Cytopathic mechanisms of HIV-1 – is the envelope glycoprotein a viroporin?
The human immunodeficiency virus type 1 (HIV-1) has been intensely investigated since its discovery in 1983 as the cause of acquired immune deficiency syndrome (AIDS). With relatively few proteins made by the virus, it is able to accomplish many tasks, with each protein serving multiple functions. The envelope glycoprotein, composed of the two non-covalently linked subunits, SU (surface glycoprotein) and TM (transmembrane glycoprotein) is largely responsible for host cell recognition and entry respectively. While the roles of the N-terminal residues of TM is well established as a fusion pore and anchor for Env into cell membranes, the role of the C-terminus of the protein is not well understood and is fiercely debated.
Mechanisms by which HIV-1 mediates reductions in CD4+ cell levels in infected persons have been intensely investigated, and have broad implications for AIDS drug and vaccine development. Virus-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.
When individual peptides 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. 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.
Cytopathic Mechanisms of HIV-1. Virology Journal 2007 4:100
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Tags: Biology, Health, HIV/AIDS, Medicine, Microbiology, Science, Virology
