Mice with an immune system which has been partially "humanised" have been used to select peptides of interest for an anti-HIV vaccine, as is shown by a study carried out by the Antiviral Cellular Immunity Unit of the Institut Pasteur , shortly to appear in the European Journal of Immunology. The work, which was performed in collaboration with Généthon* (immunology laboratory) and INSERM, have already made it possible to build a candidate vaccine which has induced long-term cellular immune responses in animals.
The principal weapon of the immune system against HIV infection is a class of white blood cells capable of destroying infected cells: Cytotoxic T lymphocytes (CTL). Moreover, the presence of several different types of CTL, each directed towards a given peptide in the virus, seems to be associated with better defence. It therefore seems to be important for triggering a good immune response by vaccination - whether it is intended for preventive or therapeutic purposes - to associate different immunogenic peptides (epitopes) which are CTL inducing. Many laboratories throughout the world have devoted recent years to the search for such epitopes. How can they be selected, evaluated, and even be improved? Mice with a partially humanised immune system**, developed over the last few years by the Antiviral Cellular Immunity Unit, have been used for these goals.
This animal model has firstly made it possible to compare the immunogenic power of 17 HIV-1 epitopes already reported in the literature. The researchers then evaluated the possibility of improving the immunogenicity of certain of these epitopes, using a method developed in the unit with the collaboration of researchers in INSERM, and have shown that optimisation could indeed be achieved.
This work has made it possible to select 13 highly immunogenic epitopes, relatively well preserved among viral isolates, and capable of inducing CTL responses equally active against the principal natural variants of the virus.
They have been put together to build a polyepitope which was coupled with a hepatitis-B viral surface protein (to act as the vector) with a view to a DNA vaccination. This candidate vaccine, injected into mouse muscle, has induced long-term CTL responses against the greater part of the epitopes of the candidate vaccine.
It is still too soon to confirm the significance of such a candidate vaccine in man, since the transposition of observations made in mice to the human system are always open to debate. However, the researchers have high hopes that by means of their model they will be able to select the most promising epitopes for man. Moreover, this model seems to be applicable to the optimisation of their potential as vaccines. Indeed, presentation of the epitopes to the immune system depends on molecules thanks to which the cytotoxic lymphocytes differentiate between self (a normal cell) and non-self (a cell infected by a virus). It is by improving the anchoring of the epitopes to these molecules that the researchers have succeeded in increasing their immunogenic power. Now, these molecules are precisely the human molecules in the mice which were used in this study. The method of optimisation of the peptides of interest as vaccines is therefore theoretically transposable to man.
Beyond promising data on the question of a candidate vaccine against infection by the AIDS virus, this study equally underlines the relevance of an animal model which can help in the evaluation of other vaccine strategies, whether against AIDS or other pathologies.
*Généthon is the AFM laboratory financed thanks to donations by Téléthon
**Transgenic mice with a human self-recognition
system (HLA) representative of a great part of the population (notably,
50% of the Caucasian population). Mice whose self- and non-self-recognition
system covers a greater part of the human population are in the process
of development at the Cellular Antiviral Immunity Unit.
Reference: "Design of a polyepitope construct for the induction of HLA-A0201-restricted HIV 1 - specific CTL responses using HLA-A*0201 transgenic, h-2 class IKO mice": European Journal of Immunology. 1st October 2001
Hüseyin Firat (1,5), Sophie Tourdot (2), Abel Ureta-Vidal (1), Antonio Scardino (2), Andreas Suhrbier (3), Florence Buseyne (4), Yves Rivière (4), Olivier Danos (5), Marie-Louise Michel (6), Konstadinos Kosmatopoulos (2) and François A. Lemonnier (1)
1. Cellular Antiviral Immunity Unit, AIDS-Retrovirus
Department, Pasteur Institute, France INSERM Unit 487, Villlejuif, France
2. Queensland Institute of Medical Research, PO Royal Brisbane Hospital,
Australia
3. Genetic Recombination and Expression Unit, INSERM Unit 163, AIDS-Retrovirus
Department, Pasteur Institute, Paris, France
4. Généthon III, CNRS, URA 1923, Evry, France
5. Viral Immunopathology Laboratory, URA CNRS 1930, AIDS-Retrovirus Department,
Pasteur Institute, France
Contacts:
- François Lemonnier :
Phone: +33 (0) 145 688 146 - Fax: +33 (0) 145 688 942 - E-mail: flemonn@pasteur.fr
- Press Office Institut Pasteur :
Phone: +33 (0) 145 688 146 - Fax: +33 (0) 140 613 030 - E-mail: presse@pasteur.fr