Antibodies that Act on Envelope of HIV-1 Revealed

Researchers at Harvard Medical School found that a class of antibodies may become a necessary ingredient for effective HIV-1 vaccine, as they have shown some promise in blocking the virus.

Researchers at Harvard Medical School found that a class of antibodies may become a necessary ingredient for preparing an effective HIV-1 vaccine, as they have shown some promise in blocking the virus.

The findings attain significance as recent attempts to harness only T cells of the immune system to protect humans from contracting HIV-1 fizzled out.

'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, a major affiliate of Harvard Medical School.

The BNAbs that have been identified are directed against a portion of HIV-1 called the membrane proximal ectodomain region (MPER), which lies at the base of the viral envelope protein, the only target for neutralizing antibodies.

However, the HIV-1 envelope protein is highly variable among its different viral isolates, and sugar molecules masking it prevent human antibody response against the MPER segment.

The current study has now revealed that much of the MPER is actually embedded in the viral membrane. This stealthy segment appears to divert the immune attack elsewhere — 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 like 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. Consequently, 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.

The structure of the lipid-embedded MPER also reveals some residues poking out from the viral membrane. The researchers believe that they 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.

The study, which is still at an early experimental stage, has been reported in the journal Immunity, a Cell Press publication.

Source-ANI
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