Structure and function for the lentivirus lytic peptide (LLP) domains of HIV-1
Description
Mechanisms by which HIV-1 mediates reductions in CD4+ cell levels in infected persons are intensely investigated, and have broad implications for AIDS drug and vaccine development. Virally induced changes in membrane ionic permeability contribute to cytopathogenesis induced by lytic viruses of many families. HIV-1 induces disturbances in plasma membrane ion transport. The carboxyl terminus of TM contains amphipathic alpha-helical motifs identified because of their structural similarities to melittin, a naturally occurring cytolytic peptide, and were dubbed lentiviral lytic peptides (LLP)-1, -2, and -3. Peptides corresponding to these domains partition into lipid membranes as alpha-helices and disrupt model lipid membranes. When individual peptides from HIV-1HXB2 (a clade B laboratory adapted virus) are incubated exogenously with Xenopus oocytes, LLP-1 and -2, but not LLP-3 increased the whole cell conductance across the plasma membrane. The increased conductance observed with LLP-1 and -2 appears to be at least in part due to an increased permeability of Na+ ions. A peptide corresponding to the LLP-1 domain of a clade D HIV-1 virus, dubbed 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. Combinations of LLP peptides appear to act cooperatively to increase the whole cell conductance of Xenopus oocyte plasma membranes. Injection of HIV-1 Env in vitro mRNA transcripts into Xenopus oocytes increased the conductance of the plasma membrane and caused a positive shift in the reversal potential. Taken together, these results suggest that the C-terminal domains of HIV-1 Env proteins may form an ion channel, or viroporin, that is capable of conducting Na + ions. Alternatively, HIV-1 Env protein may activate a silent Xenopus oocyte Na+-conductive ion channel. 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