Uncovering The Achilles' Heel Of The HIV-1 Envelope

Profound challenges have interfered with creation of a preventative vaccination to halt the global spread of HIV-1. For example, the HIV-1 envelope protein, the only target for neutralizing antibodies, is highly variable among isolates and masked by sugar molecules, allowing the virus to escape antibody attack. "Not surprisingly, only a handful of broadly neutralizing antibodies (BNAbs) have been identified and they are rarely elicited during natural human infection," explains research leader Dr. Ellis L. Reinherz from the Dana-Farber Cancer Institute and Harvard Medical School in Boston, Massachusetts.

The BNAbs that have been identified are directed against a portion of HIV-1 called the membrane proximal ectodomain region (MPER). This region lies at the base of the viral envelope protein comprised of the gp120 protein plus the membrane anchoring gp41 subunits adjacent to the viral membrane. A major conundrum has been the basis for the lack of human antibody response against the MPER segment since it is accessible to antibody and is highly conserved, even among different HIV-1 viral isolates around the world.

The present study reveals that much of the MPER is actually embedded in the viral membrane. As such, this stealthy segment appears to divert the immune attack elsewhere, namely to the exposed variable elements of the viral envelope and immunodominant regions which do not confer useful neutralization. The researchers also discovered a hinge in the middle of the MPER permitting segmental flexibility, an important feature in facilitating fusion of the virus with the human host immune cells.

BNAbs such as the monoclonal 4E10 antibody target this hinge area and cause the MPER to undergo dynamic changes that reveal key pieces of itself critical for viral fusion that were buried deep in the membrane. As a result, the antibody is then able to achieve a tighter hold on the virus, restrict hinge mobility and impede the ability of the virus to fuse to the membrane of the host cell.

Importantly, the published structure of the lipid-embedded MPER also identifies those few residues poking out from the viral membrane. These may be ideal targets for vaccine design if properly configured in a synthetic lipid coat that conserves the native shape of the MPER and focuses production of antibodies against this Achilles' heel of the viral envelope.

While this research is still at an early experimental stage, it provides a plausible explanation as to why previous attempts, which neglected to preserve the native conformation of the MPER necessary for eliciting a broadly neutralizing antibody with 4E10-like specificity, were unsuccessful and offers a new approach to the design of antibody-eliciting vaccines to prevent HIV-1.

The findings are published by Cell Press in the January issue of Immunity.

The researchers include Zhen-Yu J. Sun, Harvard Medical School, Boston, MA, USA; Kyoung Joon Oh, Harvard Medical School, Boston, MA, USA, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Mikyung Kim, Harvard Medical School, Boston, MA, USA, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Jessica Yu, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Vladimir Brusic, Harvard Medical School, Boston, MA, USA, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Likai Song, Harvard Medical School, Boston, MA, USA, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Zhisong Qiao, Harvard Medical School, Boston, MA, USA, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Jia-huai Wang, Harvard Medical School, Boston, MA, USA, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Gerhard Wagner, Harvard Medical School, Boston, MA, USA; and Ellis L. Reinherz, Harvard Medical School, Boston, MA, USA, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.