Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2006 Jun;5(3):347-63.
doi: 10.1586/14760584.5.3.347.

Aiming to induce broadly reactive neutralizing antibody responses with HIV-1 vaccine candidates

Barton F Haynes  1 , David C Montefiori
Affiliations
Review

Aiming to induce broadly reactive neutralizing antibody responses with HIV-1 vaccine candidates

Barton F Haynes et al. Expert Rev Vaccines. 2006 Jun.

Abstract

Neutralizing antibody induction is a key feature of many effective vaccines and is the only immune response that has proven to be capable of completely blocking AIDS virus infection in animal models. Unfortunately, the extensive genetic variability and complex immune-evasion strategies of HIV-1 have thwarted all attempts to date at eliciting an effective neutralizing antibody response with candidate HIV-1 vaccine immunogens. Recent advances in our understanding of how these evasion strategies operate, coupled with growing progress in unravelling the structure and immunobiology of the viral envelope glycoproteins, are contributing to novel immunogen designs to overcome the many barriers to inducing protective antibodies against HIV-1.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Proposed models for gp120/gp41 trimers in unliganded and CD4-bound conformations
(A) A trimer in the unliganded conformation, viewed along the threefold axis from outside the virion towards gp41. The polypeptide chain backbones are in ribbon representation; N-linked glycans are stick models; deleted V1–V2 and V3 segments are transparent balloons. The three monomers are in red, green and blue, respectively; the sugars, in grey. Gp41 is shown as a circle in the rear. (B) The same view of a gp120/gp41 trimer as in panel A, but in the CD4-bound conformation, generated by superposing the CD4-bound HIV gp120 structure onto the unliganded SIV gp120 subunits in panel A, assuming that the three-strand, inner-domain-sheet remains roughly in place. Structural elements depicted as in panel A; CD4 omitted for clarity. (C) "Side" view of the same model as in panel A. The N and C termini of the gp120 core are labelled. Gp41 is shown as a cylinder at the bottom. Green arrows indicate CD4-binding loops. (D) Side view of the same model as in panel B. The first two domains of CD4 are shown in light green on only one gp120 monomer. N and C termini of the gp120 core are labelled. Gp41 is shown as a cylinder at the bottom. gp: Glycoprotein; SIV: Simian immunodeficiency virus. Reproduced with permission from [62] Nature Publishing Group® (2005).
Figure 2
Figure 2. Model for HIV-1 host cell fusion
Schematic representation of the ligand-triggered conformational changes in gp120/gp41 that promote membrane fusion. (A) Encounter between virus, with gp120/gp41 on its surface, and cell, with CD4 and coreceptor. The Env trimers are shown with gp120 (red), gp41 (blue) and the fusion peptide at the N-terminus of gp41 (green). CD4 and coreceptor (yellow), anchored in the cell membrane (green). Viral membrane in brown. (B) Binding of receptor and coreceptor triggers conformational change in gp120, leading to its release from gp41. Gp41 unfolds into an extended, intermediate conformation, so that the fusion peptides at one end insert into the target-cell membrane. Residues 25–75 (light blue) of gp41 form a central, three-chain coiled coil. The C-terminal part of the gp41 ectodomain (darker blue) may have a less ordered conformation. This intermediate has a relatively long lifetime (at least several minutes). (C) The C-terminal segment of the gp41 ectodomain (residues ~117–170) zips up into an outer-layer helix, bringing the transmembrane anchor of gp41 toward the fusion peptide. Two Env trimers are shown cooperating here, but a single trimer may be sufficient. The coming together of the fusion peptide at the N-terminus of gp41 and the transmembrane anchor toward its C-terminus draws the two membranes toward each other and ultimately promotes hemifusion. (D) A hemifusion stalk has formed. The apposed leaflets of the two bilayers have merged, but not the distal leaflets. If the fusion peptides insert only into the outer leaflets (as is the case for flavivirus and alphavirus fusion loops and probably for the influenza HA fusion peptide), then they can migrate into the hemifusion stalk, as shown here. However, direct evidence for this arrangement is lacking. (E) Formation of a complete fusion pore. The C-terminal residues of the gp41 ectodomain, which contain the 2F5 and 4E10 epitopes, snap into place, bringing the cytoplasmic domains of gp41 through the fusion pore and making the fusion step irreversible. Reproduced with permission from Stephen Harrison, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA.
Figure 3
Figure 3. Carbohydrates on gp120, and the binding sites of CD4 and mAb 17b
Molecular surface representations of gp120 core structures in liganded and unliganded states. Residues in direct contact with CD4 (green); residues contacting human mAb 17b (red); carbohydrate (blue). The arrow indicates the mouth of the envelope hydrophobic cavity. BS; Binding sites; gp: Glycoprotein; mAb: Monoclonal antibody. Reproduced with permission from [62] Nature Publishing Group® (2005).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Klausner R, Fauci A, Corey L, et al. Medicine. The need for a global vaccine enterprise. Science. 2003;5628:2036–2039. - PubMed
    1. Esparza J, Klausner RI The Coordinating Committee of the Global HIV/AIDS Vaccine Enterprise. The Global HIV/AIDS Vaccine Enterprise: Scientific Strategic Plan. 2005;2:e25. - PubMed
    1. Derived from Statistics in Global Summary of the AIDS Epidemic, ‘AIDS Epidemic Update’ UNAIDS. World Health Organization; 2005. Dec,
    1. Letvin NL. Progress toward a HIV vaccine. Ann. Rev. Med. 2005;56:213–223. - PubMed
    1. Gandhi R, Walker B. Immunologic control of HIV-1. Ann. Rev. Med. 2002;53:149–172. - PubMed

Publication types

MeSH terms

Substances