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The Role of Lipids in Retrovirus Replication.

Waheed AA, Freed EO - Viruses (2010)

Bottom Line: Retroviruses undergo several critical steps to complete a replication cycle.These include the complex processes of virus entry, assembly, and budding that often take place at the plasma membrane of the host cell.In this review, we outline the current understanding of the role of lipids and membrane microdomains in retroviral replication.

View Article: PubMed Central - PubMed

Affiliation: Virus-Cell Interaction Section, HIV Drug Resistance Program, National Cancer Institute, Frederick, MD 21702, USA.

ABSTRACT
Retroviruses undergo several critical steps to complete a replication cycle. These include the complex processes of virus entry, assembly, and budding that often take place at the plasma membrane of the host cell. Both virus entry and release involve membrane fusion/fission reactions between the viral envelopes and host cell membranes. Accumulating evidence indicates important roles for lipids and lipid microdomains in virus entry and egress. In this review, we outline the current understanding of the role of lipids and membrane microdomains in retroviral replication.

No MeSH data available.


Related in: MedlinePlus

Complex between HIV-1 MA and PI(4,5)P2. The highly basic surface of MA (blue) exhibits electrostatic interactions with PI(4,5)P2 (yellow and red phosphates). The 2′-unsaturated acyl chain of PI(4,5)P2 (yellow) binds to the hydrophobic cleft in MA and the myristyl group (green) of MA inserts into the lipid bilayer. Unpublished image provided by Dr. M. Summers, based on the data of Saad et al. [124].
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f6-viruses-02-01146: Complex between HIV-1 MA and PI(4,5)P2. The highly basic surface of MA (blue) exhibits electrostatic interactions with PI(4,5)P2 (yellow and red phosphates). The 2′-unsaturated acyl chain of PI(4,5)P2 (yellow) binds to the hydrophobic cleft in MA and the myristyl group (green) of MA inserts into the lipid bilayer. Unpublished image provided by Dr. M. Summers, based on the data of Saad et al. [124].

Mentions: Several groups, using different approaches, have demonstrated a direct interaction between MA and PI(4,5)P2 [38,124,170,172]. Summers and co-workers used nuclear magnetic resonance (NMR) spectroscopy to solve the structure of a complex between myristylated MA and a soluble derivative of PI(4,5)P2 [124,173]. This study suggested that besides electrostatic interactions between the negatively charged headgroup of PI(4,5)P2 and basic residues in MA, the 2′-unsaturated acyl chain of PI(4,5)P2 binds to a hydrophobic cleft within the globular core of MA (Figure 6) [124,173]. The extrusion of the unsaturated acyl chain from the lipid bilayer upon Gag binding could promote the partitioning of Gag to the more saturated lipid raft microenvironment [124]. Furthermore, these NMR data also suggested that PI(4,5)P2 binding to MA triggers the myristyl switch, leading to myristate exposure. Thus, according to this model, PI(4,5)P2 acts as both a membrane anchor and a trigger for myristate exposure. Shkriabai et al. used mass spectrometric protein footprinting analysis with a lysine-modifying agent to identify MA residues 29 and 31 as being important for the MA-PI(4,5)P2 interaction [172]. Notably, mutation of these basic residues mistargets Gag and virus assembly to MVBs [165,167,174,175]. Ono’s group used liposome-binding assays to show that full-length myristylated Gag binds to PI(4,5)P2-enriched vesicles, and the residue 29/31 mutant showed reduced PI(4,5)P2-dependent liposome binding, again highlighting the importance of these residues in the Gag-PI(4,5)P2 interaction [170]. Chan et al. reported that HIV-1 and MLV virions are enriched in PI(4,5)P2 relative to the plasma membrane, and mutating the basic residues in MA significantly reduced the incorporation of PI(4,5)P2 into particles [38]. These observations suggest that MA interacts with PI(4,5)P2 not only in vitro but also in cells. Direct binding of PI(4,5)P2 is also reported for other retroviruses, e.g., HIV-2 [176], EIAV [177], and MLV [178]. Barklis and co-workers recently reported that myristylated MA organizes into hexameric rings of trimers on artificial membranes containing 60% PC, 20% PI(4,5)P2, and 20% cholesterol [179]. Interestingly, cholesterol was observed to enhance the selectivity of MA for PI(4,5)P2 in this in vitro system. Collectively, these studies demonstrate that diverse retroviruses exploit MA-PI(4,5)P2 interactions for Gag trafficking and virus release.


