Virion-associated cholesterol is critical for the maintenance of HIV-1 structure and infectivity

Campbell, Sally; Crowe, Suzanne; Mak, Johnson

doi:10.1097/00002030-200211220-00004

Cited by 127 publications

(145 citation statements)

References 48 publications

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“…Thus, cholesterol may enhance fusion by facilitating the formation of the complex between gp120, CD4, and CXCR4. This interpretation is supported by recent reports that cholesterol is essential for (17,18) and that Nef increases the entry of HIV into cells (40). Importantly, the deletion or point mutation of the cholesterolbinding site in gp41 disrupts significantly the formation of giant cell syncytia (41,42).…”

Section: Discussionmentioning

confidence: 52%

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Nef increases the synthesis of and transports cholesterol to lipid rafts and HIV-1 progeny virions

Zheng

Plemenitaš

Fielding

et al. 2003

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

160

169

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HIV buds from lipid rafts and requires cholesterol for its egress from and entry into cells. Viral accessory protein Nef plays a major role in this process. In this study, it not only increased the biosynthesis of lipid rafts and viral particles with newly synthesized cholesterol, but also enriched them. Furthermore, via the consensus cholesterol recognition motif at its C terminus, Nef bound cholesterol. When this sequence was mutated, Nef became unable to transport newly synthesized cholesterol into lipid rafts and viral particles. Interestingly, although its levels in lipid rafts were not affected, this mutant Nef protein was poorly incorporated into viral particles, and viral infectivity decreased dramatically. Thus, Nef also transports newly synthesized cholesterol to the site of viral budding. As such, it provides essential building blocks for the formation of viruses that replicate optimally in the host.T he negative effector (Nef) protein from human and simian immunodeficiency viruses is a membrane-associated myristoylated protein that measures 27-35 kDa (1-3). It is critical for high levels of viremia and the progression to AIDS in infected humans (4) and monkeys (5). This phenotype has been correlated with increased viral infectivity in vitro, which provides a convenient assay to study its effects in cultured cells (6, 7). This infectivity enhancement can be dependent on or independent of CD4 that serves as the receptor for viral entry. In the former case, Nef decreases the expression of CD4 on the cell surface, thereby increasing the incorporation of viral envelope (Env) proteins into virions (8). In the latter case, Nef still increases viral infectivity significantly (9, 10). This enhancement cannot be complemented by the expression of Nef in target cells. Although no differences were identified in major structural components and morphology between wild-type and mutant virions that lack Nef, ⌬Nef viruses displayed less efficient reverse transcription in target cells. Because Nef is expressed abundantly at the earliest stages of the viral replicative cycle (11), Nef could affect viral morphogenesis and budding to increase the fitness of the virus and facilitate its entry into recipient cells.Lipid rafts, also known as detergent-resistant membranes (DRMs), are microdomains in the plasma membrane that are enriched in sphingolipids, cholesterol, and a subset of cellular proteins (12, 13). Two major pathways contribute to cholesterol homeostasis in mammalian cells (14). Most exogenous cholesterol, which originates from low-density lipoproteins, is internalized via coated pits and distributed to intracellular pools. In addition, cells can synthesize cholesterol in their endoplasmic reticulum when the uptake of exogenous cholesterol is blocked. The newly synthesized cholesterol is then transported into the Golgi apparatus and distributed to various intracellular pools. Because cellular cholesterol is compartmentalized, some sites (including DRMs) are enriched in this newly synthesized lipid (15,16).Previous...

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Section: Discussionmentioning

confidence: 52%

“…Previous studies determined that cholesterol is essential for the egress from and entry of HIV into cells (17)(18)(19)(20)(21)(22)(23). Indeed, Nef not only colocalized with viral structural components in the DRMs (24,25), but its ability to increase viral infectivity depended on cholesterol (25).…”

mentioning

confidence: 97%

Nef increases the synthesis of and transports cholesterol to lipid rafts and HIV-1 progeny virions

Zheng

Plemenitaš

Fielding

et al. 2003

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

160

169

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“…Phosphatidylcholine accounts to 75% of total phospholipid [85] GP Viral envelopes are enriched in sphingomyelin [8,86] SP Envelope cholesterol is critical for structure and infectivity [87][88][89] ST 2 Phosphatidylserine stimulates entry of enveloped viruses [90,91] Mannose receptor binds to the ManLAM mannose caps of mycobacteria and mediates phagocytosis [92] GPI anchored proteins (host [35,36] and parasite [37] …”

