HIV Latency

[Mishma]

NATURE | LETTER previous article next article
Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy

N. M. Archin,    A. L. Liberty,    A. D. Kashuba,    S. K. Choudhary,    J. D. Kuruc,    A. M. Crooks,    D. C. Parker, E. M. Anderson,    M. F. Kearney,    M. C. Strain,    D. D. Richman,    M. G. Hudgens,    R. J. Bosch,    J. M. Coffin,    J. J. Eron,    D. J. Hazuda    & D. M. Margolis

AffiliationsContributionsCorresponding author
Nature 487, 482–485 (26 July 2012) doi:10.1038/nature11286
Received 13 February 2012 Accepted 07 June 2012 Published online 25 July 2012


Despite antiretroviral therapy, proviral latency of human immunodeficiency virus type 1 (HIV-1) remains a principal obstacle to curing the infection1. Inducing the expression of latent genomes within resting CD4+ T cells is the primary strategy to clear this reservoir2, 3. Although histone deacetylase inhibitors such as suberoylanilide hydroxamic acid (also known as vorinostat, VOR) can disrupt HIV-1 latency in vitro4, 5, 6, the utility of this approach has never been directly proven in a translational clinical study of HIV-infected patients. Here we isolated the circulating resting CD4+ T cells of patients in whom viraemia was fully suppressed by antiretroviral therapy, and directly studied the effect of VOR on this latent reservoir. In each of eight patients, a single dose of VOR increased both biomarkers of cellular acetylation, and simultaneously induced an increase in HIV RNA expression in resting CD4+ cells (mean increase, 4.8-fold). This demonstrates that a molecular mechanism known to enforce HIV latency can be therapeutically targeted in humans, provides proof-of-concept for histone deacetylase inhibitors as a therapeutic class, and defines a precise approach to test novel strategies to attack and eradicate latent HIV infection directly.

http://www.nature.com/nature/journal/v487/n7408/full/nature11286.html

http://www.washingtonpost.com/national/health-science/aids-research-anticipates-a-functional-cure/2012/07/26/gJQA2YGdCX_story_1.html

[Common_ground]

Are there any ongoing trials or more data for Vorinostat?

[Dr.Strangelove]

vorinostat is also referred to as SAHA
As far as I know there are at least two trials.
Don't have the link here right now

[elf]

The commercial name is Zolinza, and it is used as a medication for some lymphatic tumors.
http://www.zolinza.com/

http://www.drugs.com/pro/zolinza.html

[Common_ground]

A quick google search revealed that its a rather fresh discovery but the data is promising. What makes it so interesting is the simplicity of this method.

[geobee]

Yeah, but Zolinza itself is a carcinogenic.  Don't want to be taking a lot of that stuff.  Hopefully they'll develop analogues of it which aren't as toxic. 

[buginme2]

Are there any ongoing trials or more data for Vorinostat?

Ongoing? No.  There are two trials, one in the US and one in Australia.  The US trial was small and had people take The drug for only one day.  The Australian trial is also small and is to study safety and people are taking it for 14 days. 

http://clinicaltrials.gov/ct2/results?term=Vorinostat+and+HIV+

[Ann]

NATURE | LETTER previous article next article
Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy

N. M. Archin,    A. L. Liberty,    A. D. Kashuba,    S. K. Choudhary,    J. D. Kuruc,    A. M. Crooks,    D. C. Parker, E. M. Anderson,    M. F. Kearney,    M. C. Strain,    D. D. Richman,    M. G. Hudgens,    R. J. Bosch,    J. M. Coffin,    J. J. Eron,    D. J. Hazuda    & D. M. Margolis

AffiliationsContributionsCorresponding author
Nature 487, 482–485 (26 July 2012) doi:10.1038/nature11286
Received 13 February 2012 Accepted 07 June 2012 Published online 25 July 2012


Despite antiretroviral therapy, proviral latency of human immunodeficiency virus type 1 (HIV-1) remains a principal obstacle to curing the infection1. Inducing the expression of latent genomes within resting CD4+ T cells is the primary strategy to clear this reservoir2, 3. Although histone deacetylase inhibitors such as suberoylanilide hydroxamic acid (also known as vorinostat, VOR) can disrupt HIV-1 latency in vitro4, 5, 6, the utility of this approach has never been directly proven in a translational clinical study of HIV-infected patients. Here we isolated the circulating resting CD4+ T cells of patients in whom viraemia was fully suppressed by antiretroviral therapy, and directly studied the effect of VOR on this latent reservoir. In each of eight patients, a single dose of VOR increased both biomarkers of cellular acetylation, and simultaneously induced an increase in HIV RNA expression in resting CD4+ cells (mean increase, 4.8-fold). This demonstrates that a molecular mechanism known to enforce HIV latency can be therapeutically targeted in humans, provides proof-of-concept for histone deacetylase inhibitors as a therapeutic class, and defines a precise approach to test novel strategies to attack and eradicate latent HIV infection directly.