The Role of Lipids in Retrovirus Replication.

Waheed AA, Freed EO - Viruses (2010)

Complex between HIV-1 MA and PI(4,5)P2. The highly basic surface of MA (blue) exhibits electrostatic interactions with PI(4,5)P2 (yellow and red phosphates). The 2′-unsaturated acyl chain of PI(4,5)P2 (yellow) binds to the hydrophobic cleft in MA and the myristyl group (green) of MA inserts into the lipid bilayer. Unpublished image provided by Dr. M. Summers, based on the data of Saad et al. [124].
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2927015&req=5

f6-viruses-02-01146: Complex between HIV-1 MA and PI(4,5)P2. The highly basic surface of MA (blue) exhibits electrostatic interactions with PI(4,5)P2 (yellow and red phosphates). The 2′-unsaturated acyl chain of PI(4,5)P2 (yellow) binds to the hydrophobic cleft in MA and the myristyl group (green) of MA inserts into the lipid bilayer. Unpublished image provided by Dr. M. Summers, based on the data of Saad et al. [124].
Mentions: Several groups, using different approaches, have demonstrated a direct interaction between MA and PI(4,5)P2 [38,124,170,172]. Summers and co-workers used nuclear magnetic resonance (NMR) spectroscopy to solve the structure of a complex between myristylated MA and a soluble derivative of PI(4,5)P2 [124,173]. This study suggested that besides electrostatic interactions between the negatively charged headgroup of PI(4,5)P2 and basic residues in MA, the 2′-unsaturated acyl chain of PI(4,5)P2 binds to a hydrophobic cleft within the globular core of MA (Figure 6) [124,173]. The extrusion of the unsaturated acyl chain from the lipid bilayer upon Gag binding could promote the partitioning of Gag to the more saturated lipid raft microenvironment [124]. Furthermore, these NMR data also suggested that PI(4,5)P2 binding to MA triggers the myristyl switch, leading to myristate exposure. Thus, according to this model, PI(4,5)P2 acts as both a membrane anchor and a trigger for myristate exposure. Shkriabai et al. used mass spectrometric protein footprinting analysis with a lysine-modifying agent to identify MA residues 29 and 31 as being important for the MA-PI(4,5)P2 interaction [172]. Notably, mutation of these basic residues mistargets Gag and virus assembly to MVBs [165,167,174,175]. Ono’s group used liposome-binding assays to show that full-length myristylated Gag binds to PI(4,5)P2-enriched vesicles, and the residue 29/31 mutant showed reduced PI(4,5)P2-dependent liposome binding, again highlighting the importance of these residues in the Gag-PI(4,5)P2 interaction [170]. Chan et al. reported that HIV-1 and MLV virions are enriched in PI(4,5)P2 relative to the plasma membrane, and mutating the basic residues in MA significantly reduced the incorporation of PI(4,5)P2 into particles [38]. These observations suggest that MA interacts with PI(4,5)P2 not only in vitro but also in cells. Direct binding of PI(4,5)P2 is also reported for other retroviruses, e.g., HIV-2 [176], EIAV [177], and MLV [178]. Barklis and co-workers recently reported that myristylated MA organizes into hexameric rings of trimers on artificial membranes containing 60% PC, 20% PI(4,5)P2, and 20% cholesterol [179]. Interestingly, cholesterol was observed to enhance the selectivity of MA for PI(4,5)P2 in this in vitro system. Collectively, these studies demonstrate that diverse retroviruses exploit MA-PI(4,5)P2 interactions for Gag trafficking and virus release.

Bottom Line: Retroviruses undergo several critical steps to complete a replication cycle.These include the complex processes of virus entry, assembly, and budding that often take place at the plasma membrane of the host cell.In this review, we outline the current understanding of the role of lipids and membrane microdomains in retroviral replication.

View Article: PubMed Central - PubMed

Affiliation: Virus-Cell Interaction Section, HIV Drug Resistance Program, National Cancer Institute, Frederick, MD 21702, USA.

ABSTRACT
Retroviruses undergo several critical steps to complete a replication cycle. These include the complex processes of virus entry, assembly, and budding that often take place at the plasma membrane of the host cell. Both virus entry and release involve membrane fusion/fission reactions between the viral envelopes and host cell membranes. Accumulating evidence indicates important roles for lipids and lipid microdomains in virus entry and egress. In this review, we outline the current understanding of the role of lipids and membrane microdomains in retroviral replication.

No MeSH data available.


Related in: MedlinePlus