A Synthetic Peptide Corresponding to the Carboxy Terminus of Human Immunodeficiency Virus Type 1 Transmembrane Glycoprotein Induces Alterations in the Ionic Permeability ofXenopus laevisOocytes

Abstract

The carboxy-terminal 29 amino acids of the human immunodeficiency virus type 1 transmembrane glycoprotein (HIV-1 TM) are referred to as lentivirus lytic peptide 1 (LLP-1). Synthetic peptides corresponding to LLP-1 have been shown to induce cytolysis and to alter the permeability of cultured cells to various small molecules. To address the mechanisms by which LLP-1 induces cytolysis and membrane permeability changes, various concentrations of LLP-1 were incubated with Xenopus laevis oocytes, and two-electrode, voltage-clamp recording measurements were performed. LLP-1 at concentrations of 75 nM and above induced dramatic alterations in the resting membrane potential and ionic permeability of Xenopus oocytes. These concentrations of LLP-1 appeared to induce a major disruption of plasma membrane electrophysiological integrity. In contrast, concentrations of LLP-1 of 20-50 nM induced changes in membrane ionic permeability that mimic changes induced by compounds, such as the bee venom peptide melittin, that are known to form channel-like structures in biological membranes at sublytic concentrations. An analog of LLP-1 with greatly reduced cytolytic activity failed to alter the electrophysiological properties of Xenopus oocytes. Thus, by altering plasma membrane ionic permeability, the carboxy terminus of TM may contribute to cytolysis of HIV-1-infected CD4+ cells.

The Membrane-Proximal External Region of the Human Immunodeficiency Virus Type 1 Envelope: Dominant Site of Antibody Neutralization and Target for Vaccine Design

“…Several studies with these peptides have shown that they bind to membranes (118,214,231), perturb membranes (9,40,47), and bind to calmodulin (213,225). Structural modeling has described gp41 as a type I single-pass membrane protein (77); however, the work of Cleveland et al, who used a MAb that targets intracellular CT, suggests that the protein could have other membrane-spanning domains (45).…”

Surface Exposure of the HIV-1 Env Cytoplasmic Tail LLP2 Domain during the Membrane Fusion Process

“…The HIV-1 gp41 CT consists of the "Kennedy" polypeptide sequence (aa 731-752) and the lentivirus lytic peptide (LLP1-2, aa 773-862), which contains three highly conserved ␣-helix domains as follows: LLP1 (aa 833-862), LLP2 (aa 773-793), and LLP3 (aa785-807) (11). The HIV-1 gp41 CT has many functions, including interaction with the plasma membrane, decrease of bilayer stability, alteration of membrane ionic permeability, and mediation of cell killing (10,(12)(13)(14)(15)(16). Recent studies have shown that the gp41 CTs of HIV and simian immunodeficiency virus correlate with their infectivity and Env-mediated cell-cell fusion (10,15).…”

Mutational Analysis of Conserved Domains within the Cytoplasmic Tail of gp41 from Human Immunodeficiency Virus Type 1: Effects on Glycoprotein Incorporation and Infectivity

“…These two predicted amphipathic helices are also referred to as helices 2 and 1 or lentiviral lytic peptides 2 and 1 (LLP-2 and -1), respectively. Extensive work using synthetic peptides comprising these regions demonstrated that they are able to bind (20,31,33) and perturb (1,7,8,25) membranes and also interact with calmodulin (30,32). The role of these regions in the context of the entire glycoprotein is not yet fully understood.…”