Hi Mishma. I need you to read the two threads that are stickied at the top of this forum - the Welcome Thread and the one entitled A Request PLEASE READ THIS THREAD!!!.

When you read those two threads, you will realise that we require you to provide links to any articles you copy and paste into your posts. You have 48 hours in which you will be able to edit your post to add the links. If you miss the time-slot, please PM me the links so I can add them for you.

Thank you for your cooperation.

Ann

[elf]

Yeah, but Zolinza itself is a carcinogenic.  Don't want to be taking a lot of that stuff.  Hopefully they'll develop analogues of it which aren't as toxic.

It's how chemotherapy works. It's kinda difficult to separate their effect on toxic/cancerous cells from affecting healthy cells. 

[Mishma]

My apologies to all. I'm still learning.
http://www.nature.com/nature/journal/v487/n7408/full/nature11286.html

[Ann]

My apologies to all. I'm still learning.
http://www.nature.com/nature/journal/v487/n7408/full/nature11286.html

No worries, Mish. Thanks for adding the link. Please remember to do so in future as well.

[Mishma]

By now most folks know what is commonly referred to as the central dogma of Molecular Biology. Our genes, in response to specific signals, are transcribed into RNA which in turn serves as the blueprint from which proteins are made. Genes are inheritable and are passed down with occasionally some modifications from generation to generation. The new wrinkle to this established dogma is what is called epigenetics.

Epigenetics is the study of the chemical modification of the DNA and the proteins surrounding our DNA by for example, methylation and histone modification. The authors of this particular study used a drug that removes acetylation on the surrounding histones where the HIV virus has integrated itself. Of course the drug is non specific and other genes are thus "exposed" to the transcription machinery in the process. Chemotherapy for cancer often uses drugs that either demethylate or deacetylate the DNA or histones respectively. In rapidly dividing cells, like cancer, the drugs result in what is called genomic instability and the cell self destructs.

 

Wikipedia has an excellent entry on the subject of epigenetics for those of you who are interested. http://en.wikipedia.org/wiki/Epigenetics

There is a nice diagram that makes this much clearer than my crude attempt.

[songs06]

it is really simple and very good solution. it looks like trial will end in 2016. even if it does not work, it might lead to another interesting theories those might be end of HIV. i still hope i will see the cure before i turn 50

[Mishma]

A recap of what has been happening lately in HIV latency/reservoir research.


http://www.nature.com/news/dormant-hiv-gets-rude-awakening-1.11077?WT.ec_id=NEWS-20120731

NATURE | NEWS

Dormant HIV gets rude awakening
Researchers tackle virus particles hiding in the immune system as part of efforts to find a cure for AIDS.

Cassandra Willyard

Song06  My hope is before I turn 60 but I don't know how realistic that is because I'm 57 now.

[songs06]

well it could be anytime but this reseaches takes time. there are 3 phases and this research will end in 2016. you should say 61 at least

but i am always pessimistic. really hard to find a cure for a viral disease. i am 25 now, but i believe in science will progress so much further in 25 years. well, i really want to wake up one morning and remember all these HIV years are just history. but it is quite unlikely for now

[Common_ground]

I think its all down to what risks you are willing to take. There are a lot of "almost" methods for curing HIV, but there is so many things to consider when developing these like safety, cost etc.

If you had the money and a "doc" not afraid to experiment AND you were willing to put basically your life at stake, then I do believe It could be done today. But since the treatment is working pretty good for most people there are few patients and docs thinking like this.

In one way its good that we dont rush the development and end up with a cure with similar side effects like the really early meds which could actually do more harm than good. Research is quite intense and fast moving in HIV and I am sure we will have a functional cure before 2020. Just look at where we were 10,20,30 years ago. Pretty friggin amazing development if you ask me

[buginme2]

If you had the money and a "doc" not afraid to experiment AND you were willing to put basically your life at stake, then I do believe It could be done today. But since the treatment is working pretty good for most people there are few patients and docs thinking like this.

