Cholesterol in the Viral Membrane is a Molecular Switch Governing HIV‐1 Env Clustering

Nieto-Garai, Jon Ander; Arboleya, Aroa; Otaegi, Sara; Chojnacki, Jakub; Casas, Josefina; Fabriàs, Gemma; Contreras, F.‐Xabier; Kräusslich, Hans‐Georg; Lorizate, Maier

doi:10.1002/advs.202003468

Cited by 26 publications

(27 citation statements)

References 72 publications

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“…In addition, the entry of HIV-1 requires not only envelope glycoproteins to be redistributed into clusters but also cholesterol in the viral membrane. A residue in the cytoplasmic tail of gp41 directly interacts with cholesterol in the viral cell membrane 47 . There is evidence that the C-terminal of the spike's cytoplasmic tail of SARS-CoV-2 is the key to retention of membrane-mediated spike in the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) 48 .…”

Section: Cholesterol Affects Susceptibility By Influencing the Process Of Membrane Fusionmentioning

confidence: 99%

Possible mechanisms of cholesterol elevation aggravating COVID-19

Tang¹,

Hu²,

Liu³

et al. 2021

Int. J. Med. Sci.

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Importance: Despite the availability of a vaccine against the severe acute respiratory syndromecoronavirus-2 (SARS-CoV-2), humans will have to live with this virus and the after-effects of the coronavirus disease 2019 (COVID-19) infection for a long time. Cholesterol plays an important role in the infection and prognosis of SARS-CoV-2, and the study of its mechanism is of great significance not only for the treatment of COVID-19 but also for research on generic antiviral drugs. Observations: Cholesterol promotes the development of atherosclerosis by activating NLR family pyrin domain containing 3 (NLRP3), and the resulting inflammatory environment indirectly contributes to COVID-19 infection and subsequent deterioration. In in vitro studies, membrane cholesterol increased the number of viral entry sites on the host cell membrane and the number of angiotensin-converting enzyme 2 (ACE2) receptors in the membrane fusion site. Previous studies have shown that the fusion protein of the virus interacts with cholesterol, and the spike protein of SARS-CoV-2 also requires cholesterol to enter the host cells. Cholesterol in blood interacts with the spike protein to promote the entry of spike cells, wherein the scavenger receptor class B type 1 (SR-B1) plays an important role. Because of the cardiovascular protective effects of lipid-lowering therapy and the additional anti-inflammatory effects of lipid-lowering drugs, it is currently recommended to continue lipid-lowering therapy for patients with COVID-19, but the safety of extremely low LDL-C is questionable. Conclusions and Relevance: Cholesterol can indirectly increase the susceptibility of patients to SARS-CoV-2 and increase the risk of death from COVID-19, which are mediated by NLRP3 and atherosclerotic plaques, respectively. Cholesterol present in the host cell membrane, virus, and blood may also directly participate in the virus cell entry process, but the specific mechanism still needs further study. Patients with COVID-19 are recommended to continue lipid-lowering therapy.

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Section: Cholesterol Affects Susceptibility By Influencing the Process Of Membrane Fusionmentioning

confidence: 99%

Possible mechanisms of cholesterol elevation aggravating COVID-19

Tang¹,

Hu²,

Liu³

et al. 2021

Int. J. Med. Sci.

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“…As defined earlier in results, the bulk cell membrane differs from the final budded virus membranes [32], though Env can cluster and associate with cholesterol even in the absence of supporting viral proteins such as Gag [31,33], and cell-presented Env retains enough functionality for cell-cell fusion assays [34][35][36]. Moreover, the survival of Env-presenting cells through KR13 treatment, in contrast to the shriveled and disordered morphology of KR13-treated virions [23], may be in part due to the more heterogeneous composition of cell membranes compared to the more defined and rigid virus membrane.…”

Section: Env-transfected Cells Function As Suitable Models For Evaluating Transformations Of Surface Env and Membranementioning

confidence: 65%

“…The known synthesis and trafficking pathways of Env account for no further processing or modification to the Env trimer between transport to cell surface and budding and assembly into free virions, and should leave Env in the same conformation [30,31]. While the cell membrane as a whole differs from the subset of regions that bud to form virus particles [32], there is evidence for the association of Env's cytoplasmic tail with cholesterol even without supporting viral proteins such as Gag [31,33], and the functionality of cell-cell fusion assays as alternative or complement to virus-cell assays indicates a sufficiently similar Env-membrane complex that retains fusion functionality [34][35][36].…”

