Starving HIV virus could be the basis for future therapy: Study

By Dr. Ananya Mandal, MDFeb 13 2012

In a medical breakthrough researchers at NYU Langone Medical Center and colleagues have shown how some cells in the body can repel attacks from HIV by starving the virus of the building blocks of life.

In usual cases the viruses cannot replicate on by themselves. They need resources from the cells they parasitize and eventually turn them into virus production factories. A study, published in Nature Immunology, showed how some parts of the immune system destroy their own raw materials, stopping HIV. It is uncertain whether this could be used in therapy experts caution.

“A lot of research on viruses, especially HIV, is aimed at trying to understand what the body's mechanisms of resistance are and then to understand how the virus has gotten around these mechanisms,: said co-lead investigator Nathaniel R. Landau, PhD, a professor of microbiology at the Joan and Joel Smilow Research Center at NYU School of Medicine.

HIV attacks the immune system and can weaken the body's defenses to the point that everyday infections become fatal. However, not all parts of the immune system become subverted to the virus' cause. Macrophages and dendritic cells, which have important roles in orchestrating the immune response, seem to be more resistant say researchers.

Last year researchers identified the protein SAMHD1 as being a critical part of this resistance. Now scientists believe they know how it works. They have shown that SAMHD1 breaks down the building blocks of DNA. So if a cell needs to make a copy of itself it will have a pool of these building blocks - deoxynucleoside triphosphates or dNTPs - which make the new copies of the DNA. However, they can also be used by viruses. The study showed that SAMHD1 lowered the levels of dNTPs below that needed to build viral DNA and prevented infection. When they removed SAMHD1 then those cells had higher levels of dNTPs and were infected by HIV.

The report said, “By depleting the pool of available dNTPs, SAMHD1 effectively starves the virus of a building block that is central to its replication strategy.” It is possible for macrophages and dendritic cells to produce SAMHD1 as they are “mature cells” which do not go on to produce new cells.

Prof Baek Kim, one of the researchers from the University of Rochester Medical Center, said, “It makes sense that a mechanism like this is active in macrophages. Macrophages literally eat up dangerous organisms, and you don't want those organisms to have available the cellular machinery needed to replicate and macrophages themselves don't need it, because they don't replicate. So macrophages have SAMHD1 to get rid of the raw material those organisms need to copy themselves. It's a great host defense.”

Dr Jonathan Stoye, virologist at the Medical Research Council National Institute of Medical Research, was part of the team which determined the chemical structure of SAMHD1 last year and predicted that it would attack the dNTPs. “We hypothesized that it works in this fashion and the paper tells us we were right. It is depleting cells of these dNTPs, in cells which are not proliferating (dividing).” However, some cells do need to divide to boost numbers as part of the immune defence. Such as CD4 cells which are the prime target for HIV infection. “Cells which are proliferating would be in trouble if we took dNTPs away,” Dr Stoye said.

“Viruses are remarkably clever about evading our immune defenses,” Dr. Landau said. “They can evolve quickly and have developed ways to get around the systems we naturally have in place to protect us. It's a bit of evolutionary warfare and the viruses, unfortunately, usually win. We want to understand how the enemy fights so that we can outsmart it in the end.” Understanding the mechanism by which SAMHD1 provides protection to cells may provide a new idea about how to stop or slow the virus' ability to spread, Dr. Landau explained. Potential future research efforts, for example, might focus on finding a way to increase the amount of SAMHD1 in cells where it does not exist, or to reduce the amount of dNTPs in cells vulnerable to infection.

Harnessing this mechanism may open up new paths for therapeutic research aimed at slowing the virus' progression to AIDS feel many experts. The study appears online ahead of print in Nature Immunology.