Sunday, February 12, 2012

Mechanism found that protects against HIV infection

One particular protein appears to be effective in preventing HIV to enter a cell. Scientists from New York University studied it, and found out how it works. We can use this knowledge to develop new strategies in order to prevent HIV infection, ultimately preventing AIDS. As this disease is still not curable, studies regarding new treatment options are highly relevant.

The protein in question is dubbed SAMHD1, and it is present on a particular kind of cell from the immune system. HIV is known to infect immune cells, which results in failure of our bodily defence system. When it knocks down the mechanism that prevents intruders from nesting in our tissues, it leaves us unable to eradicate incoming threats. Therefore a protein such as SAMHD1 is of the utmost interest to researchers.

Building blocks
SAMHD1 protects cells from infection by eliminating the capabilities of HIV to procreate. When a virus enters a cell, it wants to create copies of itself. Because they are often nothing more than strains of genetic material, they hijack cellular machinery and its resources to build new viral particles. After HIV enters the cell, SAMHD1 sends an alarm which results in depletion of the required building blocks to make more genetic material.

Our genetic code is made up of four building blocks that are universal to all forms of life that we are aware of. The blocks are abbreviated as A, T, C and G. Indeed, even viruses use these building blocks: they are often nothing more than a string of nucleotides, which is what we call these building blocks, covered by a capsule. We create copies of our DNA when cells want to divide, so that a daughter cell can also get a 'print' of life's instruction manual. It means we need to have a pool of building blocks available and 'machines' capable of copying DNA. Viruses abuse those systems.

It is known that dendritic cells possessing SAMHD1 are immune to HIV infection. Dendritic cells are tasked with 'eating' foreign threats and presenting them to more specialized immune cells. Basically, HIV is starved to death after it enters, leaving the dendritic cell intact. Scientists think the virus has evolved and 'learned' to invade other cells: currently, they mostly focus on CD4+ T lymphocytes, which is a type of cell that helps set up the immune response. Sadly, some variants of HIV have found a way to eradicate the function of SAMHD1, as is shown below.

Current viral therapies often consist of administering a drug that mimics one of the DNA building blocks. Compounds such as aciclovir pretend to be a 'G molecule', but halt the synthesis of viral DNA when it is actually being used. If the virus cannot complete the formation of the required genetic code, it cannot create new copies, effectively halting the infection by preventing further spread. A novel therapy based on SAMHD1's mechanism of action could prove to be similarly effective. It could keep cells alive that would otherwise be hampered and killed by infection. Because viruses have ways to adapt and evade the therapies we throw at them, getting something new into the clinic is quite welcome. It is now our turn to come up with something that functions in a similar way as SAMHD1, preferably in all cells targeted by HIV.
A: HIV variant enters cell and inhibits SAMHD1 by binding Vpx to it. A bunch of other molecules get recruited (CUL4, DDB1 and DCAF1) resulting in destruction of SAMHD1. B: HIV enters the cell, but SAMHD1 prevents DNA copy, leading to eventual destruction of viral material. (Credit: Lim et al. Nature. 2011: 474, 587–588)

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