Abstract
The Nef protein acts as critical factor during HIV pathogenesis by increasing HIV replication in vivo via the modulation of host cell vesicle transport and signal transduction processes. Recent studies suggested that Nef alters formation and function of immunological synapses (IS), thereby modulating exogenous T-cell receptor (TCR) stimulation to balance between partial T cell activation required for HIV-1 spread and prevention of activation induced cell death. Alterations of IS function by Nef include interference with cell spreading and actin polymerization upon TCR engagement, a pronounced intracellular accumulation of the Src kinase Lck and its reduced IS recruitment. Here we use a combination of Nef mutagenesis and pharmacological inhibition to analyze the relative contribution of these effects to Nef mediated alterations of IS organization and function on TCR stimulatory surfaces. Inhibition of actin polymerization and IS recruitment of Lck were governed by identical Nef determinants and correlated well with Nef's association with Pak2 kinase activity. In contrast, Nef mediated Lck endosomal accumulation was separable from these effects, occurred independently of Pak2, required integrity of the microtubule rather than the actin filament system and thus represents a distinct Nef activity. Finally, reduction of TCR signal transmission by Nef was linked to altered actin remodeling and Lck IS recruitment but did not require endosomal Lck rerouting. Thus, Nef affects IS function via multiple independent mechanisms to optimize virus replication in the infected host.
Highlights
The activation state of target cells often dictates the efficacy by which virus pathogens spread in the infected host
Jurkat T lymphocytes were transiently transfected with expression plasmids for GFP (GFP) or a GFP fusion protein of Nef from Human Immunodeficiency Virus (HIV)-1 SF2 (Nef.GFP) that is functionally analogous to non fusion Nef [11,22] and the intracellulular localization of endogenous Lck was analyzed by confocal microscopy (Fig. 1A)
The HIV-1 pathogenicity factor Nef affects several processes that are triggered upon engagement of the T cell receptor (TCR), including actin remodeling and recruitment of Lck to stimulatory contacts
Summary
The activation state of target cells often dictates the efficacy by which virus pathogens spread in the infected host. Host cell death, induced by expression of viral gene products or hyperactivation of the cells, imposes an additional limitation to virus spread [2]. A large body of evidence suggests that Nef profoundly manipulates HIV target cells by altering a variety of signal transduction and protein sorting processes. With respect to T lymphocyte infection, Nef is known to affect T cell receptor (TCR) signaling transduction. Several reports indicate that, in the context of exogenous TCR activation, Nef expression causes a reduction of signal transmission to prevent cell hyperactivation to prolong the lifespan of infected cells [13,14,15]
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