Keywords: HIV; AIDS; Nef; structure-function analysis; assay development; high-throughput screening; drug discovery; antiviral agents
The objective of this project is to extend the ongoing basic research in the laboratories of this consortium in order to transform the HIV-1 pathogenicity factor Nef into a therapeutic target that would be attractive and readily available to the pharmaceutical industry for exploitation in drug discovery.
At the end of 2001, an estimated 40 million people globally were living with HIV. Although the number of new HIV-1 infections per year in EU countries has not recently decreased, the new combinations of anti-HIV drugs have reduced AIDS deaths significantly and improved the quality of life and capacity to contribute to society for many HIV-infected individuals in Europe. Despite these positive developments, however, it is painfully apparent that the current AIDS therapies are insufficient and problematic, and this situation is likely to get worse as multiresistant HIV strains become more common. Therefore, finding new drugs against the current molecular targets of anti-HIV therapies, as well as innovative new drugs that target novel HIV functions is critically needed.
HIV-1 Nef is a promising candidate for a novel therapeutic target in AIDS. Although Nef is not required for the replicative cycle of HIV, Nef is critical for the development of AIDS in HIV-infected individuals and SIV-infected rhesus monkeys. By enhancing HIV replication and protecting the infected cells from the immune system, Nef can contribute to the development of high viral loads, which is the driving force of HIV disease progression. In addition, Nef has an independent pathogenic function, and when expressed in transgenic mice in the absence of any other HIV components can cause a pathological condition that recapitulates many of the salient features of human AIDS. Therefore, drugs that target Nef might not only inhibit HIV replication, but could also have a completely new, and possibly highly beneficial, therapeutic effect through the inhibition of Nef-induced pathogenicity. Moreover, blocking the immune-evading effects of Nef, would also be anticipated to lead to a better immunological control of HIV infection, which is particularly noteworthy considering that, with the current therapies, eradication of HIV from a patient has to date remained a theoretical possibility. Despite this remarkable promise, Nef has so far not been widely exploited as a therapeutic target. This has been mainly because the molecular mechanisms by which Nef functions in the infected cell remain incompletely understood. Thus, Nef has been considered a difficult target for pharmaceutical exploitation.
The first aim of this project is to develop a consensus regarding the biochemical and cellular functions of Nef and the molecular surfaces of Nef that are critical for mediating these functions. By using carefully standardised study systems and reagents, by examining multiple putative Nef functions in parallel, and by testing a large number of potentially relevant function-modifying mutations in the background of a single molecular clone of Nef, this project aims to resolve the current controversies regarding Nef function. We also aim to develop novel mouse models that could be used to test the pathogenic function of Nef and the ability of different mutations in Nef to abolish it in an in vivo setting. The most important aim of the project is to generate a set of user-friendly high-throughput assays that could be used by the pharmaceutical industry to screen for compounds that would block those Nef functions that were found to be most relevant for its pathogenic effect.
The expected results of this project will be:
The results of this project are expected to be applicable to the discovery of novel anti-HIV drugs by the pharmaceutical industry. Because of the multifactorial role of Nef in AIDS pathogenesis explained above, such Nef inhibitors could be highly synergistic if combined with the drugs currently used to treat HIV infection that act by directly inhibiting viral enzymes involved in HIV replication.
|Official Address||Other Information|
|2||Andreas Baur||University of Erlangen |
Dermatologische Klinik und Poliklinik
|Tel: +49 9131 853 6307 |
Fax: +49 9131 8532724
|3||Mark Harris||University of Leeds |
Division of Microbiology
UK-LS2 9JT Leeds
|Tel: +44 113 343 5632 |
Fax: +44 113 343 5638
|4||Hans-Georg Kraeusslich||University of Heidelberg |
Hygiene-Institut / Abt. Virologie
Im Neuenheimer Feld 324
|Tel: +49 6221 565001 |
Fax: +49 6221 565003
|5||Olivier Schwartz||Institut Pasteur |
Laboratoire Rétrovirus et Transfert Génétique
25 rue du Roux
FR-75724 Paris Cedex 15
|Tel: +33 1 45 68 83 53 |
Fax: +33 1 45 68 89 40