Sphingomyelin and Cholesterol Promote HIV-1 gp41 Pretransmembrane Sequence Surface Aggregation and Membrane Restructuring

Sáez‐Cirión, Asier; Nir, Shlomo; Lorizate, Maier; Agirre, Aitziber; Cruz, Antonio; Pérez‐Gil, Jesús; Nieva, José L.

doi:10.1074/jbc.m202255200

Cited by 122 publications

(146 citation statements)

References 68 publications

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“…Several studies have examined the effect of cholesterol incorporation in lipid vesicles on peptide-mediated leakage of vesicle contents. Although some studies report that inclusion of cholesterol in membranes reduces leakage (55,77), other studies report increased activity (78). The latter is observed when cholesterol is included along with other lipid molecules, especially sphingomyelin.…”

Section: Discussionmentioning

confidence: 99%

The Aromatic Domain of the Coronavirus Class I Viral Fusion Protein Induces Membrane Permeabilization: Putative Role during Viral Entry

et al. 2004

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Coronavirus (CoV) entry is mediated by the viral spike (S) glycoprotein, a class I viral fusion protein. During viral and target cell membrane fusion, the heptad repeat (HR) regions of the S2 subunit assume a trimer-of-hairpins structure, positioning the fusion peptide in close proximity to the C-terminal region of the ectodomain. The formation of this structure appears to drive apposition and subsequent fusion of viral and target cell membranes; however, the exact mechanism is unclear. Here, we characterize an aromatic amino acid rich region within the ectodomain of the S2 subunit that both partitions into lipid membranes and has the capacity to perturb lipid vesicle integrity. Circular dichroism analysis indicated that peptides analogous to the aromatic domains of the severe acute respiratory syndrome (SARS)-CoV, mouse hepatitis virus (MHV) and the human CoV OC43 S2 subunits, did not have a propensity for a defined secondary structure. These peptides strongly partitioned into lipid membranes and induced lipid vesicle permeabilization at peptide/lipid ratios of 1:100 in two independent leakage assays. Thus, partitioning of the peptides into the lipid interface is sufficient to disorganize membrane integrity. Our study of the S2 aromatic domain of three CoVs provides supportive evidence for a functional role of this region. We propose that, when aligned with the fusion peptide and transmembrane domains during membrane apposition, the aromatic domain of the CoV S protein functions to perturb the target cell membrane and provides a continuous track of hydrophobic surface, resulting in lipid-membrane fusion and subsequent viral nucleocapsid entry.

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Section: Discussionmentioning

confidence: 99%

The Aromatic Domain of the Coronavirus Class I Viral Fusion Protein Induces Membrane Permeabilization: Putative Role during Viral Entry

et al. 2004

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“…When PC, SPM and Chol were combined to emulate conditions of liquid ordered (Lo)-liquid disordered (Ld) lipid domain segregation, putatively existing at the external membrane monolayer of HI virion, high levels of PreTM surface self-aggregation, concomitant to an enhancement in fusion and lytic activities were observed at low peptide doses (in the order of 1:1000 peptide-to-lipid ratio). Conditions described to disturb occurrence of lateral separation of Lo-Ld lipid phases in these systems, reproduced the high peptide-dose requirements for leakage as found in pure PC vesicles and inhibited fusion [77]. Thus, the lipid dependence observed in the vesicular systems suggests a functional role for MPER membrane activity in destabilizing the envelope lipid bilayer architecture at the loci of fusion.…”

Section: Mper Structure-functionmentioning

confidence: 62%

“…The membrane-activity of MPER-derived peptides detected in vitro provides experimental evidence to support a functional role for this gp41 MTR during fusion [18,25,77]. Characterization of the HIV-1 lipidome has revealed high levels of cholesterol (Chol) and sphingomyelin (SPM) [78][79][80], an observation that correlates with the selectivity for specific segregated membrane regions through which virions emerge during maturation [81,82].…”

Section: Mper Structure-functionmentioning

confidence: 99%

“…Characterization of the HIV-1 lipidome has revealed high levels of cholesterol (Chol) and sphingomyelin (SPM) [78][79][80], an observation that correlates with the selectivity for specific segregated membrane regions through which virions emerge during maturation [81,82]. The membrane activity of the MPER-derived peptide 664 DKWASLWNWFNITNWLWYIK 683 (PreTM) was modulated by these envelope lipids [77]. Specifically, Chol greatly stimulated PreTM's lytic activity and activated its fusogenic capacity [77].…”

