Limits...
Envelope Glycoprotein Trimers as HIV-1 Vaccine Immunogens.

Sattentau QJ - Vaccines (Basel) (2013)

Bottom Line: The HIV-1 envelope glycoprotein spike is the target of neutralizing antibody attack, and hence represents the only relevant viral antigen for antibody-based vaccine design.Various approaches have been attempted to recapitulate Env in membrane-anchored and soluble forms, and these will be discussed here in the context of recent successes and challenges still to be overcome.

View Article: PubMed Central - PubMed

Affiliation: The Sir William Dunn School of Pathology, The University of Oxford, South Parks Road, Oxford OX13RE, UK. quentin.sattentau@path.ox.ac.uk.

ABSTRACT
The HIV-1 envelope glycoprotein spike is the target of neutralizing antibody attack, and hence represents the only relevant viral antigen for antibody-based vaccine design. Various approaches have been attempted to recapitulate Env in membrane-anchored and soluble forms, and these will be discussed here in the context of recent successes and challenges still to be overcome.

No MeSH data available.


HIV-1 Env. (A) Cartoon of gp120 with major features represented. The location of the V1V2 loops, missing from gp120 crystal structures, is predicted from analysis of trimeric Env by electron tomography [10,11] and from the location of the quaternary conformation epitope-specific antibody PG9 by negative stain electron microscopy [12]; (B) Molecular model of gp120 based on crystal structures and obtained with permission from [13]. The gp120 surface is colored grey for inner domain, red for outer domain and blue for the bridging sheet. The initial contact surface for CD4 is shown in yellow cross-hatching, and the recognition surface of broadly neutralizing CD4bs antibody VRC01 is green; (C) Cartoon of the Env trimer with broadly neutralizing antibody epitopes depicted; (D) Molecular model of Env trimer with glycans. Red surface is gp120 density, yellow represents the CD4 binding site, hybrid and complex glycans are represented in blue and the 2G12 epitope high mannose glycans in white (from [14]).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4494206&req=5

vaccines-01-00497-f001: HIV-1 Env. (A) Cartoon of gp120 with major features represented. The location of the V1V2 loops, missing from gp120 crystal structures, is predicted from analysis of trimeric Env by electron tomography [10,11] and from the location of the quaternary conformation epitope-specific antibody PG9 by negative stain electron microscopy [12]; (B) Molecular model of gp120 based on crystal structures and obtained with permission from [13]. The gp120 surface is colored grey for inner domain, red for outer domain and blue for the bridging sheet. The initial contact surface for CD4 is shown in yellow cross-hatching, and the recognition surface of broadly neutralizing CD4bs antibody VRC01 is green; (C) Cartoon of the Env trimer with broadly neutralizing antibody epitopes depicted; (D) Molecular model of Env trimer with glycans. Red surface is gp120 density, yellow represents the CD4 binding site, hybrid and complex glycans are represented in blue and the 2G12 epitope high mannose glycans in white (from [14]).

Mentions: To fully grasp the potential of the HIV-1 Env trimer for vaccine use, its structure and function need to be understood. HIV-1 carries a single virally-encoded structure on the outer surface of its envelope, the Envelope glycoprotein (Env). Env consists of a non-covalently linked trimer of heterodimers, each heterodimer composed of one surface gp120 subunit and one transmembrane subunit (Figure 1). The env open reading frame codes for a precursor trimer polypeptide (gp160) that is trafficked from the endoplasmic reticulum to the Golgi, within which it is cleaved by a cellular protease into its mature components [1]. Cleavage refolds Env into an activated, fusion-competent state via undefined structural rearrangements within the trimer. The mature trimer is then trafficked to the plasma membrane via a poorly defined pathway [1] that may involve regulated secretion induced by contact of the infected cells with an uninfected, receptor-bearing cell [2]. The cytoplasmic tail of gp41 carries endocytic motifs that drive traffic Env from the plasma membrane into either maturing endosomes leading to degradation or recycling endosomes, meaning that at steady state a large proportion of Env is within intracellular compartments [3,4]. This is suggested to be an immune evasion strategy, reducing cell surface Env recognition by B cells. Env targets lipid rafts via an acylation signal on gp41, meeting Gag at the cell membrane to initiate budding of the nascent virion [1]. The surface location of Env is dependent upon the infected cell type: CD4+ T cells predominantly express Env at the plasma membrane, whereas macrophages express Env principally within an intracellular compartment continuous with the plasma membrane called the virus-containing compartment (VCC) [5,6].


