Abstract
BackgroundMicroglia are one of the main cell types to be productively infected by HIV-1 in the central nervous system (CNS). Leukotriene B4 (LTB4) and cysteinyl-leukotrienes such as LTC4 are some of the proinflammatory molecules produced in infected individuals that contribute to neuroinflammation. We therefore sought to investigate the role of leukotrienes (LTs) in HIV-1 infection of microglial cells.MethodsTo evaluate the role of LTs on HIV-1 infection in the CNS, monocyte-derived microglial-like cells (MDMis) were utilized in this study. Leukotriene-treated MDMis were infected with either fully replicative brain-derived HIV-1 isolates (YU2) or R5-tropic luciferase-encoding particles in order to assess viral production and expression. The efficacy of various steps of the replication cycle was evaluated by means of p24 quantification by ELISA, luciferase activity determination and quantitative real-time polymerase chain reaction (RT-PCR).ResultsWe report in this study that virus replication is reduced upon treatment of MDMis with LTB4 and LTC4. Additional experiments indicate that these proinflammatory molecules alter the pH-independent entry and early post-fusion events of the viral life cycle. Indeed, LT treatment induced a diminution in integrated proviral DNA while reverse-transcribed viral products remained unaffected. Furthermore, decreased C-C chemokine receptor type 5 (CCR5) surface expression was observed in LT-treated MDMis. Finally, the effect of LTs on HIV-1 infection in MDMis appears to be mediated partly via a signal transduction pathway involving protein kinase C.ConclusionsThese data show for the first time that LTs influence microglial cell infection by HIV-1, and may be a factor in the control of viral load in the CNS.
Highlights
Microglia are one of the main cell types to be productively infected by human immunodeficiency virus type 1 (HIV-1) in the central nervous system (CNS)
The results of this study indicate that Leukotriene B4 (LTB4) and LTC4 inhibit some early events of the HIV-1 replication cycle in monocyte-derived microglial-like cells (MDMis) and that this effect relies on protein kinase C (PKC)
If confirmed in vivo, what physiological relevance would be presented by the observed attenuation of HIV-1 infection by LTs? In the postHAART era, individuals still show mild symptoms of neuroinflammation associated to HIV-1 infection
Summary
Microglia are one of the main cell types to be productively infected by HIV-1 in the central nervous system (CNS). Infection of the central nervous system (CNS) by human immunodeficiency virus type 1 (HIV-1) causes neurotoxicity and inflammatory disorders such as encephalitis and associated neurocognitive deficits [1]. It has been postulated that elevated concentrations of the bacterial endotoxin lipopolysaccharide (LPS) in the plasma of HIV-1-infected patients, in combination with several cytokines, viral proteins and eicosanoid lipid mediators, increase permeability of the BBB, facilitating invasion of HIV-1 into the CNS [11,14,15]. There, perivascular macrophages and microglia, along with astrocytes to some extent, are the cells permissive to HIV-1 infection; they act as long-lived viral reservoirs despite antiviral therapies [6,16,17,18,19,20]
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