Envelope glycoprotein mobility on HIV-1 particles depends on the virus maturation state

Chojnacki, Jakub; Waithe, Dominic; Carravilla, Pablo; Huarte, Nerea; Galiani, Silvia; Enderlein, Joerg; Eggeling, Christian

doi:10.1038/s41467-017-00515-6

Cited by 95 publications

(145 citation statements)

References 40 publications

Supporting

Mentioning

124

Contrasting

Order By: Relevance

“…It is possible that in our simulations with 2 gp41 trimers, because the trimers were placed diametrically opposite each other, they never approached such close separations within our simulation time. Env spikes of a mature HIV-1 virion have been observed to form small clusters (17), possibly to drive fusion. To the best of our knowledge, we report for the first time the minimum distance of approach between two gp41 trimeric units that is essential to initiate inter-membrane lipid contact and hence fusion.…”

Section: Resultsmentioning

confidence: 99%

Concerted interactions between multiple gp41 trimers and the target cell lipidome may be required for HIV-1 entry

Gorai

Sahoo

Srivastava

et al. 2020

Preprint

View full text Add to dashboard Cite

The HIV-1 envelope glycoprotein gp41 mediates the fusion between viral and host cell membranes leading to virus entry and target cell infection. Despite years of research, important aspects of this process such as the number of gp41 trimers involved and how they orchestrate the rearrangement of the lipids in the apposed membranes along the fusion pathway remain obscure. To elucidate these molecular underpinnings, we performed coarse-grained molecular dynamics simulations of HIV-1 virions pinned to the CD4 T cell membrane by different numbers of gp41 trimers. We built realistic cell and viral membranes by mimicking their respective lipid compositions. We found that a single gp41 was inadequate for mediating fusion. Lipid mixing between membranes, indicating the onset of fusion, was efficient when 3 or more gp41 trimers pinned the membranes. The gp41 trimers interacted strongly with many different lipids in the host cell membrane, triggering lipid configurational rearrangements, exchange, and mixing. Simpler membranes, comprising fewer lipid types, displayed strong resistance to fusion, revealing the crucial role of the lipidomes in HIV-1 entry. Performing simulations at different temperatures, we estimated the free energy barrier to lipid mixing, and hence membrane stalk formation, with 4 tethering gp41 trimers to be ∼6.2 kcal/mol, a >4-fold reduction over estimates without gp41. Together, these findings present molecular-level, quantitative insights into the early stages of gp41-mediated HIV-1 entry. Preventing the requisite gp41 molecules from tethering the membranes or altering membrane lipid compositions may be potential intervention strategies. SIGNIFICANCEInteractions between viral envelope proteins and host cell surface receptors leading to HIV-1 entry are well studied, however the role of membrane lipids remains obscure, although entry hinges on lipid mixing and the fusion of viral and cell membranes. We performed detailed simulations of HIV-1 and target cell membranes tethered by viral gp41 trimeric proteins to elucidate the proteo-lipidic contributions to viral entry. We found that the cooperative effects of multiple gp41 trimers and natural lipidomes of the membranes facilitate membrane fusion. The functional domains of gp41 altered local lipid concentrations, reduced membrane repulsions, and facilitated inter-membrane lipid mixing. These molecular-level insights offer a glimpse of the cryptic mechanisms underlying HIV-1 entry and suggest new interventions to combat HIV-1 infection.

show abstract

Section: Resultsmentioning

confidence: 99%

Concerted interactions between multiple gp41 trimers and the target cell lipidome may be required for HIV-1 entry

Gorai

Sahoo

Srivastava

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…It is enriched in sphingomyelins (SPMs), glycosphingolipids, cholesterol (Chol), and phosphoinositides, such as phosphatidylinositol (4,5) bisphosphate lipid (PI(4,5)P2) (1,2) and characterized by highly ordered, i.e. densely packed, lipid organization (1,3) . This raises the question on how virus components interact with lipids in the plasma membrane of the host cells to gather such specific lipid environment during assembly.…”

Section: Introductionmentioning

confidence: 99%

HIV-1 Gag specifically restricts PI(4,5)P2 and cholesterol mobility in living cells creating a nanodomain platform for virus assembly

Favard

Chojnacki

Mérida

et al. 2019

Preprint

View full text Add to dashboard Cite

HIV-1 Gag protein self-assembles at the plasma membrane of infected cells for viral particle formation. Gag targets lipids, mainly the phosphatidylinositol (4, 5) bisphosphate, at the inner leaflet of this membrane. Here, we address the question whether Gag is able to trap specifically PI(4,5)P2 or other lipids during HIV-1 assembly in the host CD4+ T lymphocytes. Lipid dynamics within and away from HIV-1 assembly sites was determined using super-resolution STED microscopy coupled with scanning Fluorescence Correlation Spectroscopy in living T cells. Analysis of HIV-1 infected cells revealed that, upon assembly, HIV-1 is able to specifically trap PI(4,5)P2, and cholesterol, but not phosphatidylethanolamine or sphingomyelin. Furthermore, our data show that Gag is the main driving force to restrict PI(4,5)P2 and cholesterol mobility at the cell plasma membrane. This is first direct evidence showing that HIV-1 creates its own specific lipid environment by selectively recruiting PI(4,5)P2 and cholesterol, as a membrane nano-platform for virus assembly.

show abstract

“…Fluorescence correlation spectroscopy (FCS) is such a spectroscopic tool used to measure molecular mobility in membranes 15,16 , which is an important parameter to understand the molecular dynamics in cells [15][16][17][18][19][20] . Combination of STED with FCS (STED-FCS) has been used extensively to address the nanoscale membrane structure [21][22][23][24][25][26][27] . Recently STED has also been combined with spectral imaging and polarity-sensitive probes to quantitatively study the nanoscale physiochemical properties of the membrane 11 .…”

Section: Introductionmentioning

confidence: 99%

z-STED imaging and spectroscopy to investigate nanoscale membrane structure and dynamics

Barbotin

Urbančič

Galiani

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

AbstractSuper-resolution STED microcopy provides optical resolution beyond the diffraction limit. The resolution can be increased laterally (xy/2D) or axially (z/3D). 2D STED has been extensively used to elucidate the nanoscale membrane structure and dynamics, via imaging or combined with spectroscopy techniques such as fluorescence correlation spectroscopy (FCS) and spectral imaging. On the contrary, z-STED has not been used in this context. Here, we show that a combination of z-STED with FCS or spectral imaging enables us to see previously unobservable aspects of cellular membranes. We show that thanks to an axial resolution of approximately 100 nm, z-STED can be used to distinguish axially close-by membranes, early endocytic vesicles or tubular membrane structures. Combination of z-STED with FCS and spectral imaging showed diffusion dynamics and lipid organization in these structures, respectively.

show abstract

Envelope glycoprotein mobility on HIV-1 particles depends on the virus maturation state

Cited by 95 publications

References 40 publications

Concerted interactions between multiple gp41 trimers and the target cell lipidome may be required for HIV-1 entry

Concerted interactions between multiple gp41 trimers and the target cell lipidome may be required for HIV-1 entry

HIV-1 Gag specifically restricts PI(4,5)P2 and cholesterol mobility in living cells creating a nanodomain platform for virus assembly

z-STED imaging and spectroscopy to investigate nanoscale membrane structure and dynamics

Contact Info

Product

Resources

About