Keywords: Immunotherapy; immunostimulatory drug; HIV; AIDS; immunodeficiencies; cAMP; protein kinase A type I (PKAI); T lymphocyte; antagonist
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.
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.
The aim of the project is development and evaluation of immunostimulatory drugs that will reverse the immunodeficiency in HIV and other immunodeficiencies. Such treatment is called for since the present treatment does not offer a cure for the disease, is associated with resistance and has significant side effects. Immunostimulatory drugs 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, such as common variable immunodeficiency, septicemia (commonly caused by nosocomial infections) and the immunodeficient state occurring in cancer-induced cachexia, as well as following administration of cytostatic drugs.
Treatment based on immunostimulation, which will improve the function of the immune system of patients, can make the immune system competent in driving out the virus from the reservoirs. This appears to be an attractive and important addition to the present treatment of HIV, which only offers antiretroviral drugs. Furthermore, immunostimulation may be a prerequisite for efficient therapeutic vaccination strategies to work effectively.
|Official Address||Other Information|
|2||Hans-G.Genieser||BIOLOG Life Science Institute, Forschungslabor und Biochemica-Vertrieb GmbH |
|Tel: +49 421 591355 |
Fax: +49 421 5979713
|3||Bastian Zimmerman||Biaffin GmbH & Co KG |
AVZ 2, Heinrich-Plett-Str. 40
|Tel: +49 561 804 4661/-4662 |
Fax: +49 561 804 4665
Website: http://www.biaffin.com, http://www.proteinkinase.de
|4||Jo Klaveness, Ph.D.||Department of Medical Chemistry, School of Pharmacy, University of Oslo |
P.O.Box 1068 Blindern
|Tel: +47 2285 5043 |
Fax: +47 2285 7975
|5||Friedrich W. Herberg||Universität Kassel |
FB 18, Abteilung Biochemie
|Tel: +49 561 804 4511 / 4161 |
Fax: +49 561 804 4466
|6||Kjetil Taskén||The Biotechnology Centre of Oslo, University of Oslo |
P.O. Box 1125, Blindern
|Tel: +47 2284 0505 |
Fax: +47 2284 0506
|7||Michel Moutschen||University of Liège |
|Tel: +32 4 366 2410 |
Fax: +32 4 366 2919