Hiv env proteins

From Proteopedia

(Difference between revisions)

Revision as of 23:41, 27 November 2012

Molecular structure for the HIV-1 gp120 trimer in the unliganded state (PDB entry 3dnn)

Drag the structure with the mouse to rotate

1 Introduction
2 Env Structure
3 gp120 Binding
4 Broadly Neutralizing Antibody b12
- 4.1 Immune Evasion

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.

^[2]

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]. "Direct interatomic contacts are made between 22 CD4 residues and 26 gp120 amino-acid residues. These include 219 van der Waals contacts and 12 hydrogen bonds" ^[3]. "Residues in contact are concentrated in the 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].

^[2]

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. "Binding of the brodly neutralizing antibody b12... appears to lock gp120 and trimeric Env in a state that prevents further conformation changes that would normally lead to exposure of the gp41 stalk" ^[2].

Immune Evasion

One reason that HIV is able to escape inhibition by the immune system, is because of its conformational variability and resistance to antibodies. Essentially "the conformational flexibility of gp120 facilitates a decoy strategy that misdirects the humoral immune response" ^[2].

crystal structure of the cluster II Fab 1281 in complex with HIV-1 gp41 ectodomain (PDB entry 3p30)

Drag the structure with the mouse to rotate

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.

^[1]

There are three main types of antibodies that can potentially bind gp 41: MPER antibodies, cluter I antibodies, and cluster II antibodies. These are either neutralizing antibodies or non-neutralizing antibodies. MPER "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 I antibodies target a part of gp41 that is not readily accessible while "Cluster II antibodies recognize another (residues 644–663) next to the MPER" ^[1]. Cluster II antibodies 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].

== Other Research ==

Molecular structure for the HIV-1 gp120 trimer in the unliganded state (PDB entry 3dnn)

Drag the structure with the mouse to rotate

References

↑ ^1.0 ^1.1 ^1.2 ^1.3 ^1.4 ^1.5 ^1.6 ^1.7 ^1.8 Frey G, Chen J, Rits-Volloch S, Freeman MM, Zolla-Pazner S, Chen B. Distinct conformational states of HIV-1 gp41 are recognized by neutralizing and non-neutralizing antibodies. Nat Struct Mol Biol. 2010 Dec;17(12):1486-91. Epub 2010 Nov 14. PMID:21076402 doi:10.1038/nsmb.1950
↑ ^2.0 ^2.1 ^2.2 ^2.3 ^2.4 ^2.5 ^2.6 ^2.7 Liu J, Bartesaghi A, Borgnia MJ, Sapiro G, Subramaniam S. Molecular architecture of native HIV-1 gp120 trimers. Nature. 2008 Sep 4;455(7209):109-13. Epub 2008 Jul 30. PMID:18668044 doi:10.1038/nature07159
↑ ^3.0 ^3.1 ^3.2 Kwong PD, Wyatt R, Robinson J, Sweet RW, Sodroski J, Hendrickson WA. Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature. 1998 Jun 18;393(6686):648-59. PMID:9641677 doi:10.1038/31405

Proteopedia Page Contributors and Editors (what is this?)

Nicholas Flores, Michal Harel, Alexander Berchansky

Retrieved from "http://52.214.119.220/wiki/index.php/Hiv_env_proteins"

