Abstract
Over the past decade, the number of reported human immunodeficiency virus type-1 (HIV-1)/Leishmania co-infections has risen dramatically, particularly in regions where both diseases are endemic. Although it is known that HIV-1 infection leads to an increase in susceptibility to Leishmania infection and leishmaniasis relapse, little remains known on how HIV-1 contributes to Leishmania parasitaemia. Both pathogens infect human macrophages, and the intracellular growth of Leishmania is increased by HIV-1 in co-infected cultures. We now report that uninfected bystander cells, not macrophages productively infected with HIV-1, account for enhanced phagocytosis and higher multiplication of Leishmania parasites. This effect can be driven by HIV-1 Tat protein and transforming growth factor-beta (TGF-β). Furthermore, we show for the first time that HIV-1 infection increases surface expression of phosphatidylserine receptor CD91/LRP-1 on human macrophages, thereby leading to a Leishmania uptake by uninfected bystander cells in HIV-1-infected macrophage populations. The more important internalization of parasites is due to interactions between the scavenger receptor CD91/LRP-1 and phosphatidylserine residues exposed at the surface of Leishmania. We determined also that enhanced CD91/LRP-1 surface expression occurs rapidly following HIV-1 infection, and is triggered by the activation of extracellular TGF-β. Thus, these results establish an intricate link between HIV-1 infection, Tat, surface CD91/LRP-1, TGF-β, and enhanced Leishmania phosphatidylserine-mediated phagocytosis.
Highlights
The continuing expansion of the AIDS pandemic has resulted in the establishment of new opportunistic diseases which take advantage of the immunocompromised state prevailing in individuals infected with human immunodeficiency virus type-1 (HIV-1) [1,2,3]
We confirmed the previously reported enhancing effect of Tat and transforming growth factor-beta (TGF-b) on parasite internalization by monocyte-derived macrophages (MDMs) [14], we found that uninfected bystander macrophages respond to soluble factors secreted by their HIV-1-infected cellular counterparts, and that the former cell population greatly accounts for the reported enhancing effect on Leishmania internalization [14]
We demonstrate that uninfected bystander macrophages, through HIV-1-mediated induction of greater surface expression of CD91/ LRP-1 more actively bind phosphatidylserines located at the surface of the parasite, eventually leading to a superior Leishmania entry and replication in the uninfected bystander macrophage subpopulation
Summary
The continuing expansion of the AIDS pandemic has resulted in the establishment of new opportunistic diseases which take advantage of the immunocompromised state prevailing in individuals infected with human immunodeficiency virus type-1 (HIV-1) [1,2,3]. Of these newly recognized opportunistic pathogens, Leishmania has risen to considerable importance over the past decade, in large part due to the increased urbanization of (and HIV-1 access to) rural regions in developing countries, and the cotransmission of this protozoan parasite and HIV-1 through the use of contaminated seringes by intravenous drug users [1,2]. The biphasic life cycle of the parasite alternates between motile promastigotes, which are transmitted by the bite of infected sandflies, and the non-motile amastigotes, the major form of the parasite found in humans, which replicate in intracellular phagosomes of infected monocytes and macrophages
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