Section: Glmentioning

confidence: 99%

Lipidomics of host–pathogen interactions

Wenk

2006

FEBS Letters

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The cell biology of intracellular pathogens (viruses, bacteria, eukaryotic parasites) has provided us with molecular information of host-pathogen interactions. As a result it is becoming increasingly evident that lipids play important roles at various stages of host-pathogen interactions. They act in first line recognition and host cell signaling during pathogen docking, invasion and intracellular trafficking. Lipid metabolism is a housekeeping function in energy homeostasis and biomembrane synthesis during pathogen replication and persistence. Lipids of enormous chemical diversity play roles as immunomodulatory factors. Thus, novel biochemical analytics in combination with cell and molecular biology are a promising recipe for dissecting the roles of lipids in host-pathogen interactions.

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“…Alde batetik, lipido-estalki hau garrantzi handiko egitu-GIBaren aurkako txertoaren bila ra-osagaia da eta beste aldetik, infekzioa gerta dadin, ezinbestekoa da bere osaketa espezifikoari eustea. Oso aipatzekoa da lipido-estalki honek duen % 45eko kolesterol kontzentrazioa [11], infekzioa murrizten baita kolesterol kontzentrazioa behera egiten badu [12].…”

Section: Gib Birusaunclassified

GIBaren aurkako txertoaren bila

Torralba¹,

Goikoetxea²,

Apellániz

2017

EKAIA

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Laburpena: GIB birusa, giza historian zehar gertatu den pandemiarik hilgarrienetariko baten eragilea da, HIESa alegia. Nahiz eta azken urteetan HAART terapia antirretrobiralari esker heriotza tasa asko murriztu den, infekzio berrien kopurua etengabe emendatzen ari da. Hori dela eta, badirudi pandemiari azkenik amaiera eman ahal izateko txerto prebentibo baten garapena izan daitekeela jokaera eraginkorrena. Hala ere, birusak garatu dituen estrategia natural desberdinek eta immunizazioz sortu nahi diren antigorputz neutralizatzaileen ezaugarri bereziek oso zaila egiten dute infekziotik babestuko lukeen txertoaren garapena. RV144 entsegu klinikoaren eraginkortasun apalek eta espektro zabaleko antigorputz neutralizatzaileekin immunizazio pasiboz lorturiko emaitzek iradokitzen dute hurbilago gaudela txerto eraginkor baten garapena lortzetik. Orain arte hainbat txerto mota erabili diren arren, emaitza onik ez da lortu. Hala ere, sakon aztertzen ari da bai immunogeno naturalen egitura, bai immunogenoak ezagutzen dituzten antigorputzen egitura, eta badirudi, besteak beste, ikerketa horiek bide berriak irekiko dituztela txerto berrien diseinuan. Hitz gakoak: GIB, txertoa, antigorputz neutralizatzaileak, Env fusio-glukoproteina.Abstract: HIV is the causative agent of one of the most lethal pandemics in human history, AIDS. Although in recent years HAART therapy has considerably reduced death rate, new infections keep arising. Therefore, a preventive vaccine remains the most promising tool to end the pandemic. However, the virus has developed many natural strategies to evade the immune system and, moreover, the special characteristics of the neutralizing antibodies that a vaccine aims to elicit, makes vaccine design extremely challenging. The efficiency of the RV144 clinical trial and the promising results obtained by passive immunization with broadly neutralizing antibodies suggest that the objective of obtaining an effective vaccine is closer. Until now, a myriad of vaccine strategies have been attempted but the expected results have not been yet ob-EKAIA 32.indd 7 EKAIA 32.indd 7

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Virion-associated cholesterol is critical for the maintenance of HIV-1 structure and infectivity

Cited by 127 publications

References 48 publications

Nef increases the synthesis of and transports cholesterol to lipid rafts and HIV-1 progeny virions

Nef increases the synthesis of and transports cholesterol to lipid rafts and HIV-1 progeny virions

Lipidomics of host–pathogen interactions

GIBaren aurkako txertoaren bila

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