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How do HIV-protease inhibitors cause diarrhea?

The gastrointestinal tract is one of the most important target organs for HIV infection and its clinical manifestations. The virus frequently enters the body via the intestine and since most immune cells of the body are located in this organ, it substantially contributes to HIV pathogenesis. Throughout the course of HIV infection, the intestinal mucosa is a place of active virus production. Within weeks after primary infection a massive loss of CD4 T cells occurs in the mucosa.

Highly active antiretroviral therapy (HAART) improves intestinal immune function and reduces HIV-induced gastrointestinal symptoms and opportunistic infections. On the other hand, diarrhea is a common adverse effect of HIV-protease inhibitors, which are an important component of HAART.

First experiments from our laboratory using a cell model of the mucosa suggest that these substances damage the barrier between the bowel wall and the intestinal lumen. This would lead to the leakage of ions and water from the tissue into the lumen, which can cause diarrhea.

In our project, we will first investigate whether additives in the capsules apart from the protease inhibitors itself contribute to this effect. In addition, the mechanism of the mucosal damage will be analyzed. Cell death (necrosis or apoptosis) or disruption of the cellular tight junctions could be responsible. Finally, intracellular pathways involved will be studied using specific inhibitors.

Investigation into the pathogenesis of HIV-protease inhibitor-induced diarrhea could lead to strategies to reduce or avoid this adverse effect. Reduction of adverse effects facilitates the consequent taking of HAART for HIV-infected patients, which is essential for a sustained success of their therapy.


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