Tuesday, March 20, 2012

Flush the hidden HIV out….

    HIV (Human immunodeficiency virus) is the one virus, which has dominated the microbiology research over the years. No matter, how good a drug you design or a combination of it, the virus always has a way to get out of it.

Writing the entire biology of HIV is impossible as there is too much amount of data available in the literature. So let me try to concise. HIV is a retrovirus member belonging to Lentivirus group. The virus roughly spherical in shape with a cone shaped core possessing 2 single stranded RNA of Positive sense. The T lymphocytes that possess CD4 are the target for the HIV. In addition to CD4 receptor, CXCR4 or CCR5 serve as the co receptor.

Fig 1: Genetic structural organization of HIV. (Click here for source)
       Despite a + sense RNA the virus doesn’t follow the usual route of making all the components in cytoplasm and escape in the form of progeny. It instead makes a proviral DNA that integrates itself into the genome. Here again, unlike most of the viruses, HIV doesn’t wait for the cell to divide (The cells which divide, during mitosis provides an open nucleus, which gives the virus a chance to mix into our nucleus). Instead, the virus has the capability to pass through the nuclear pore. This enables the virus to infect quiescent cells also. (That’s the damn good and important feature of HIV in comparison to other retrovirus). The exact mechanism, how the virus enters the nucleus is still under study. Many components are implicated such as the LEDGF, Integrase, MA protein, Central DNA flap, capsid etc etc. (Click here for more details by Michael bukrinsky, Jeremy Luban, Yamashita etal 1, 2)

        Now that you understand what the HIV does, u can understand what the problem is. If you know that the anti HIV drugs works well only when the virus is active my job of saying more is saved. (If I could say in a more generalized way, a drug works on the target, only when the target is active). So you see the immediate problem. What about those HIV which are latent, inside a cell. This is exactly what happens. No matter how good your antiviral is, you get an elimination of upto 99% (as in HAART), but the one’s hiding there are not eliminated.

So, how do you treat these patients??

         There are two options. The first is to keep treating. You give antiretroviral therapy and continue to give so that every time the HIV is lurking out, the ART attacks. The protocol induces selection pressure and soon the resistance emerges.

         How about trying to flush the hidden HIV? That’s what exactly David Margolis team did. The clinical study conducted by Margolis tried to flush out the HIV thus providing the second method stated above. It is too early to start talking about this. However, that’s definitely worth news. (For link click here).

         Before I go further, let me give you a bit of information on Vorinostat (suberoylanilide hydroxamic acid). It is a lab hydroxamic acid derivative intended for anti-neoplastic activity. A second generation polar-planar compound, it binds to the catalytic domain of the histone deacetylases (HDACs). Vorinostat crosses the blood-brain barrier.

Fig 2: Structure of Vorinostat (chemically N-hydroxy-N'-phenyloctanediamide) (Click here for details)

        Bear with me, a note on HDAC also. HDAC is a very important enzyme almost ubiquitously found inside nucleus to carry out normal process. A NF-κB p50–HDAC1 complex is shown to constitutively bind the latent HIV LTR and induce histone deacetylation and repressive changes in chromatin structure of the HIV LTR, causing changes that impair recruitment of RNA polymerase II and transcriptional initiation. (Click here for source).
Fig 3: Action of vorinostat
So, what did the study team do?

         They selected six stable HIV infected men who were on ART. They administered Vorinostat to them and within hours the RNA expression of HIV was induced in CD4 cells. Quote from science news “evidence that the virus was being forced out of its hiding place”. So far so good, but this is where I want to interfere.

        The coming out of RNA definitely is good, as the virus is now out of hiding and available for target. But, it’s the RNA that’s out. The master DNA is still in. So I really wonder if we have pushed the hiding HIV out or woken up the sleeping HIV. (Don’t consider me a negative critique. As far as I know the results are not yet published, as on March 20, 2012. Once the article is out I guess I have answers to many of my questions).

My take home message is simple…“We now know how to get the HIV out of its latent stage”.

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