Section: Ptt Kr13 Treatment Causes Transformation Of Cell-presented Env Resulting In Membrane Disruption Calcein Leakage and Specific Epimentioning

confidence: 99%

Peptide Triazole Thiol Irreversibly Inactivates Metastable HIV-1 Env by Accessing Conformational Triggers Intrinsic to Virus–Cell Entry

et al. 2021

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KR13, a peptide triazole thiol previously established to inhibit HIV-1 infection and cause virus lysis, was evaluated by flow cytometry against JRFL Env-presenting cells to characterize induced Env and membrane transformations leading to irreversible inactivation. Transiently transfected HEK293T cells were preloaded with calcein dye, treated with KR13 or its thiol-blocked analogue KR13b, fixed, and stained for gp120 (35O22), MPER (10E8), 6-helix-bundle (NC-1), immunodominant loop (50-69), and fusion peptide (VRC34.01). KR13 induced dose-dependent transformations of Env and membrane characterized by transient poration, MPER exposure, and 6-helix-bundle formation (analogous to native fusion events), but also reduced immunodominant loop and fusion peptide exposure. Using a fusion peptide mutant (V504E), we found that KR13 transformation does not require functional fusion peptide for poration. In contrast, simultaneous treatment with fusion inhibitor T20 alongside KR13 prevented membrane poration and MPER exposure, showing that these events require 6-helix-bundle formation. Based on these results, we formulated a model for PTT-induced Env transformation portraying how, in the absence of CD4/co-receptor signaling, PTT may provide alternate means of perturbing the metastable Env-membrane complex, and inducing fusion-like transformation. In turn, the results show that such transformations are intrinsic to Env and can be diverted for irreversible inactivation of the protein complex.

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“…IFITMs have also been reported to restrict HIV-1 fusion and entry by modulation of the lipid bilayer ( 75 ). Biochemical studies have shown membrane fluidity influences HIV-1 Env mobility, stability, and conformation ( 76 , 77 ). Importantly, Env clustering and mobility in lipid membranes is dependent on the EnvCT.…”

Section: Discussionmentioning

confidence: 99%

HIV envelope tail truncation confers resistance to SERINC5 restriction

Haider

Snetkov

Jolly

2021

Proc. Natl. Acad. Sci. U.S.A.

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SERINC5 is a potent lentiviral restriction factor that gets incorporated into nascent virions and inhibits viral fusion and infectivity. The envelope glycoprotein (Env) is a key determinant for SERINC restriction, but many aspects of this relationship remain incompletely understood, and the mechanism of SERINC5 restriction remains unresolved. Here, we have used mutants of HIV-1 and HIV-2 to show that truncation of the Env cytoplasmic tail (ΔCT) confers complete resistance of both viruses to SERINC5 and SERINC3 restriction. Critically, fusion of HIV-1 ΔCT virus was not inhibited by SERINC5 incorporation into virions, providing a mechanism to explain how EnvCT truncation allows escape from restriction. Neutralization and inhibitor assays showed ΔCT viruses have an altered Env conformation and fusion kinetics, suggesting that EnvCT truncation dysregulates the processivity of entry, in turn allowing Env to escape targeting by SERINC5. Furthermore, HIV-1 and HIV-2 ΔCT viruses were also resistant to IFITMs, another entry-targeting family of restriction factors. Notably, while the EnvCT is essential for Env incorporation into HIV-1 virions and spreading infection in T cells, HIV-2 does not require the EnvCT. Here, we reveal a mechanism by which human lentiviruses can evade two potent Env-targeting restriction factors but show key differences in the capacity of HIV-1 and HIV-2 to exploit this. Taken together, this study provides insights into the interplay between HIV and entry-targeting restriction factors, revealing viral plasticity toward mechanisms of escape and a key role for the long lentiviral EnvCT in regulating these processes.

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Cholesterol in the Viral Membrane is a Molecular Switch Governing HIV‐1 Env Clustering

Cited by 26 publications

References 72 publications

Possible mechanisms of cholesterol elevation aggravating COVID-19

Possible mechanisms of cholesterol elevation aggravating COVID-19

Peptide Triazole Thiol Irreversibly Inactivates Metastable HIV-1 Env by Accessing Conformational Triggers Intrinsic to Virus–Cell Entry

HIV envelope tail truncation confers resistance to SERINC5 restriction

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