In order to be able to ward off disease pathogens, immune cells must be mobile and able to establish contact with each other. Professor Dr. Oliver Fackler’s group of researchers in the Department of Virology of the Institute of Hygiene at the University of Heidelberg has discovered a mechanism in an animal model revealing how HI viruses cripple immune cells: The mobility of cells is inhibited by the protein Nef. The study, which was published in the highly renowned journal “Cell Host & Microbe”, might potentially also open up new therapeutic strategies.
More than 30 million people worldwide are infected with HIV. Typically, the initial infection is accompanied by acute symptoms and then is followed by a latency period of several years before the acquired immunodeficiency syndrome (AIDS) manifests. The HI virus has developed numerous strategies for eluding the body’s immune defence as well as the effect of the drugs used to treat the infection. The viral Nef protein is a major prerequisite for the efficient reproduction of the virus in the affected individuals. The development of AIDS is significantly slowed without Nef, or even stops completely. The underlying mechanism of this observation has, however, previously not been known.
Viruses alter the support structure of affected cells in turn enabling them to enter the cells more easily. The cell structure element actin, which also gives muscles their mobility, aids in the motility of immune cells. The mobility is necessary for immune cells to be able to establish contact with each other and ward off the virus. After each movement, actin must be returned to its original state in order to be available again. HIV preferentially attacks the immune cells of the T-helper cell type. These cells support not only the direct defence mounted against the enemy, but are also necessary for producing sufficient antibodies against the invader. In order to do so, they must rely on their mobility.
The researchers examined the movement of cells in living zebra fish embryos and were able to show that cell mobility is inhibited by the HIV Nef protein. In subsequent experiments involving cell cultures, they were able to explain the underlying mechanism: Nef causes an enzyme, which normally has nothing to do with cell mobility, to deactivate a regulator for actin regeneration. Nef, therefore, causes a short-circuit of two cellular mechanisms, thereby inhibiting the reorganisation of the cell structure element actin and the cell's ability to move. Thus, the affected immune cells can no longer fulfil their function.
"We speculate that the negative effect of Nef on the mobility of T-helper cells has far reaching consequences for the efficient formation of antibodies by B-lymphocytes in the patient. The mechanism we have described could be involved in the increasingly observed malfunction of B-lymphocytes in AIDS patients," explains Professor Fackler. Up to now, Nef has not yet been a target of antiviral therapy. However, since one of the first molecular mechanisms has now been uncovered, and the importance of Nef for this disease has become clearer, this could change in the future.