Abstract
BackgroundMechanisms 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 α-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.ResultsPeptides corresponding to the LLP domains (from a clade B virus) partition into lipid membranes, fold into α-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.ConclusionThese 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.
Highlights
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
We demonstrate that synthetic peptides corresponding to the three lentiviral lytic peptides (LLP) domains are capable of partitioning into POPC:POPG membranes, and in doing so adopt a more ordered amphipathic α-helical secondary structure
If 3 Env proteins form a viral pore, based on the proposed trimer arrangement of Env proteins [42,43,61], this would result in 24 viroporins per virion
Summary
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. The carboxyl terminus of TM (gp41) contains potential amphipathic α-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. The two noncovalently associated envelope glycoproteins, surface (SU) and transmembrane (TM), of HIV-1 are responsible for attachment and entry into target cells. TM contains several additional functional domains, including the lentivirus lytic peptide (LLP) domains These domains were identified on the basis of their structural motifs and similarities to several natural cytolytic peptides [1].
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