Nuclear MR sheds light on elusive HIV vaccine

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By coaxing the HIV-1 protein to reveal a hidden portion of its protein coat, scientists have provided a newly detailed picture of how protective, or broadly neutralizing, antibodies block HIV-1 infection, according to the January issue of Immunity.

The main stumbling blocks to finding an HIV vaccine are the virus's envelope protein--the target for any antibody-based vaccine, which varies greatly from one viral strain to the next and is strewn with sugar molecules, which make it difficult for the immune system to select the virus for destruction.

Ellis Reinherz, MD, and colleagues of the Cancer Vaccine Center at Dana-Farber Cancer Institute and Harvard Medical School--both located in Boston--focused on an HIV-1 surface protein called gp41 and, specifically, on a portion of it known as the membrane proximal ectodomain region (MPER). The region lies at the base of HIV's envelope protein, and is consistent across different strains of the virus.

The scientists studied its structure using nuclear MR, electron paramagnetic resonance and surface plasmon resonance imaging technologies. They discovered that MPER is immersed in the viral membrane, giving it refuge from immune system attack, and it also has a hinge in the middle, which provides flexibility and helps it attach to white blood cells known as T lymphocytes.

The researchers found that a BNAb, called 4E10, fixates on the hinge area, which pulls out key portions of MPER that had been buried inside the membrane. Then, 4E10 latches onto these newly exposed sections, forming a tighter bond with the virus and blunting its ability to fuse with the cell membrane, the first step in viral infection.

"The new features of MPER that we've discovered may be useful targets for antibody-based vaccines if they can be held in proper configuration," co-author Mikyung Kim, PhD, said. “One way of doing this would be to place them in a synthetic lipid coat on nanoparticles. If the antibodies aren't 'confused' by other elements of the virus' protein envelope, this approach may elicit a strong immune response to viral presence,” Kim said.