NIH-Led Team Advances HIV Vaccine Design with Specially Shaped Protein

An HIV vaccine research team led by scientists from the National Institutes of Health has engineered a protein to maintain the particular shape predicted to be most effective at stimulating the immune system to produce powerful antibodies against the virus. The work was led by John R. Mascola, M.D., and Peter D. Kwong, Ph.D., of the Vaccine Research Center (VRC) at the National Institute of Allergy and Infectious Diseases (NIAID), part of NIH.

One way HIV hides from the immune system is by continuously changing the shape of a surface molecule where powerful antibodies could potentially bind to stop infection. This shape-shifting of the so-called viral spike helps conceal key antibody-binding sites and instead exposes other sites on the virus that lure minimally effective antibodies.

In previous work, scientists from the VRC and elsewhere found that an effective HIV vaccine that teaches the immune system to neutralize the virus should be based on a particular form of the viral spike called the closed, pre-fusion configuration. In the new research, Drs. Mascola, Kwong and colleagues report the stabilization of a protein that maintains this very configuration and confirm that it allows binding of effective antibodies but not ineffective ones.

In addition, while the viral spike typically changes shape in the presence of a common immune-cell receptor called CD4, the newly stabilized protein does not. This is critical because the protein needs to stay in the closed, pre-fusion configuration to elicit potent antibodies that broadly neutralize HIV.

The authors note that more molecular work remains to overcome other hurdles to eliciting HIV antibodies that could stop most strains of the virus from causing infection.

ARTICLE:
YD Kwon et al. Crystal structure, conformational fixation and entry-related interactions of mature, ligand-free HIV-1 Env. Nature Structural & Molecular Biology DOI: 10.1038/nsmb.3051 (2015).

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