Section: Mper Structure-functionmentioning

confidence: 99%

“…The membrane activity of the MPER-derived peptide 664 DKWASLWNWFNITNWLWYIK 683 (PreTM) was modulated by these envelope lipids [77]. Specifically, Chol greatly stimulated PreTM's lytic activity and activated its fusogenic capacity [77]. When PC, SPM and Chol were combined to emulate conditions of liquid ordered (Lo)-liquid disordered (Ld) lipid domain segregation, putatively existing at the external membrane monolayer of HI virion, high levels of PreTM surface self-aggregation, concomitant to an enhancement in fusion and lytic activities were observed at low peptide doses (in the order of 1:1000 peptide-to-lipid ratio).…”

Section: Mper Structure-functionmentioning

confidence: 99%

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Membrane-Transferring Regions of gp41 as Targets for HIV-1 Fusion Inhibition and Viral Neutralization

Huarte

Lorizate²,

Pérez‐Payá³

et al. 2011

CTMC

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Abstract:The fusogenic function of HIV-1 gp41 transmembrane Env subunit relies on two different kinds of structural elements: i) a collapsible ectodomain structure (the hairpin or six-helix bundle) that opens and closes, and ii) two membrane-transferring regions (MTRs), the fusion peptide (FP) and the membrane-proximal external region (MPER), which ensure coupling of hairpin closure to apposition and fusion of cell and viral membranes. The isolation of naturally produced short peptides and neutralizing IgG-s, that interact with FP and MPER, respectively, and block viral infection, suggests that these conserved regions might represent useful targets for clinical intervention.Furthermore, MTR-derived peptides have been shown to be membrane-active. Here, it is discussed the potential use of these molecules and how the analysis of their membrane activity in vitro could contribute to the development of HIV fusion inhibitors and effective immunogens.2

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Role of Protein–Lipid Interactions in Viral Entry

et al. 2022

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description, lipid raft has generated equal levels of enthusiasm and controversy in the research community. [1,5] This controversy arises from the lack of suitable tools to unravel the existence of such nanostructures in living organisms at resting state. [5][6][7] Despite this long-lasting controversy, what we can ascertain is that the alteration of membrane physicochemical properties such as curvature, elasticity, or fluidity can have a direct effect in membrane protein properties and function, and finally, in viral infectivity. [8,9] Therefore, viruses are a clear example of how cell membrane physicochemical properties are of high evolutionary relevance, as they are exploited by these pathogens in the infection cycle.Viruses are obligatory intracellular parasites that are simple in structure and compositions but hijack the host cellular mechanisms to ensure viral infection and progression. Naked viruses contain a genome encased in a protein shell called capsid, which in the case of enveloped viruses is surrounded by a host cell-derived lipid membrane.The viral entry process is a complex and determinant step necessary for establishing viral infection since viral replication occurs exclusively inside the host cell. It compiles sequential events starting from viral attachment to the host cell to penetration to cell cytoplasm. Attachment of virus particles to host cell molecules that act as cellular receptors, such as lipid or proteins, determines cellular tropism and, therefore, specificity. After adhesion, virus penetration occurs either at the plasma membrane or the endomembrane system upon environment acidification. For enveloped viruses, transfer is achieved by fusion of the viral and cellular membranes. The fusion event is catalyzed by the fusion protein, which engages to receptor(s) triggering a conformational change necessary to induce fusion between both membranes. This conformational change can occur in the plasma membrane at neutral pH or in the endosomal membranes upon endosome acidification. In the case of naked viruses, endosome acidification is needed to trigger conformational changes of the viral protein required in order to transiently destabilize the target membrane without compromising its overall integrity. [10][11][12] Virus entry is not a passive process, since productive entry, and downstream events rely on normal cellular processes including endocytosis (clathrin-mediated, clathrin-independent pathway, raft-dependent pathways, and macropinocytosis), vesicular trafficking, and membrane fusion, all of which involve dynamic membrane processes. [10,13] The fact that lipid interactions, including membrane envelopment, membrane fusion, and membrane remodeling are crucial for successful replication of many viruses triggered studies on compounds that either affect lipid biosynthesis,The viral entry consists of several sequential events that ensure the attachment of the virus to the host cell and the introduction of its genetic material for the continuation of the replication cycle. Both cellular an...

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Sphingomyelin and Cholesterol Promote HIV-1 gp41 Pretransmembrane Sequence Surface Aggregation and Membrane Restructuring

Cited by 122 publications

References 68 publications

The Aromatic Domain of the Coronavirus Class I Viral Fusion Protein Induces Membrane Permeabilization: Putative Role during Viral Entry

The Aromatic Domain of the Coronavirus Class I Viral Fusion Protein Induces Membrane Permeabilization: Putative Role during Viral Entry

Membrane-Transferring Regions of gp41 as Targets for HIV-1 Fusion Inhibition and Viral Neutralization

Role of Protein–Lipid Interactions in Viral Entry

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