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Toward an HIV Cure: Overview and Latest Strategies

November 3, 2012

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Persistent HIV Production and CD4+ Cell Infection Despite Antiretroviral Therapy

Despite technically being virally suppressed (typically defined as a viral load below 50 copies/mL), most HIV-infected patients are found to still have small but measurable amounts of virus in their blood when using more sensitive assays. About 70% of suppressed patients showed detectable virus using a single-copy assay, Eron said, referencing a study by Frank Maldarelli, M.D., and others.

While there are debates about where this extremely low-level viremia is coming from, Eron believes that it's almost certainly coming from the latent HIV reservoir, with HIV replicating from resting CD4+ cells.

The reservoir turns out to be incredibly stable, Eron said: Even if a patient had only one million resting CD4+ cells, it would take about 73 years of perfect treatment to eradicate the HIV within it, based on calculations by Robert Siliciano, M.D., and others.


Potential Cure Strategies

Targeting the Reservoir

Awakening the latently infected cells and getting them to express virus was the first step Eron listed that would bring us to a cure. "We want to use anti-latency serum therapy, something that you can do to get the virus out of latency, and then have the patient remain on therapy so that new infections are blocked. These cells [would] become productively infected and then die," he said.

"But there are challenges. If you produce these infected cells, something's got to clear them. You've got to clear the virions. You've got to block new infection of these cells. You've got to figure out how to do this," he added.

There are many potential ways to disrupt latently infected cells, Eron pointed out, including stimulating the chromatin, P-TEFb, or Tat and NF-kB proteins. Chromatin is the mass of DNA and proteins that condense to form chromosomes, located within a cell's nucleus. P-TEFb, Tat and NF-kB all play essential roles in HIV transcription.

Out of all of these ideas, Eron thinks the one that's gone the farthest is unwinding the chromatin. "HIV lives within chromatin, and the chromatin tips the balance away from activation and expression," he explained. "There are arguments about how much HIV is bound up in chromatin. If it's deacetylated, it's closed. If it's acetylated, it's open and could be transcribed. One thing you could use is a histone deacetylase [HDAC] inhibitor."


One HDAC inhibitor that's currently being studied for latency disruption is vorinostat, or suberoylanilide hydroxamic acid (SAHA), a drug approved in the U.S. for the treatment of cutaneous CD4+ cell lymphoma.

"It clearly inhibits a bunch of HDACs that are in the body. And it definitely works in vitro: You can show expression of HIV from latently infected cells across multiple labs," Eron said. This was first shown in a proof-of-concept study by David Margolis, M.D., Eron himself and others.

"In eight out of eight patients, HIV was expressed from these resting CD4+ cells. [Vorinostat] was given in vivo, cells taken in vivo. These cells were expressing [HIV] RNA. So it was successful disruption of latency in people," Eron noted.

However, he added, "We didn't show that you could actually reduce the reservoir. We didn't show that these cells died. We did show that there were no adverse events, which was good, but these were only single doses." Still, Eron said, this study marked the first successful in vivo demonstration of an HDAC inhibitor disrupting latency.

To see whether the size of the reservoir can be reduced, further studies using HDAC inhibitors in multiple doses are ongoing or being developed.

Are HDAC Inhibitors the Answer?

While HDAC inhibitors show promise, Eron remained hesitant. "Will HDAC inhibitors be enough? Are we done? I bet not. Not all studies show induction of viral expression by HDAC inhibitors ex vivo. There are some studies that show over time you get less induction ex vivo," he cautioned.

Instead, Eron suggested, "It's possible the combination of anti-latency compounds with different mechanisms might be more effective. Where have we heard that before? Combinations with different mechanisms." Undoubtedly, Eron was referring to the evolution of HIV antiretroviral therapy, which started off with single drugs and mediocre results. It wasn't until the advent of combination antiretroviral therapy, which combined drugs with different mechanisms of action, that patients began to see more potent treatment and widespread success.

"What if latently infected cells produce virus, but then they don't die?" Eron asked aloud. He then once again highlighted work by Siliciano's team: "They actually showed that when you stimulated resting cells with vorinostat, ex vivo, they actually didn't die," Eron noted. "They produce virus, but then they didn't die. Prior to treatment, they're dosed with vorinostat. Then they look at infectious units per million, and it hasn't changed. So virus was expressed, but perhaps those latently infected cells just became quiescent again."

Kick and Kill

While getting latently infected cells to express virus is a key first step, researchers also need a way to actually eradicate those cells once latency has been disrupted. Hence, what is now being called the "kick and kill" approach.

"You could give an HIV-specific vaccine to wake up the immune system and then give the kick," Eron hypothesized. "Perhaps you could manipulate CD8 cells ex vivo, then give them back and 'kick' to see if they get killed. Pablo Tebas and others are working on CD4+ cell receptor enhancement to try to improve CD8 cells. Maybe you could infuse a broadly neutralizing antibody, or antibody prime for antibody-dependent cell-mediated cytotoxicity [an immune response in which an infected target cell that is coated with antibody is destroyed by an immune cell] to kill the cells."

