How Isentress Works: An Interview With David Wohl, M.D.

Executive Editor

This is Part II of an update on Isentress. For a general overview, please click here.

Could you briefly describe how Isentress differs from other meds?

Isentress, also called raltegravir [called MK-0518 during its early development], is a drug that works against the HIV virus in a different way, at a different step in the virus's life cycle, inside of our cells. I think most people appreciate that HIV attaches to the T cell, it unloads its genetic information into the T cell, and that genetic information gets integrated, or combined, with our genes.

Then the cell goes about the business of making proteins -- that's what a cell does for a living -- and it makes not only just the cell's proteins, but also [once HIV is in the T cell] some HIV proteins. Those HIV proteins can get packaged by an enzyme called a protease, and then bud out from that cell and become a mature, infectious HIV that spreads to another cell. But it's not just one HIV, it's lots of HIV that come out of that cell, possibly killing that cell, and then spread to other cells.

David Wohl, M.D., Associate Professor of Medicine at the University of North Carolina at Chapel Hill, and co-director of HIV services for the North Carolina Department of CorrectionsIt's along that pathway that medicines could work, if you have some sort of entry inhibitor medication that doesn't allow HIV to come along and attach itself to the T cell.

If that does happen [, meaning if the HIV is able to attach to the T cell], and the genetic information from the virus gets into the cell -- well, the virus uses a different type of encoding for its genetic information than we do, because a virus is much more primitive, so it's genetic information and our genetic information don't really speak the same language.

To get around that, the virus converts its genetic information from its template, which is RNA, to our template, which is DNA. It's sort of like converting music from a CD to a tape: It's still music, but there are two different formats. The enzyme that does that is known as reverse transcriptase. We have a bunch of medicines currently approved that target the reverse transcriptase.

Let's say the reverse transcriptase is working, and there are no medicines to inhibit that. That genetic information that is now in a format that we can recognize -- that our genes can recognize -- that DNA now gets integrated into our DNA. There's an enzyme that does that. The enzyme is a workhorse that makes this happen chemically. That enzyme is called an integrase. This is where Isentress works.

Isentress doesn't allow for the viral DNA to get zipped up into our DNA. If that doesn't happen [, meaning if the viral DNA doesn't get integrated into our DNA], then the cell never gets fooled into making viral proteins, and you stop and terminate the viral life cycle in its track. The virus just can't do what it wants to do, which is make copies of itself using our cells. Now, if the virus was able to do that [, meaning if the viral DNA was integrated into our DNA], it would then make those proteins, the protease would then let those proteins get packaged into a virus that would be dangerous to other cells and to that cell, and then you'd have the normal life cycle of HIV.

So now we have several vantage points, or Achilles' heels, that we can use to attack HIV.

  • We have something that can interfere with HIV's entry into the cell -- the fusion and entry of the virus into the cell. [Fusion inhibitors like Fuzeon and entry inhibitors like Selzentry (Celsentri)]
  • We have something that inhibits the ability of the virus to take its genetic information and convert it to our genetic information. [NRTIs such as: Combivir, Emtriva, Epivir, Retrovir, Truvada, Videx, Viread, Zerit and Ziagen; and NNRTIs such as: Sustiva (Stocrin) and Viramune]
  • We now have something that can prevent the virus from integrating its genetic information into ours. [An integrase inhibitor called Isentress]
  • We have something that can prevent the assembly of the viral proteins that are made. [Protease inhibitors such as: Aptivus, Crixivan, Kaletra, Lexiva (Telzir), Prezista, Reyataz and Viracept]

So you have sort of an upstream, midstream and downstream blockage of HIV that you can just imagine could be very powerful when used together.

For our full interview about Isentress with David Wohl, M.D., click here.

For more information on Isentress, please visit our collection of articles.

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