Not to mention that goes squarely against the philosophy of "do no harm" that all doctors must subscribe to in order to practice medicine. 

[Skydrake]

Not to mention that goes squarely against the philosophy of "do no harm" that all doctors must subscribe to in order to practice medicine.

People is more sophistic. Almost every argument might be crafted to appear logical.
In the History there is plenty of researches ready to sacrifice single patients in the altar of the medical science.
What is it one person in comparison to multitudes of future generations?
So belevied Josef Mengele. He was very proud of his abominable experiments.

[Cosmicdancer]

Scientists Develop Technique to Decipher the Dormant AIDS Virus Concealed in Cells

ScienceDaily (Sep. 11, 2012) — Scientists at the Gladstone Institutes have gotten us one step closer to understanding and overcoming one of the least-understood mechanisms of HIV infection -- by devising a method to precisely track the life cycle of individual cells infected with HIV, the virus that causes AIDS.

In a paper being published online today in Lab on a Chip, the laboratory of Gladstone Investigator Leor Weinberger, PhD, announced the development of a device that can pinpoint and track HIV inside CD4 T cells -- the type of white blood cell that the AIDS virus targets. This development is particularly important for understanding "HIV latency," a state in which the virus goes dormant after the patient begins standard antiretroviral treatment. Current antiretroviral drugs do not kill HIV -- they only keep it at bay -- meaning that those with HIV must continue a lifetime of drug treatment so as not to develop AIDS. If they discontinue the drugs, the latent virus "wakes up" within just a few weeks and begins an onslaught against the body's immune system.

The breakthrough comes as the AIDS-researcher community is beginning to speak publicly about the possibility of curing HIV/AIDS. Understanding -- and consequently interrupting -- HIV latency is a key element in the effort to discover a cure for this devastating disease.

"HIV latency is perhaps the single greatest obstacle to eradicating HIV/AIDS in the 34 million people who live with the disease worldwide," said Dr. Weinberger, who is also an associate professor of biochemistry and biophysics at the University of California, San Francisco (UCSF), with which Gladstone is affiliated. "Existing techniques that try to uncover the cellular and viral mechanisms behind HIV latency are inefficient at studying very rare cells -- and cells housing the latent HIV virus are one-in-a-million. Our technique presents a clear path towards understanding how HIV latency is regulated within a single cell, by tracking the individual cells that traditionally had been difficult to monitor."

Singe-cell, time-lapse microscopy -- a state-of-the-art technique that scientists have lately used to track some viral infections and map antibiotic resistance to drugs -- has not worked for tracking the HIV-infection cycle in CD4 T cells, especially in the latent state. This is because these cells are notoriously evasive. They spontaneously move around, attaching and detaching from their neighbors, making it nearly impossible to monitor individual HIV-infected cells over time.
However, Dr. Weinberger's team devised a clever system that essentially guides and suspends HIV-infected T cells into tiny finger-like channels -- reducing their ability to move or detach from their neighbors.

"First, we load the T cells into a small well, allowing them to settle into the bottom -- which is filled with nutrients that keep the cells well-fed and stress-free," explained the paper's lead author Brandon Razooky, a Gladstone and UCSF graduate student. "Next, we tilt the device and the cells slide into microscopic finger-like channels that are attached to the well. Finally, we return the device to its upright position, locking about 25 T cells inside each channel and essentially 'freezing' them in place."

The device has several advantages over current methods. First and foremost, individual cells stay in place so investigators can follow them over time with single-cell, time-lapse microscopy. Second, the fact that each T cell is suspended in nutrients in close physical contact with other cells results in near optimal conditions for keeping the infected cell alive for the virus' entire life cycle.

"This means that we now have the potential to analyze the entire course of an HIV infection in an individual cell -- especially during the crucial latency stage -- for which we know so little," said Dr. Weinberger. "In the future, we plan to expand the device's design to include a larger number of wells and channels to track HIV infection on a larger scale. We want to use the information gleaned here to finally unravel the mechanisms behind HIV latency. With that knowledge, we hope to devise a treatment to bring the latent virus out of hiding in order to flush it from a patient's system, once and for all."

This research was funded by the National Institutes of Health and the National Science Foundation.

http://www.sciencedaily.com/releases/2012/09/120911125343.htm