Hiv env proteins

spinqualitylabelsall models Molecular structure for the HIV-1 gp120 trimer in the unliganded state (PDB entry 3dnn) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Contents 1 Introduction 2 Env Structure 3 gp120 Binding 4 Broadly Neutralizing Antibody b12

Introduction

Human Immunodeficiency Virus (HIV) is a retrovirus/lentivirus that expresses a spike protein on its viral envelope (Env). "The envelope protein is synthesized as a precursor, gp160, which trimerizes and undergoes cleavage into two noncovalently associated fragments, the receptor-binding fragment gp120 and the fusion fragment gp41" ^[1]. Thus, Env is a heterodimer consisting of gp120 and gp41 and forms trimers on the surface of the viral membrane. As "the sole antigen on the virion surface," an understanding of Env (gp 120 & 41) and the conformational changes that occur in gp120 and gp41 during binding and fusion, respectively, is necessary in developing new fusion inhibitors and possible vaccines ^{[1] [2]}. The protein structure shown on the right is the gp120 portion of Env in its unbound trimer state ^[2].

Env Structure

The viral Env protein, as mentioned above, is composed of gp120 and gp41 that forms trimers on the viral membrane surface. The image to the right, displays the undecorated Env trimer. Within the gp120 monomeric proteins are variable loops that undergo conformational changes that support binding or restrict binding of receptors such as CD4 or antibodies. Two important loops in this regard are the V1/V2 loops. The V1/V2 loops are located at the apex of the structure in the center of the three monomeric gp120 proteins. Depending on the gp120 conformation changes, the three gp41 transmembrane proteins, located beneath the gp120 surface proteins (located by the white arrow in F2.b), will undergo "irreversible refolding," bringing the viral membrane and host cell membrane closer together, consequently inducing fusion ^[1].

gp120 Binding

gp120 is responsible for the binding of HIV to CD4 cells. "Binding of gp120 to the primary receptor CD4 and coreceptor (for example, CCR5 and CXCR4) induces large conformational changes, which then trigger dissociation of gp120 and a cascade of refolding events in gp41" ^[1]. In the unliganded state, the are located at the center of the apex of the trimer and hold the trimer together. However, when binds to gp120, the V1/V2 loops undergo an outward rotational change that expose the central gp41 proteins at the base of the Env protein. gp120 is often complexed with and an antibody Fab (17b-Fab). "The 17b antibody has been shown to stabilize and lock gp120 in the CD4-bound conformation" ^[2]. "Residues in contact are concentrated in the span from 25 to 64 of CD4, but they are distributed over six segments of gp120" ^[3]. However, the most important gp120/CD4 are between "Phe 43 and Arg 59 of CD4 [which] make multiple contacts centered on residues Asp 368, Glu 370 and Trp427 of gp120, which are all conserved among primate immunodeficiency viruses" ^[3].

Broadly Neutralizing Antibody b12

b12 is a broadly neutralizing antibody that can bind to gp120 and inhibit the binding to primary corecptor CD4. "The binding of b12 results in a partial opening of the spike, coupled with roation of each monomer by ~20-25 degrees"^[2]. Even though, b12 and CD4 bind roughly in the same areas, they shift the orientation of the gp120 monomers very differently.

spinqualitylabelsall models crystal structure of the cluster II Fab 1281 in complex with HIV-1 gp41 ectodomain (PDB entry 3p30) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

gp41

gp41 is a transmembrane protein on the viral envelope of HIV, with its "C-terminal transmembrane segment inserted in the viral membrane" and its N-terminal outside the viral membrane beneath the gp120 proteins ^[1]. gp41 facilitates fusion of HIV with the host cell. There are 3 different conformations that gp41 can exist in: prefusion state, prehairpin intermediate, and post fusion state. In the prefusion state gp41 exists as the transmembrane segment mentioned above. Upon binding of gp120 to CD4, gp41 enters the prehairpin intermediate, where it extends into the host cell and the C-terminal segment remains in the viral envelope. Further rearrangement induces the post fusion state, where gp41 is completely enters the host cell, causing fusion of the membranes. gp41 potentially binds to neutralizing antibodies or non-neutralizing antibodies. "Neutralizing antibodies target a region on gp41 adjacent to the viral membrane, called the

(MPER)" represented by the red region ^[1]. Two broadly neutralizing proteins that target this region in the prehairpin-intermediate state are: 4E10 and 2F5. However, non-neutralizing antibodies are more prevalent in infected individuals. "Cluster II antibodies recognize another (residues 644–663) next to the MPER" ^[1]. These are non-neutralizing because they bind to gp41 in the post fusion conformation, after the fusion is already complete or when gp120 proteins are prematurely shed. Cluster II epitopes, like the six alpha helix bundle, facilitate HIV-1 immune evasion by triggering the production cluster II antibodies that are non-neutralizing. "HIV-1 may thereby exploit the envelope stability as one of its immune-evasion tactics to distract the immune system from the native, functional trimers" ^[1].