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Viroporin potential of the lentivirus lytic peptide (LLP) domains of the HIV-1 gp41 protein.

Costin JM, Rausch JM, Garry RF, Wimley WC - Virol. J. (2007)

Bottom Line: Mechanisms by which HIV-1 mediates reductions in CD4+ cell levels in infected persons are being intensely investigated, and have broad implications for AIDS drug and vaccine development.These results suggest that the C-terminal domains of HIV-1 Env proteins may form an ion channel, or viroporin.Increased understanding of the function of LLP domains and their role in the viral replication cycle could allow for the development of novel HIV drugs.

View Article: PubMed Central - HTML - PubMed

Affiliation: Biotechnology Research Group, Department of Biology, Florida Gulf Coast University, 10501 FGCU Blvd. S., Fort Myers, FL 33965, USA. jcostin@fgcu.edu

ABSTRACT

Background: Mechanisms by which HIV-1 mediates reductions in CD4+ cell levels in infected persons are being intensely investigated, and have broad implications for AIDS drug and vaccine development. Virally induced changes in membrane ionic permeability induced by lytic viruses of many families contribute to cytopathogenesis. HIV-1 induces disturbances in plasma membrane ion transport. The carboxyl terminus of TM (gp41) contains potential amphipathic alpha-helical motifs identified through their structural similarities to naturally occurring cytolytic peptides. These sequences have been dubbed lentiviral lytic peptides (LLP) -1, -2, and -3.

Results: Peptides corresponding to the LLP domains (from a clade B virus) partition into lipid membranes, fold into alpha-helices and disrupt model membrane permeability. A peptide corresponding to the LLP-1 domain of a clade D HIV-1 virus, LLP-1D displayed similar activity to the LLP-1 domain of the clade B virus in all assays, despite a lack of amino acid sequence identity.

Conclusion: These results suggest that the C-terminal domains of HIV-1 Env proteins may form an ion channel, or viroporin. Increased understanding of the function of LLP domains and their role in the viral replication cycle could allow for the development of novel HIV drugs.

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Proposed models of the C-terminus of TM. Proposed models of LLP domains in the context of TM and in a lipid membrane. a) A nine pass transmembrane configuration and b) Association of the LLP domains with the inner leaflet of the lipid membrane allowing for interaction with calmodulin. It is possible that the LLP domains flip-flop between this configuration and a transmembrane configuration.
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Figure 5: Proposed models of the C-terminus of TM. Proposed models of LLP domains in the context of TM and in a lipid membrane. a) A nine pass transmembrane configuration and b) Association of the LLP domains with the inner leaflet of the lipid membrane allowing for interaction with calmodulin. It is possible that the LLP domains flip-flop between this configuration and a transmembrane configuration.

Mentions: Integrating the current biochemical and physiological data gathered using the lentiviral lytic peptides, a hypothetical model of their action in the membrane is proposed in Figure 5. The LLP regions of TM are α-helical in a lipid environment, partition into lipid bilayers, and disrupt lipid membranes. Since Env is known to associate in trimers on the cell surface and in virions [42,43], it is easy to speculate that the LLP regions of the Env trimers could associate with each other, forming a pore or channel in the area between them.


Viroporin potential of the lentivirus lytic peptide (LLP) domains of the HIV-1 gp41 protein.

Costin JM, Rausch JM, Garry RF, Wimley WC - Virol. J. (2007)

Proposed models of the C-terminus of TM. Proposed models of LLP domains in the context of TM and in a lipid membrane. a) A nine pass transmembrane configuration and b) Association of the LLP domains with the inner leaflet of the lipid membrane allowing for interaction with calmodulin. It is possible that the LLP domains flip-flop between this configuration and a transmembrane configuration.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2211469&req=5

Figure 5: Proposed models of the C-terminus of TM. Proposed models of LLP domains in the context of TM and in a lipid membrane. a) A nine pass transmembrane configuration and b) Association of the LLP domains with the inner leaflet of the lipid membrane allowing for interaction with calmodulin. It is possible that the LLP domains flip-flop between this configuration and a transmembrane configuration.
Mentions: Integrating the current biochemical and physiological data gathered using the lentiviral lytic peptides, a hypothetical model of their action in the membrane is proposed in Figure 5. The LLP regions of TM are α-helical in a lipid environment, partition into lipid bilayers, and disrupt lipid membranes. Since Env is known to associate in trimers on the cell surface and in virions [42,43], it is easy to speculate that the LLP regions of the Env trimers could associate with each other, forming a pore or channel in the area between them.

Bottom Line: Mechanisms by which HIV-1 mediates reductions in CD4+ cell levels in infected persons are being intensely investigated, and have broad implications for AIDS drug and vaccine development.These results suggest that the C-terminal domains of HIV-1 Env proteins may form an ion channel, or viroporin.Increased understanding of the function of LLP domains and their role in the viral replication cycle could allow for the development of novel HIV drugs.

View Article: PubMed Central - HTML - PubMed

Affiliation: Biotechnology Research Group, Department of Biology, Florida Gulf Coast University, 10501 FGCU Blvd. S., Fort Myers, FL 33965, USA. jcostin@fgcu.edu

ABSTRACT

Background: Mechanisms by which HIV-1 mediates reductions in CD4+ cell levels in infected persons are being intensely investigated, and have broad implications for AIDS drug and vaccine development. Virally induced changes in membrane ionic permeability induced by lytic viruses of many families contribute to cytopathogenesis. HIV-1 induces disturbances in plasma membrane ion transport. The carboxyl terminus of TM (gp41) contains potential amphipathic alpha-helical motifs identified through their structural similarities to naturally occurring cytolytic peptides. These sequences have been dubbed lentiviral lytic peptides (LLP) -1, -2, and -3.

Results: Peptides corresponding to the LLP domains (from a clade B virus) partition into lipid membranes, fold into alpha-helices and disrupt model membrane permeability. A peptide corresponding to the LLP-1 domain of a clade D HIV-1 virus, LLP-1D displayed similar activity to the LLP-1 domain of the clade B virus in all assays, despite a lack of amino acid sequence identity.

Conclusion: These results suggest that the C-terminal domains of HIV-1 Env proteins may form an ion channel, or viroporin. Increased understanding of the function of LLP domains and their role in the viral replication cycle could allow for the development of novel HIV drugs.

Show MeSH
Related in: MedlinePlus