Definition
Simian immunodeficiency virus (SIV) gp140 (also called gp160e) is a soluble, trimeric ectodomain of the SIV envelope glycoprotein, gp160 1.
Related Peptides
The envelope proteins (Env) of human immunodeficiency virus type 1 (HIV-1) and SIV form homo-oligomers in the endoplasmic reticulum. The oligomeric structure of Env is maintained, but is less stable, after cleavage in a Golgi compartment and transport to the surface of infected cells. Functional, virion-associated HIV-1 and SIV Env have an almost exclusively trimeric structure 2.
Discovery
The SIVmac251 (gp140) Fragment (171-190) was first synthesized and used by Kent et al., in 1991 to evoke humoral response in experimentally SIV mac-infected macaques 3.
Structural Characteristics
SIV virion-associated env and gp140 form largely homogeneous populations of trimers. Furthermore, a triangular or tri-lobed morphology is clearly visualized in a subset of the trimers. Immunoblotting of EGS-crosslinked proteins revealed that essentially all SIV gp140 had an electrophoretic mobility less than that expected for monomer, which migrates more rapidly than a 250 kDa mass standard, suggesting that all gp140 was oligomeric. Allowing for the broadness of bands typically observed for crosslinked glycoproteins, most gp140 appear to belong to a single oligomeric species. Immunoblotting of non-crosslinked sample reveals a small amount of protein with an apparent mass between 105 and 160 kDa within fractions 65–67, consistent with the presence of monomeric gp120 derived from cleaved gp140 4.
Mode of Action
SIV envelope glycoproteins mediate viral attachment and entry. They are also the principal targets of neutralizing antibodies. The single-chain precursor, gp160, forms a trimer. It is cleaved by a furin-like protease in a late compartment of the export pathway into fragments known as gp120 and gp41. The fragments remain noncovalently associated in a trimeric assembly, even after cleavage, but the interfragment contact is relatively weak, and gp120 dissociates slowly (sheds) from mature virions. The mature, cleaved Env protein (both from HIV and from SIV) is referred to as gp120/gp41. Gp140 is the part of the gp160 polypeptide chain that lies outside the viral membrane (the ectodomain); after cleavage at the furin sites, gp140 would contain gp120 and the ectodomain of gp41 2. Interaction of HIV gp120/gp41 with the viral receptor, CD4, induces a conformational change, detected by altered antigenic properties, enhanced proteolytic sensitivity of the gp120 moiety, and enhanced spontaneous dissociation. The change increases affinity of gp120/gp41 for the chemokine-binding coreceptor (CXCR4 or CCR5), perhaps by exposing or stabilizing the site of coreceptor binding. Interaction with the coreceptor leads to membrane fusion, probably because the coreceptor induces yet another conformational rearrangement in which gp120 dissociates, the fusion protein is exposed, and gp41 refolds into a helical hairpin 1.
Functions
SIV gp140 mediate viral entry into host cells by fusing viral and target cell membranes. Epitope mapping of two monoclonal antibodies (MAbs) generated against the external envelope glycoprotein of the SIV of macaque monkey and displaying a cell-free virus-neutralizing activity, delineated a neutralizing domain localized in the second variable region of the SIVmac251 gp105, between amino acids 171 and 188. This neutralizing domain usually induces a specific humoral response in experimentally SIVmac-infected macaques 3.
References
1. Chen B, Cheng Y, Calder L, Harrison SC, Reinherz EL, Skehel JJ, Wiley DC (2004). A Chimeric Protein of Simian Immunodeficiency Virus Envelope Glyco-protein gp140 and Escherichia coli Aspartate Transcarbamoylase. J Virol., 78(9):4508-4516.
2. Center RJ, Lebowitz J, Leapman RD, Moss B (2004). Promoting trimerization of soluble human immunodeficiency virus type 1 (HIV-1) Env through the use of HIV-1/simian immunodeficiency virus chimeras. J Virol., 78(5):2265-2276.
3. Babas T, Le Grand R, Dormont D, Bahraoui E (1991). Production and characterization of monoclonal antibodies to simian immunodeficiency virus envelope glycoproteins. AIDS Res Hum Retroviruses., 13(13):1109-1119.
4. Center RJ, Schuck P, Leapman RD, Arthur LO, Earl PL, Moss B, Lebowitz J (2001). Oligomeric structure of virion-associated and soluble forms of the simian immunodeficiency virus envelope protein in the prefusion activated conformation. PNAS., 98(26):14877-14882.