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NNRTI&NRTI with no PI
Jun 6, 2007

Dr Wohl,

I can't thank you enough for taking the time to help with my education. There is SO much to learn...

You recently answered my question on Integrase Inhibitor action (THANKS!)

Now I don't understand how using an NNRTI&NRTI (or even IH&NRTI)combo *without* a PI, result in undetectable viral loads?

If all three of these classes (plus entry inhibitors) essentially work only for cells that don't already have viral DNA integrated into their genome, then wouldn't the cells *already* infected with provirus DNA just keep pumping out new virions?

I get that most cells that are provirus infected die off pretty quickly, but what about lymphoblasts (and other latent reservoir cells) that becomes infected with provirus DNA? Wouldn't they continue to reproduce and differentiate thus passing on more "pre-infected cells" that then pump out more virions?

I'm I just not seeing the big picture in the "scale" of this process?

THANKS SO MUCH!

Response from Dr. Wohl

The NRTIs, NNRTIs and PIs all work to prevent the virus from making copies of itself in cells. The NRTIs and NNRTIs work at an early stage, soon after the virus has entered the cell. Both classes prevent the virus from converting its RNA to the DNA format our cells use.

As you know, the integrase inhibitors prevent viral DNA that was created from getting incorporated into our DNA.

Now, even further downstream after HIV DNA is placed into our genome, PIs work to stop proteins made from the corrupted DNA from assembling into an actual HIV virus.

So all of these work on the intracellular life cycle of HIV. The important thing is that none of these meds do what they are intended to do unless the cell is active, that is making proteins. If the virus infects a cell that then remains quiet, as many of our cells do, then the cellular activities which HIV piggy backs onto (e.g. using DNA to make proteins) are not happening. This is why current HIV therapies do not cure HIV. Once these 'latent' cells do become active - which can be infrequent - they can start producing HIV and then the medications can become effective.

Attempts to cure HIV have centered on activating resting cells or destroying them.

I hope this helps.

DW



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