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TARGETING NEF


HIV/AIDS

The HIV-1 Pathogenicity Factor Nef as a Novel Therapeutic Target>
Framework programme:
5
Project number:
QLK2-CT-2000-01630
EC contribution:
€ 1 300 000
Duration:
36 months
Type:
RS
Starting date:
1 September 2000

Keywords: HIV; AIDS; Nef; structure-function analysis; assay development; high-throughput screening; drug discovery; antiviral agents

Summary:

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.

Problem:

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.

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