@@ Line 12: / Line 12: @@
 == 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" <ref name=Guan>PMID: 21076402 </ref>. In the unliganded state, the <scene name='Sandbox/Gp120_v1_v2_loops/1'>V1/V2 loops</scene> are located at the center of the apex of the trimer and hold the trimer together. However, when <scene name='Sandbox/Gp120_v1_v2_loops/2'>CD4</scene> 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 <scene name='Hiv_env_proteins/Cd4_gp120_complex/1'>CD4</scene> and an antibody Fab (17b-Fab). "The 17b antibody has been shown to stabilize and lock gp120 in the CD4-bound conformation" <ref name=Nick>PMID: 18668044 </ref>. "Residues in contact are concentrated in the span from 25 to 64 of CD4, but they are distributed over six segments of gp120" <ref name=Nich>PMID: 9641677 </ref>. However, the most important gp120/CD4 <scene name='Hiv_env_proteins/Cd4_gp120_complex/2'>interactions</scene> 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" <ref name=Nich>PMID: 9641677 </ref>. [[Image:3D structure of the HIV-1 spike in complex with CD4 and 17b- Fab.png|thumb|left|<ref name=Nick>PMID: 18668044 </ref>]]
+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" <ref name=Guan>PMID: 21076402 </ref>. In the unliganded state, the <scene name='Sandbox/Gp120_v1_v2_loops/1'>V1/V2 loops</scene> are located at the center of the apex of the trimer and hold the trimer together. However, when <scene name='Sandbox/Gp120_v1_v2_loops/2'>CD4</scene> 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 <scene name='Hiv_env_proteins/Cd4_gp120_complex/1'>CD4</scene> and an antibody Fab (17b-Fab). "The 17b antibody has been shown to stabilize and lock gp120 in the CD4-bound conformation" <ref name=Nick>PMID: 18668044 </ref>. "Direct interatomic contacts are made between 22 CD4 residues and 26 gp120 amino-acid residues. These include 219 van der Waals contacts and 12 hydrogen bonds" <ref name=Nich>PMID: 9641677 </ref>. "Residues in contact are concentrated in the <scene name='Hiv_env_proteins/Cd4_gp120_interface/1'>span</scene> from 25 to 64 of CD4, but they are distributed over six segments of gp120" <ref name=Nich>PMID: 9641677 </ref>. However, the most important gp120/CD4 <scene name='Hiv_env_proteins/Cd4_gp120_complex/2'>interactions</scene> 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" <ref name=Nich>PMID: 9641677 </ref>. [[Image:3D structure of the HIV-1 spike in complex with CD4 and 17b- Fab.png|thumb|left|<ref name=Nick>PMID: 18668044 </ref>]]
 == 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 <scene name='Hiv_env_proteins/B12_gp120_complex/1'>gp120</scene> monomer by ~20-25 degrees"<ref name=Nick>PMID: 18668044 </ref>. Even though, b12 and CD4 bind roughly in the same areas, they shift the orientation of the gp120 monomers very differently.
+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 <scene name='Hiv_env_proteins/B12_gp120_complex/1'>gp120</scene> monomer by ~20-25 degrees"<ref name=Nick>PMID: 18668044 </ref>. Even though, b12 and CD4 bind roughly in the same areas, they shift the orientation of the gp120 monomers very differently. "Binding of the brodly neutralizing antibody b12... appears to lock gp120 and trimeric Env in a state that prevents further conformation changes that would normally lead to exposure of the gp41 stalk" <ref name=Nick>PMID: 18668044 </ref>.
+=== Immune Evasion ===
+One reason that HIV is able to escape inhibition by the immune system, is because of its conformational variability and resistance to antibodies. Essentially "the conformational flexibility of gp120 facilitates a decoy strategy that misdirects the humoral immune response" <ref name=Nick>PMID: 19965434 </ref>.
@@ Line 23: / Line 27: @@
 <StructureSection load='3p30' size='400' side='left' caption='crystal structure of the cluster II Fab 1281 in complex with HIV-1 gp41 ectodomain (PDB entry [[3p30]])' scene=''>
 == 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 <ref name=Guan>PMID: 21076402 </ref>. 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. [[Image:Structure complex gp41-post 1281Fab.png|thumb|right|<ref name=Guan>PMID: 21076402 </ref>]] gp41 potentially binds to neutralizing antibodies or non-neutralizing antibodies. "Neutralizing antibodies target a region on gp41 adjacent to the viral membrane, called the
+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 <ref name=Guan>PMID: 21076402 </ref>. 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. [[Image:Structure complex gp41-post 1281Fab.png|thumb|right|<ref name=Guan>PMID: 21076402 </ref>]] There are three main types of antibodies that can potentially bind gp 41: MPER antibodies, cluter I antibodies, and cluster II antibodies. These are either neutralizing antibodies or non-neutralizing antibodies. MPER "neutralizing antibodies target a region on gp41 adjacent to the viral membrane, called the <scene name='Hiv_env_proteins/Gp41_mper/1'>membrane-proximal external region</scene> (MPER)" represented by the red region <ref name=Guan>PMID: 21076402 </ref>. 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 I antibodies target a part of gp41 that is not readily accessible while "Cluster II antibodies recognize another <scene name='Hiv_env_proteins/Gp41_mper/2'>immunodominant segment</scene> (residues 644–663) next to the MPER" <ref name=Guan>PMID: 21076402 </ref>. Cluster II antibodies 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" <ref name=Guan>PMID: 21076402 </ref>.
-<scene name='Hiv_env_proteins/Gp41_mper/1'>membrane-proximal external region</scene> (MPER)" represented by the red region <ref name=Guan>PMID: 21076402 </ref>. 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 <scene name='Hiv_env_proteins/Gp41_mper/2'>immunodominant segment</scene> (residues 644–663) next to the MPER" <ref name=Guan>PMID: 21076402 </ref>. 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" <ref name=Guan>PMID: 21076402 </ref>.
 </StructureSection>
@@ Line 30: / Line 33: @@
+== Other Research ==<StructureSection load='3dnn' size='400' side='right' caption='Molecular structure for the HIV-1 gp120 trimer in the unliganded state (PDB entry [[3dnn]])' scene=''>
+There is currently no cure or vaccine for HIV. Thus, there are constantly new studies being conducted, that explore various aspects of HIV. One recent study done at the University of Amsterdam, explored the evolution of HIV post-infection and discovered that HIV can evolve glycan structures that induce the production of broadly cross neutralizing (BCN) antibodies.
+</StructureSection>

Hiv env proteins

From Proteopedia

Revision as of 23:41, 27 November 2012

Contents

Introduction

Env Structure

gp120 Binding

Broadly Neutralizing Antibody b12

Immune Evasion

gp41

References

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox