AIDS: Lab success is good news for vaccine quest Tue Nov 16 2004 10:02:15 ET
PARIS, Nov 16 (AFP) - French researchers announced on Tuesday that, in laboratory conditions, they had stimulated antibodies which dramatically barred the AIDS virus from infecting human immune cells.
The results -- the first time such a success has ever been achieved against such a wide genetic range of the virus -- "open up interesting prospects for the development of a vaccine against AIDS," the team said in a press release.
"Twenty years after the human immunodeficiency virus (HIV) was identified, the AIDS pandemic is one of the greatest challenges to public health on a global scale.
"The need for a vaccine against HIV is thus greater than ever."
Antibodies are the molecular frontline forces in the body's defence system, designed to tag an invading virus or bacterium so that it is destroyed by immune cells.
Many vaccines, such as those against the flu, polio and measles, are based on antibodies, using a piece of the virus to prime the immune system so that it identifies the intruder in the future.
But antibody designs against HIV have so far been a huge disappointment. So far, none has been found that can deliver a big immune punch.
One suspected reason is that wild types of HIV may be somewhat different from the strains used in labs.
Among wild strains, the proteins on the surface of the virus which are often used as the antibody primers may be more difficult to detect because they are folded over and may be camouflaged by slippery sugar molecules.
Another likely reason for the failure is viral variety -- with different sub-types of HIV and mutation, the antibodies may be hunting an absent or a shifting target.
The French team has taken a different and more specific tack, targeting a tiny area of a surface protein that, they say confidently, is common across the range of HIV types.
This area is called CBD1 and is part of the gp41 protein. CBD1 binds to a protein in the T-lymphocyte immune cell called caveolin-1, thus helping the AIDS virus to dock to and infiltrate its target.
The researchers synthesised a chain of peptides -- the building blocks of proteins -- corresponding to CBD1 and immunised rabbits with it.
In lab-dish experiments in which blood taken from the immunised rabbits was exposed to human T-cells and the virus, it proved to be a remarkable shield against a range of sub-types of HIV-1, the commoner and more vicious form of the two big strains of the virus.
"The anti-CBD1 antibodies work in two ways," the press statement said. "Firstly, they inhibit cellular infection by HIV, and secondly, among cells that are already infected, they lead to the production of defective viruses (which) are unable to infect other cells."
The vaccine is only experimental and has not been applied to any human volunteers to see whether it is safe or effective.
Even so, the findings are deeply encouraging, the French scientists say.
"It shows that the CBD1 area can be used as a specific target for developing an effective immune response."
The study, lead-authored by Ara Hovanessian of the Pasteur Institute and National Centre for Scientific Research (CNRS), was published on Tuesday in a specialist journal, Immunity.
More than 20 million people have died of AIDS and some 38 million more have HIV, the virus which causes it.
But in the entire 23-year history of AIDS, only one vaccine, a design based on the gp120 protein, has ever gone through the entire three-phase test process, and it proved a disappointing flop.
Here's the abstract
Article
The Caveolin-1 Binding Domain of HIV-1 Glycoprotein gp41 Is an Efficient B Cell Epitope Vaccine Candidate against Virus Infection
Ara G. HovanessianCorresponding Author Contact Information, 1, Corresponding Author Contact Information, E-mail The Corresponding Author, 4, Jean-Paul Briand2, Elias A. Said1, 4, Josette Svab1, 4, Stephane Ferris1, Hayet Dali2, Sylviane Muller2, Claude Desgranges3, 4 and Bernard Krust1, 4
1 Unité de Virologie et Immunologie Cellulaire, URA 1930 CNRS, Institut Pasteur, 28 rue du Dr. Roux, 75724, Paris Cedex 15, France
2 Institut de Biologie Moléculaire et Cellulaire, UPR 9021 CNRS, 15 rue René Descartes, F-67084, Strasbourg Cedex, France
3 Institut de Génétique Moléculaire, EMI 03-34 INSERM, Hôpital St. Louis, 75010, Paris, France
Received 12 February 2004; Revised 25 June 2004; accepted 25 August 2004 Published: November 16, 2004 Available online 16 November 2004.
Abstract
Caveolin-1 is a scaffolding protein that organizes and concentrates specific ligands within the caveolae membranes. We identified a conserved caveolin-1 binding motif in the HIV-1 transmembrane envelope glycoprotein gp41 and designed several synthetic peptides, referred to as CBD1, corresponding to the consensus caveolin-1 binding domain in gp41. In rabbits, these peptides elicit the production of antibodies that inhibit infection of primary CD4+ T lymphocytes by various primary HIV-1 isolates. Interestingly, gp41 exists as a stable complex with caveolin-1 in HIV-infected cells. Anti-CBD1 peptide antibodies, therefore, might be functional by inhibiting the potential interaction of gp41 with caveolin-1. Because of their capacity to elicit antibodies that inhibit the different clades of HIV-1, CBD1-based peptides may represent a novel synthetic universal B cell epitope vaccine candidate for HIV/AIDS. Moreover, such peptides could also have an application as a therapeutic vaccine since CBD1-specific antibodies are rare in HIV-infected individuals from several geographic origins. |
