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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.


Related in: MedlinePlus

HIV-1 Env trimers for experimental vaccine use. (A) Functional, cleaved HIV-1 Env expressed in a viral, infected cell, or VLP membrane; (B) Uncleaved soluble gp140 trimer with “open” structure; (C) Cleaved gp140 is unstable resulting in subunit dissociation; (D) SOSIP gp140 is stabilized by disulfide bonds and maintains a compact “closed” conformation; (E) EM reconstruction of BG505 SOSIP gp140 at 24A resolution showing compact globular morphology, from [93] with permission; (F) HIV-1 gp160 expressed from infected or transfected cells contains a proportion of so-called “junk” forms that may compete with the native trimeric forms for induction of neutralizing antibodies [79]. These may be at least partially removed by protease treatment [79]; (G) Disulfide (SOS)-stabilized membrane-anchored Env trimer [79,90].
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vaccines-01-00497-f002: HIV-1 Env trimers for experimental vaccine use. (A) Functional, cleaved HIV-1 Env expressed in a viral, infected cell, or VLP membrane; (B) Uncleaved soluble gp140 trimer with “open” structure; (C) Cleaved gp140 is unstable resulting in subunit dissociation; (D) SOSIP gp140 is stabilized by disulfide bonds and maintains a compact “closed” conformation; (E) EM reconstruction of BG505 SOSIP gp140 at 24A resolution showing compact globular morphology, from [93] with permission; (F) HIV-1 gp160 expressed from infected or transfected cells contains a proportion of so-called “junk” forms that may compete with the native trimeric forms for induction of neutralizing antibodies [79]. These may be at least partially removed by protease treatment [79]; (G) Disulfide (SOS)-stabilized membrane-anchored Env trimer [79,90].

Mentions: There have been numerous attempts to express both membrane-anchored and soluble forms of trimeric Env for immunization. To date none of these attempts have led to induction of potent neutralizing antibodies against highly conserved Env surfaces, but some incremental improvements in neutralization compared to immunization with gp120 have been observed, suggesting that this strategy is worth pursuing [75]. The most straightforward way to produce trimeric Env with a native, functional conformation is to express it in a membrane context. This can be achieved by in vivo expression from DNA or from vectors encoding env. Obvious advantages of this approach are that the glycoprotein is assembled and expressed in the host cells, therefore being post-translationally processed in a similar manner to the virus during an infection. A downside of this approach is that the amount of Env expressed in vivo is unknown, but is likely to be relatively low, generally resulting in weak antibody responses without further protein boosting. Moreover, the antibody evasion mechanisms inbuilt into Env, including endocytosis and the presence of misfolded, uncleaved and subunit dissociated forms will be active in this setting. A more controlled strategy that can potentially deliver greater quantities of antigen is the ex-vivo expression of env in the context of Gag, resulting in production of virus-like particles (VLPs) [76,77]. VLPs contain functional trimers and can be purified to high concentration. Membrane-anchored Env produced in high-level expression systems is not free from non-functional forms and contains uncleaved monomer gp160, gp41 stumps and other membrane-anchored “junk” [78,79] (Figure 2). Of particular interest, treatment of membrane Env with protease eliminated most non-native forms whilst preserving native Env, as probed by native gel electrophoresis and neutralizing antibody binding [79,80]. Moreover, soluble gp160 can be liberated from lipid using mild detergent and can be isolated in an intact form, allowing preparation of relatively pure forms of the antigen. Although these approaches raise the challenge of producing sufficiently large quantities of such native antigen for immunization purposes, they are nevertheless promising and deserve further development.


Envelope Glycoprotein Trimers as HIV-1 Vaccine Immunogens.

Sattentau QJ - Vaccines (Basel) (2013)

HIV-1 Env trimers for experimental vaccine use. (A) Functional, cleaved HIV-1 Env expressed in a viral, infected cell, or VLP membrane; (B) Uncleaved soluble gp140 trimer with “open” structure; (C) Cleaved gp140 is unstable resulting in subunit dissociation; (D) SOSIP gp140 is stabilized by disulfide bonds and maintains a compact “closed” conformation; (E) EM reconstruction of BG505 SOSIP gp140 at 24A resolution showing compact globular morphology, from [93] with permission; (F) HIV-1 gp160 expressed from infected or transfected cells contains a proportion of so-called “junk” forms that may compete with the native trimeric forms for induction of neutralizing antibodies [79]. These may be at least partially removed by protease treatment [79]; (G) Disulfide (SOS)-stabilized membrane-anchored Env trimer [79,90].
© Copyright Policy - open-access
Related In: Results  -  Collection

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

vaccines-01-00497-f002: HIV-1 Env trimers for experimental vaccine use. (A) Functional, cleaved HIV-1 Env expressed in a viral, infected cell, or VLP membrane; (B) Uncleaved soluble gp140 trimer with “open” structure; (C) Cleaved gp140 is unstable resulting in subunit dissociation; (D) SOSIP gp140 is stabilized by disulfide bonds and maintains a compact “closed” conformation; (E) EM reconstruction of BG505 SOSIP gp140 at 24A resolution showing compact globular morphology, from [93] with permission; (F) HIV-1 gp160 expressed from infected or transfected cells contains a proportion of so-called “junk” forms that may compete with the native trimeric forms for induction of neutralizing antibodies [79]. These may be at least partially removed by protease treatment [79]; (G) Disulfide (SOS)-stabilized membrane-anchored Env trimer [79,90].
Mentions: There have been numerous attempts to express both membrane-anchored and soluble forms of trimeric Env for immunization. To date none of these attempts have led to induction of potent neutralizing antibodies against highly conserved Env surfaces, but some incremental improvements in neutralization compared to immunization with gp120 have been observed, suggesting that this strategy is worth pursuing [75]. The most straightforward way to produce trimeric Env with a native, functional conformation is to express it in a membrane context. This can be achieved by in vivo expression from DNA or from vectors encoding env. Obvious advantages of this approach are that the glycoprotein is assembled and expressed in the host cells, therefore being post-translationally processed in a similar manner to the virus during an infection. A downside of this approach is that the amount of Env expressed in vivo is unknown, but is likely to be relatively low, generally resulting in weak antibody responses without further protein boosting. Moreover, the antibody evasion mechanisms inbuilt into Env, including endocytosis and the presence of misfolded, uncleaved and subunit dissociated forms will be active in this setting. A more controlled strategy that can potentially deliver greater quantities of antigen is the ex-vivo expression of env in the context of Gag, resulting in production of virus-like particles (VLPs) [76,77]. VLPs contain functional trimers and can be purified to high concentration. Membrane-anchored Env produced in high-level expression systems is not free from non-functional forms and contains uncleaved monomer gp160, gp41 stumps and other membrane-anchored “junk” [78,79] (Figure 2). Of particular interest, treatment of membrane Env with protease eliminated most non-native forms whilst preserving native Env, as probed by native gel electrophoresis and neutralizing antibody binding [79,80]. Moreover, soluble gp160 can be liberated from lipid using mild detergent and can be isolated in an intact form, allowing preparation of relatively pure forms of the antigen. Although these approaches raise the challenge of producing sufficiently large quantities of such native antigen for immunization purposes, they are nevertheless promising and deserve further development.

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.


Related in: MedlinePlus