A discovery by researchers revealing how HIV, the AIDS pathogen, cripples immune cells may have pointed the way towards a new treatment approach.

Over 30 million persons worldwide are infected with the human immunodeficiency virus (HIV) that causes acquired immunodeficiency syndrome (AIDS), the condition in humans in which the immune system begins to fail. Typically, after the initial infection accompanied by acute symptoms, there is a latency period of several years before AIDS manifests.

Image: HIV infection (HIV-1 protein CA in green) in actin cytoskeleton of human T-lymphocytes (red).

HIV has developed numerous strategies for eluding the body's defenses and treatments. The prerequisite for efficient reproduction of the virus in the patient's body is the virus's own Nef protein. HIV-1 Nef is a key factor in AIDS pathogenesis. Without Nef, the development of AIDS is significantly slowed or even stopped completely. Up until now the underlying mechanism of this observation was a complete mystery.

In order to be able to ward off disease pathogens, immune cells must be mobile and be able to establish contact with each other. HIV alters the cell structure system of the affected cells, enabling the virus to enter the cells more easily. The cell structure element actin that gives muscles their mobility also aids in the motility of immune cells. Motility is necessary for immune cells to be able to establish contact with each other and combat the virus. After each movement, actin must be returned to its original state in order to be available once again. HIV especially attacks immune cells of the T-helper type. These cells support not only direct "defense against the enemy", but are also necessary for building sufficient antibodies against the invader. For this, 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. As the researchers continued their experiments on cell cultures, they were able to explain the underlying mechanism: Nef causes an enzyme that 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, thus inhibiting the reorganization of the cell structure element actin and the cell's ability to move. Thus, the affected immune cells can no longer fulfill 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 study author Professor Oliver Fackler. Up to now, Nef has not been a target of antiviral therapy. Since one of the first molecular mechanisms has now been decoded, however, and the importance of Nef for the disease has become clearer, this could change in the future.
References:
1. Stolp B, Reichman-Fried M, Abraham L, Pan X, Giese SI, Hannemann S, Goulimari P, Raz E, Grosse R, Fackler OT. HIV-1 Nef interferes with host cell motility by deregulation of Cofilin. Cell Host Microbe. 2009 Aug 20;6(2):174-86. PMID: 19683683.