Uncovering The Achilles' Heel Of The HIV-1 Envelope

[J220]

From http://www.sciencedaily.com/releases/2008/01/080111105342.htm.

ScienceDaily (Jan. 11, 2008) — New structural details illustrate how a promising class of antibodies may block human immunodeficiency virus (HIV)-1 infection and reveal valuable clues for design of an effective HIV-1 vaccine. The findings are particularly significant as antibody induction appears to be a key and necessary component of an effective HIV vaccine, evidenced by the recent failure of vaccines that stimulated only the T cell arm of the immune system to protect humans from contracting HIV-1.

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.\\

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Below is a related article with a little more information on the above:



ScienceDaily (Jan. 11, 2008) — By coaxing the HIV-1 protein to reveal a hidden portion of its protein coat, scientists at Dana-Farber Cancer Institute and Harvard Medical School have provided a newly detailed picture of how protective, or so-called broadly neutralizing, antibodies block HIV-1 infection.

In a study in the January issue of Immunity, the investigators report that the discovery may help researchers overcome two of the main stumbling blocks that have arisen on the road to an HIV vaccine: the fact that the virus's envelope protein -- the target for any antibody-based vaccine -- 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.

"Not surprisingly, only a handful of broadly neutralizing antibodies (BNAbs) have been identified, and they are rarely elicited during natural human infection," says the study's senior author, Ellis Reinherz, MD, who is the faculty director of the Cancer Vaccine Center at Dana-Farber and a professor of medicine at Harvard Medical School.

The study focuses on an HIV-1 surface protein called gp41 and, specifically, on a portion of it known as the membrane proximal ectodomain region (MPER). This region, which lies at the base of HIV's envelope protein, is consistent across different strains of the virus. In theory, that should make it an attractive target for immune system antibodies, but, in fact, the antibody response to it is rather meager.

To determine why this is so, the Dana-Farber team studied its structure using nuclear magnetic resonance (NMR), electron paramagnetic resonance (EPR), and surface plasmon resonance (SPR) imaging techniques. They discovered that MPER is not only immersed in the viral membrane, giving it refuge from immune system attack, but it also has a hinge in the middle, which provides flexibility and helps it attach to white blood cells known as T lymphocytes.

Despite this stealthiness, the researchers found that a BNAb called 4E10 homes in on the hinge area and, in so doing, pulls out key portions of MPER that had been buried inside the membrane. Then, like a rock climber who finds an additional handhold, 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," says study co-author Mikyung Kim, PhD, of Dana-Farber. "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's protein envelope, this approach may elicit a strong immune response to viral presence."

Funding for the study was provided by a grant from the National Institutes of Health.

The paper will be posted on the web site of the journal Immunity on Jan. 10 in advance of the print publication. The study's lead authors, in addition to Kim, are Zhen-Yu Sun, PhD, of Harvard Medical School, and Kyung Joon Oh, PhD, of Dana-Farber and Harvard Medical School. The co-authors are Jessica Yu and Vladimir Brusic of Dana-Farber; Likai Song, MD, PhD, Zhisong Qiao, PhD and Jia-huai Wang, PhD, of Dana-Farber and Harvard Medical School; and Gerhard Wagner, PhD, of Harvard Medical School.