies have shown that both Leishmania and HIV type-1 (HIV-1) hijack dendritic cell (DC) functions to escape immune surveillance using an array of elaborate strategies. Leishmania has developed a variety of adaptations to disrupt cellular defense mechanisms, whereas HIV-1 targets DCs to achieve a more efficient dissemination. The capacity of Leishmania and HIV-1 to target DCs through a common cell-surface molecule, namely DC-SIGN (dendritic cell specific ICAM-3-grabbing non-integrin), points to a possible dangerous liaison between these two pathogens. This review explores our knowledge of how Leishmania and HIV-1 interact dynamically with DCs, and how they exploit this cell type for their reciprocal benefit. [Copyright &y& Elsevier]