Depletion of Cellular Cholesterol Inhibits Membrane Binding and Higher-order Multimerization of Human Immunodeficiency Virus Type 1 Gag

Overview

Journal Virology

Specialty Microbiology

Date 2006 Nov 11

PMID 17095032

Citations 64

Authors

Akira Ono

Abdul A Waheed

Eric O Freed

Affiliations

Soon will be listed here.

Abstract

Recent studies have suggested that the plasma membrane contains cholesterol-enriched microdomains known as lipid rafts. HIV-1 Gag binds raft-rich regions of the plasma membrane, and cholesterol depletion impairs HIV-1 particle production. In this study, we sought to define the block imposed by cholesterol depletion. We observed that membrane binding and higher-order multimerization of Gag were markedly reduced upon cholesterol depletion. Fusing to Gag a highly efficient, heterologous membrane-binding sequence reversed the defects in Gag-membrane binding and multimerization caused by cholesterol depletion, indicating that the impact of reducing the membrane cholesterol content on Gag-membrane binding and multimerization can be circumvented by increasing the affinity of Gag for membrane. Virus release efficiency of this Gag derivative was minimally affected by cholesterol depletion. Altogether, these results are consistent with the hypothesis that cholesterol-enriched membrane microdomains promote HIV-1 particle production by facilitating both Gag-membrane binding and Gag multimerization.

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References

Saad J, Miller J, Tai J, Kim A, Ghanam R, Summers M . Structural basis for targeting HIV-1 Gag proteins to the plasma membrane for virus assembly. Proc Natl Acad Sci U S A. 2006; 103(30):11364-9. PMC: 1544092. DOI: 10.1073/pnas.0602818103. View

Yang L, Ratner L . Interaction of HIV-1 gag and membranes in a cell-free system. Virology. 2002; 302(1):164-73. DOI: 10.1006/viro.2002.1532. View

Nydegger S, Foti M, Derdowski A, Spearman P, Thali M . HIV-1 egress is gated through late endosomal membranes. Traffic. 2003; 4(12):902-10. DOI: 10.1046/j.1600-0854.2003.00145.x. View

Panchal R, Ruthel G, Kenny T, Kallstrom G, Lane D, Badie S . In vivo oligomerization and raft localization of Ebola virus protein VP40 during vesicular budding. Proc Natl Acad Sci U S A. 2003; 100(26):15936-41. PMC: 307671. DOI: 10.1073/pnas.2533915100. View

Dalton A, Murray P, Murray D, Vogt V . Biochemical characterization of rous sarcoma virus MA protein interaction with membranes. J Virol. 2005; 79(10):6227-38. PMC: 1091718. DOI: 10.1128/JVI.79.10.6227-6238.2005. View

Sandefur S, Varthakavi V, Spearman P . The I domain is required for efficient plasma membrane binding of human immunodeficiency virus type 1 Pr55Gag. J Virol. 1998; 72(4):2723-32. PMC: 109715. DOI: 10.1128/JVI.72.4.2723-2732.1998. View

Rodal S, Skretting G, Garred O, Vilhardt F, van Deurs B, Sandvig K . Extraction of cholesterol with methyl-beta-cyclodextrin perturbs formation of clathrin-coated endocytic vesicles. Mol Biol Cell. 1999; 10(4):961-74. PMC: 25220. DOI: 10.1091/mbc.10.4.961. View

Ono A, Waheed A, Joshi A, Freed E . Association of human immunodeficiency virus type 1 gag with membrane does not require highly basic sequences in the nucleocapsid: use of a novel Gag multimerization assay. J Virol. 2005; 79(22):14131-40. PMC: 1280195. DOI: 10.1128/JVI.79.22.14131-14140.2005. View

Yee J, Friedmann T, Burns J . Generation of high-titer pseudotyped retroviral vectors with very broad host range. Methods Cell Biol. 1994; 43 Pt A:99-112. DOI: 10.1016/s0091-679x(08)60600-7. View

10.

Pelchen-Matthews A, Kramer B, Marsh M . Infectious HIV-1 assembles in late endosomes in primary macrophages. J Cell Biol. 2003; 162(3):443-55. PMC: 2172706. DOI: 10.1083/jcb.200304008. View

11.

Perez-Caballero D, Hatziioannou T, Martin-Serrano J, Bieniasz P . Human immunodeficiency virus type 1 matrix inhibits and confers cooperativity on gag precursor-membrane interactions. J Virol. 2004; 78(17):9560-3. PMC: 506924. DOI: 10.1128/JVI.78.17.9560-9563.2004. View

12.

Adamson C, Jones I . The molecular basis of HIV capsid assembly--five years of progress. Rev Med Virol. 2004; 14(2):107-21. DOI: 10.1002/rmv.418. View

13.

Huang M, Orenstein J, Martin M, Freed E . p6Gag is required for particle production from full-length human immunodeficiency virus type 1 molecular clones expressing protease. J Virol. 1995; 69(11):6810-8. PMC: 189593. DOI: 10.1128/JVI.69.11.6810-6818.1995. View

14.

Paillart J, Gottlinger H . Opposing effects of human immunodeficiency virus type 1 matrix mutations support a myristyl switch model of gag membrane targeting. J Virol. 1999; 73(4):2604-12. PMC: 104015. DOI: 10.1128/JVI.73.4.2604-2612.1999. View

15.

Perlman M, Resh M . Identification of an intracellular trafficking and assembly pathway for HIV-1 gag. Traffic. 2006; 7(6):731-45. DOI: 10.1111/j.1398-9219.2006.00428.x. View

16.

Yuan X, Yu X, Lee T, Essex M . Mutations in the N-terminal region of human immunodeficiency virus type 1 matrix protein block intracellular transport of the Gag precursor. J Virol. 1993; 67(11):6387-94. PMC: 238073. DOI: 10.1128/JVI.67.11.6387-6394.1993. View

17.

Shkriabai N, Datta S, Zhao Z, Hess S, Rein A, Kvaratskhelia M . Interactions of HIV-1 Gag with assembly cofactors. Biochemistry. 2006; 45(13):4077-83. DOI: 10.1021/bi052308e. View

18.

Brown D, London E . Structure and function of sphingolipid- and cholesterol-rich membrane rafts. J Biol Chem. 2000; 275(23):17221-4. DOI: 10.1074/jbc.R000005200. View

19.

Srinivasakumar N, Chazal N, Prasad S, Hammarskjold M, Rekosh D . The effect of viral regulatory protein expression on gene delivery by human immunodeficiency virus type 1 vectors produced in stable packaging cell lines. J Virol. 1997; 71(8):5841-8. PMC: 191839. DOI: 10.1128/JVI.71.8.5841-5848.1997. View

20.

Simons K, Vaz W . Model systems, lipid rafts, and cell membranes. Annu Rev Biophys Biomol Struct. 2004; 33:269-95. DOI: 10.1146/annurev.biophys.32.110601.141803. View