Abstract
BackgroundThe Nef protein of Human Immunodeficiency Viruses optimizes viral spread in the infected host by manipulating cellular transport and signal transduction machineries. Nef also boosts the infectivity of HIV particles by an unknown mechanism. Recent studies suggested a correlation between the association of Nef with lipid raft microdomains and its positive effects on virion infectivity. Furthermore, the lipidome analysis of HIV-1 particles revealed a marked enrichment of classical raft lipids and thus identified HIV-1 virions as an example for naturally occurring membrane microdomains. Since Nef modulates the protein composition and function of membrane microdomains we tested here if Nef also has the propensity to alter microdomain lipid composition.ResultsQuantitative mass spectrometric lipidome analysis of highly purified HIV-1 particles revealed that the presence of Nef during virus production from T lymphocytes enforced their raft character via a significant reduction of polyunsaturated phosphatidylcholine species and a specific enrichment of sphingomyelin. In contrast, Nef did not significantly affect virion levels of phosphoglycerolipids or cholesterol. The observed alterations in virion lipid composition were insufficient to mediate Nef's effect on particle infectivity and Nef augmented virion infectivity independently of whether virus entry was targeted to or excluded from membrane microdomains. However, altered lipid compositions similar to those observed in virions were also detected in detergent-resistant membrane preparations of virus producing cells.ConclusionNef alters not only the proteome but also the lipid composition of host cell microdomains. This novel activity represents a previously unrecognized mechanism by which Nef could manipulate HIV-1 target cells to facilitate virus propagation in vivo.
Highlights
The Nef protein of Human Immunodeficiency Viruses optimizes viral spread in the infected host by manipulating cellular transport and signal transduction machineries
Disease progression in individuals infected with nef deficient viruses is at least significantly delayed [1,2,3]. These effects are thought to mirror independent activities of Nef that prevent immune recognition of virally infected cells and directly boost the replicative potential of HIV [4,5]. To achieve such optimized spread in the infected host, Nef manipulates a variety of transport and signal transduction processes in cells infected by HIV1
We generated a corresponding proviral HIV-1 clone that encodes for a palmitoylated and detergent resistant membrane microdomains (DRMs) enriched Nef variant [20,21] (PalmNef)
Summary
The Nef protein of Human Immunodeficiency Viruses optimizes viral spread in the infected host by manipulating cellular transport and signal transduction machineries. Disease progression in individuals infected with nef deficient viruses is at least significantly delayed [1,2,3] These effects are thought to mirror independent activities of Nef that prevent immune recognition of virally infected cells and directly boost the replicative potential of HIV [4,5]. To achieve such optimized spread in the infected host, Nef manipulates a variety of transport and signal transduction processes in cells infected by HIV1. During production of progeny virus, Nef augments the intrinsic infectivity of cell-free HIV particles by a factor 5– 10 via a poorly characterized mechanism [15,16,17]
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