A different alphabet, a different treatment?

Contributed by Guest Blogger: Sean Koerner ’11

It’s easy to think of viruses as alien or lifeless – after all, they can’t reproduce on their own, eat anything, or even move around without assistance. However, viruses have evolved to use the same toolbox that human cells use, right down to the way their genes and proteins are encoded. One of the most problematic viruses for humans, HIV, works by putting its own information into our cells’ genomes, turning host cells into viral factories. This information is formed from two types of alphabets: strung-together sequences of deoxyribonucleotides, which exist intracellularly as deoxyribonucleotide triphosphate (dNTP) monomers in our own cells and ribonucletides, which form the HIV genome as well as existing independently as ribonucleotide triphosphate (rNTP) monomers within our own cells. In order to infect our cells, HIV uses a protein known as reverse transcriptase to generate the DNA that our cells are used to reading from the viral RNA genome. This reverse transcription of RNA to DNA has long been a target of anti-HIV drugs, since without this step, HIV cannot successfully infect our cells.

Recently, a team at the University of Rochester discovered a previously unknown characteristic of this process. Two of the cells most commonly infected by HIV, CD4+ lymphocytes and macrophages, displayed different levels of dNTPs and rNTPs after being infected by HIV, with the lymphocytes containing much less rNTPs and more dNTPs than the macrophages. After a biochemical analysis of the cells, the research team discovered that HIV’s reverse transcriptase is capable of using cellular rNTPs to generate RNA based upon the HIV genome, which is then reverse transcribed into cellular DNA while in the macrophage environment. This allows HIV to use the higher concentrations of rNTPs in macrophages to continue replicating efficiently, despite the relative dearth of dNTPs as compared to lymphocytes. Since HIV uses one method (dNTPs) in lymphocytes and one method (rNTPs) in macrophages, it may be possible to target HIV replication in macrophages specifically. Why care about the difference between the two cell types? Well, macrophages travel the body much more rapidly than lymphocytes; if we can stop HIV infecting them, we may be able to slow the progression of HIV infection throughout the body.

How could we do that? In short, by targeting the synthesis of rNTP strands with new drugs. Although we would likely experience side effects, they could be negligible compared with the repression of HIV. The research team at Rochester have already demonstrated that rNTP string inhibitors slow HIV’s infection of macrophages, so specific drugs targeted for this process might be able to halt it altogether.


2 thoughts on “A different alphabet, a different treatment?”

  1. I’m not sure, but theoretically it seems you would be able to do that? The researchers were describing this as a final line of defense, since inhibiting rNTP strand synthesis would have pretty detrimental effects on us as well. In the case of a microbicidal gel, though, I imagine it would have relatively negligible effects on human cells – that sounds like a really interesting direction!

  2. I wonder what form the drugs would take? If macrophages are among the first cells to be infected and current HIV drugs target the virus at stages after macrophage infection would it be possible for rNTP synthesis inhibitors to be used in a microbicide gel?

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