Eron also noted that the immune system, over time, becomes exhausted trying to control HIV. In the case of CD4+ and CD8 cells, when PD-1 (a key inhibitory receptor) attaches to the PD-L1 receptor of antigen-presenting cells, the CD4+ and CD8 cells become less effective at killing invading microbes. Therefore, according to Eron, "The idea is that you block this [PD-1/PD-L1 pathway], you reinvigorate the T cell and perhaps you could clear cancer cells -- which has been shown -- and HIV-infected cells expressing virus, which of course hasn't been shown."

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Reader Comments:

Comment by: MineMan (Texas) Wed., Oct. 1, 2014 at 4:55 pm UTC
It is definitely time to update the articles being archived. There is much new information garnered from more recent clinical trial results.
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Comment by: Jennifer B. (Granite Bay CA. 95746) Sat., Sep. 21, 2013 at 11:37 pm UTC
My brother has been HIV positive for over 25 years and has taken treatments I would think his CD4+cells and CCR5 receptor would be an interesting study. Why has he survived when all his friends that were diagnosed at the same time died. My husband told him to take half the amount of medicine that was prescribed initially .

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Comment by: luis (argentina) Tue., May. 14, 2013 at 6:15 pm UTC
sadly i believe we are far far away from finding a cure if they ever find one
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Comment by: Andrew (UK) Wed., Dec. 12, 2012 at 1:32 pm UTC
Been on treatment for a year now.
Diagnosed very late with cd4 of 121 and masive viral load.
Get told by clinic i have nothing to worry about and i will see old bones.
After reading this it is obvious they are not telling the truth and HIV is going to cut my life to an early grave.
Very dissapointed now.
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Replies to this comment:
Comment by: teddy (sweden) Wed., Jun. 26, 2013 at 5:26 pm UTC
No you have many years to live bellive me. Work out and eat helthy my friend. Dont bellive every thing u read. Trust your clinik

Comment by: Mkunde Mlay (Tanzania) Mon., Nov. 26, 2012 at 8:02 am UTC
Very good overview but in developing world we do have a very long way to go.
Example most of our patients starts treatments while in a very late stage that with CD4+ less than 350. And this is due to the social economical factors that governments can not pay for very high cost of drug denying most of infected population the benefits of early treatment and hence the "cure" in the future.
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Comment by: Ronald T. (South African ) Thu., Nov. 22, 2012 at 2:15 am UTC
I believe one of good days we will win this war and people will leave without fear of HIV. Am young man who is leaving with HIV for a year now i start my treatment early and i believe the coming generation will be free from HIV keep the good work ask God to lead you and He will show u the way
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Comment by: Claudine M G (Lynn, MA) Sat., Nov. 17, 2012 at 2:35 pm UTC
I am Claudine G. a provider case manager, advocate, liaison, Respiratory therapist, Community health Educator to name a few. Working with the HIV population from Florida end up in Boston MA. Thanks for the article I learned so much from the Stem cells to clone. What a is making us run like ants. Bon: I really would like to know what is our plan for the older HIV clients, tenants, in their 60's are we prepared yet to educate the nursing facilities what have we done who is going to do it and when. I am concern about few of the clients that I served and is still serving.... I would like one day to meet my President and seriously talk about this issues. Since college I worked with this population. We are still working hard to adjust what HIV is doing among us. We have a new population the young homosexual and the young lesbian. Don't think the substance abuse is light...don't blame is on divorce family only, we have to bring a health clinic in every high school in the State I am talking for the State of MA. This is serious in MA...We have Heath Centers few places the heavy duty hospitals need to assist in this new development....We need more money and management of that Mula $ My taxes cannot be free for some. We need to take care of the young one or we are going to swim in the ocean deeper than what we had in the 80's because we will have a package and heavy duty package the young one are complex...they have different issues that they can even explain yet the pain is too much to handle
brief examples:
A young female in high school
had a big issue at home with her single mother who is working 3 jobs to pay her rent of couple thousands.
young needs someone to talk to about sex
not too friendly with sister because her best friend lover is a female.
mother not home young girl left for a couple days to try having sex with an older man. Lover did find out exploded...young female went to a clinic near STI. young female drunk before she went home now homeless.
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Replies to this comment:
Comment by: Mathew (Birmingham Alabama) Fri., Dec. 27, 2013 at 4:40 am UTC
You and Ronald T. seem to me to be the same person. Unless you somehow share the exact same manner of speech as someone from South Africa. Or if you originally are from South Africa, and came to Florida later. I say this because you skip the same kind of words that he does. Reading the two comments back to back sounded identical. Unless its just some weird coincidence that you could be educated and raised in America and still make basic speech mistakes, then one of you is a sock puppet. What you would gain from this is beyond me, and it is quitr biizarre.

Comment by: Indian (India) Wed., Nov. 7, 2012 at 11:33 am UTC
Somehow, I was depressed by the article - it did not give hope & was too pragmatic. why can't we come up with mixed cure strategies or cocktail-cure approach that makes life a bit better. That can be an interim approach till a cure is found - isn't it?
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Comment by: marigold b. (guyana south america) Tue., Nov. 6, 2012 at 8:55 am UTC
i want a cure very badly
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Please note: Knowledge about HIV changes rapidly. Note the date of this summary's publication, and before treating patients or employing any therapies described in these materials, verify all information independently. If you are a patient, please consult a doctor or other medical professional before acting on any of the information presented in this summary. For a complete listing of our most recent conference coverage, click here.


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