Envelope Glycoprotein Trimers as HIV-1 Vaccine Immunogens.

Sattentau QJ - Vaccines (Basel) (2013)

HIV-1 Env. (A) Cartoon of gp120 with major features represented. The location of the V1V2 loops, missing from gp120 crystal structures, is predicted from analysis of trimeric Env by electron tomography [10,11] and from the location of the quaternary conformation epitope-specific antibody PG9 by negative stain electron microscopy [12]; (B) Molecular model of gp120 based on crystal structures and obtained with permission from [13]. The gp120 surface is colored grey for inner domain, red for outer domain and blue for the bridging sheet. The initial contact surface for CD4 is shown in yellow cross-hatching, and the recognition surface of broadly neutralizing CD4bs antibody VRC01 is green; (C) Cartoon of the Env trimer with broadly neutralizing antibody epitopes depicted; (D) Molecular model of Env trimer with glycans. Red surface is gp120 density, yellow represents the CD4 binding site, hybrid and complex glycans are represented in blue and the 2G12 epitope high mannose glycans in white (from [14]).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494206&req=5

vaccines-01-00497-f001: HIV-1 Env. (A) Cartoon of gp120 with major features represented. The location of the V1V2 loops, missing from gp120 crystal structures, is predicted from analysis of trimeric Env by electron tomography [10,11] and from the location of the quaternary conformation epitope-specific antibody PG9 by negative stain electron microscopy [12]; (B) Molecular model of gp120 based on crystal structures and obtained with permission from [13]. The gp120 surface is colored grey for inner domain, red for outer domain and blue for the bridging sheet. The initial contact surface for CD4 is shown in yellow cross-hatching, and the recognition surface of broadly neutralizing CD4bs antibody VRC01 is green; (C) Cartoon of the Env trimer with broadly neutralizing antibody epitopes depicted; (D) Molecular model of Env trimer with glycans. Red surface is gp120 density, yellow represents the CD4 binding site, hybrid and complex glycans are represented in blue and the 2G12 epitope high mannose glycans in white (from [14]).
Mentions: To fully grasp the potential of the HIV-1 Env trimer for vaccine use, its structure and function need to be understood. HIV-1 carries a single virally-encoded structure on the outer surface of its envelope, the Envelope glycoprotein (Env). Env consists of a non-covalently linked trimer of heterodimers, each heterodimer composed of one surface gp120 subunit and one transmembrane subunit (Figure 1). The env open reading frame codes for a precursor trimer polypeptide (gp160) that is trafficked from the endoplasmic reticulum to the Golgi, within which it is cleaved by a cellular protease into its mature components [1]. Cleavage refolds Env into an activated, fusion-competent state via undefined structural rearrangements within the trimer. The mature trimer is then trafficked to the plasma membrane via a poorly defined pathway [1] that may involve regulated secretion induced by contact of the infected cells with an uninfected, receptor-bearing cell [2]. The cytoplasmic tail of gp41 carries endocytic motifs that drive traffic Env from the plasma membrane into either maturing endosomes leading to degradation or recycling endosomes, meaning that at steady state a large proportion of Env is within intracellular compartments [3,4]. This is suggested to be an immune evasion strategy, reducing cell surface Env recognition by B cells. Env targets lipid rafts via an acylation signal on gp41, meeting Gag at the cell membrane to initiate budding of the nascent virion [1]. The surface location of Env is dependent upon the infected cell type: CD4+ T cells predominantly express Env at the plasma membrane, whereas macrophages express Env principally within an intracellular compartment continuous with the plasma membrane called the virus-containing compartment (VCC) [5,6].

Bottom Line: The HIV-1 envelope glycoprotein spike is the target of neutralizing antibody attack, and hence represents the only relevant viral antigen for antibody-based vaccine design.Various approaches have been attempted to recapitulate Env in membrane-anchored and soluble forms, and these will be discussed here in the context of recent successes and challenges still to be overcome.

View Article: PubMed Central - PubMed

Affiliation: The Sir William Dunn School of Pathology, The University of Oxford, South Parks Road, Oxford OX13RE, UK. quentin.sattentau@path.ox.ac.uk.

ABSTRACT
The HIV-1 envelope glycoprotein spike is the target of neutralizing antibody attack, and hence represents the only relevant viral antigen for antibody-based vaccine design. Various approaches have been attempted to recapitulate Env in membrane-anchored and soluble forms, and these will be discussed here in the context of recent successes and challenges still to be overcome.

No MeSH data available.