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New cAMP antagonists


HIV/AIDS

Development of Antagonists that Disrupt the Hyperactivated cAMP Signalling Pathway in Immunodeficiencies as Immunostimulatory Therapy
Framework programme:
5
Project number:
QLK2-CT-2002-72419
EC contribution:
€ 945 844
Duration:
24 months
Type:
CRAFT
Starting date:
December 2002

Keywords: Immunotherapy; immunostimulatory drug; HIV; AIDS; immunodeficiencies; cAMP; protein kinase A type I (PKAI); T lymphocyte; antagonist

Summary:

Drugs for immunomodulating therapy in HIV and other immunodeficiencies could possibly assist the immune system in driving out the HIV virus, and is expected to lower the incidence of opportunistic infections in several immunodeficiencies. The technology in the project is based on new knowledge showing that activation of a signal pathway involving the signal substance cAMP and protein kinase A type I, PKAI, inside white blood cells, T lymphocytes, inhibits the function of the immune system.
During HIV infection, the activity of this signal pathway is greatly increased due to elevated levels of cAMP and the function of the patient’s white blood cells is strongly reduced (Figure 1A). Development of immunostimulatory drugs that interfere with cAMP action by targeting and disrupting the cAMP/PKA type I signalling pathway will improve the immune function of T lymphocytes. The concept of developing PKAI selective cAMP antagonists that counteract cAMP action in T lymphocytes is demonstrated in Figure 1B. In vivo experiments and ex vivo clinical testing of compounds are on-going. The project will aim for treatment protocols that can help eradicate HIV and lower the total cost of treatment or simplify administration of the total treatment.

Problem:

HIV causes a chronic infection leading to severe dysfunction of the immune system with markedly increased incidence of a large number of infections and ultimately death. In the EU, HIV infection is the fifth leading cause of death among young adults. In the developing world, this problem is even larger. Estimates by the World Health Organisation indicate that the total number of HIV positive patients by the end of 2001 was above 40 million (including more than 1 million in the EU). The current treatments of HIV include only drugs that target the virus. These potent cocktails of anti-HIV drugs have been successful in keeping AIDS at bay in HIV-infected people. However, although these combination therapies can knock the virus back to undetectable levels in patients’ blood, HIV continues to lurk in reservoirs containing immune cells that harbour the virus where the drugs cannot reach. Thus, the present therapy does not offer cure for the disease, requires life-long treatments and has significant problems with adverse events and development of resistance. Alternative HIV therapies are now called for, and research efforts are therefore focused at developing immunostimulatory treatments that in combination with present treatment have the potential of eradicating the virus.

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