Infected macrophages' days numbered!

[J220]

Got this from the New York Times, fresh news...!

Scientists Study How HIV Hides in Body

By THE ASSOCIATED PRESS
Published: January 31, 2008
Filed at 5:17 p.m. ET

WASHINGTON (AP) -- The AIDS virus has hideouts deep in the immune system that today's drugs can't reach. Now scientists finally have discovered how HIV builds one of those fortresses -- and they're exploring whether a drug already used to fight a parasite in developing countries just might hold a key to break in.

Researchers have long struggled unsuccessfully to attack what they call reservoirs of dormant HIV, and the new work is in very early stages.

But University of Rochester scientists say it may be fairly straightforward to attack one of these reservoirs, blood cells called macrophages that HIV hijacks and turns into viral hideaways.

The new discovery shows the exact steps that HIV takes to do that -- and found that some existing drugs, including a long-used treatment for leishmaniasis called miltefosine, can block the main step and thus cause these cells to self-destruct.

''It's a very smart virus,'' said lead researcher Dr. Baek Kim. ''They have to have a very good fence to protect their house for a long time. ... Get rid of the fence, and now their house is gone.''

Today's drugs have turned HIV from a quick death sentence into, for many, a chronic infection. Yet those drugs don't eliminate HIV because they can't reach the two known pools of cells where the virus can lie dormant, ever ready to resurface.

So-called memory T cells form one such pool. As the name implies, these are the cells that ensure if you get, say, measles as a child, you're forever immune. They live for years, even decades, making them a logical HIV hideout, and one that scientists have repeatedly sought to dismantle to no avail.

Macrophages, another type of immune cell, form the second pool. They roam the body looking for invaders like bacteria to gobble up. If they get harmed, such as becoming infected by a virus, they're supposed to commit suicide. But HIV instead keeps them alive long past their normal lifespan.

''Up to now, nobody has really thought about how to eliminate the macrophage reservoir,'' said Dr. Kuan-Teh Jeang, an HIV specialist at the National Institutes of Health. ''The imagination now has turned toward, 'How do we eliminate reservoirs?' ... The best way to address our problem is to simply kill those cells.''

The Rochester team found that HIV produces a protein that turns on a particular cell-survival pathway. After a multistep process, it ultimately activates an enzyme called Akt that in turn prevents cell suicide, the researchers reported Thursday online in the journal Retrovirology.

That was good news, Kim said, because the Akt pathway is a culprit in certain cancers -- meaning oncologists have been trying to target it for some time. So Kim put human HIV-infected macrophages in lab dishes and started adding drugs known to block the Akt pathway, to see if any killed the cells.

He had luck: Miltefosine and a cousin named perifosine both rapidly killed the macrophages, thus depriving HIV of this hideout.

Perifosine is currently being studied as a possible cancer drug. But miltefosine is known to be safe through its use in leishmaniasis patients. So Kim's goal is to rapidly study the already available miltefosine in animals, to see if it truly targets infected macrophages well enough to then test in HIV patients.

''The evidence they show is in fact pretty good,'' said NIH's Jeang, who says the next step should be a test of miltefosine in monkeys infected with SIV, the monkey version of the AIDS virus.

[John2038]

Nice news !

Now about the statement:

So-called memory T cells form one such pool. As the name implies, these are the cells that ensure if you get, say, measles as a child, you're forever immune. They live for years, even decades, making them a logical HIV hideout, and one that scientists have repeatedly sought to dismantle to no avail.

It's not entirely true:
A trial is on-going, using the valproic acid to purge HIV from resting CD4+ memory cells
Pre-clinic test having provided encouraging results.

http://www.clinicaltrials.gov/ct2/show/NCT00289952?term=CTN+205&rank=1

Valproic acid and HIV

About the study
The purpose of this study is to examine whether the co-administration of valproic acid (Epival®), with highly active antiretroviral therapy (HAART) can reduce the size of HIV latent reservoirs in infected CD4 cells. Participants must be on HAART with a suppressed viral load (< 50 co/ml) for at least the previous 12 months. They will be randomly assigned to one of two groups, one group will start the valproic acid right away at week 1 for 16 weeks, and the other group will wait until week 17 to add valproic acid to their treatment for 32 weeks.

This study will enroll 50 participants at several Canadian sites, and will last 48 weeks.

About the disease/condition
Once HIV enters the body, the virus infects a large number of CD4+ T cells and replicates rapidly. During this acute (also called "primary") phase of infection, the blood contains many viral particles that spread throughout the body, seeding themselves in various organs, particularly the lymphoid tissues. Acute HIV infection often passes unrecognized, but may be present as a flu-like syndrome, especially in the weeks following infection. Usually, HIV infection is diagnosed using a test for HIV antibodies, but the diagnosis of acute infection is made by demonstrating the presence of the virus itself in the blood, often before any antibodies are present.

About the treatment/intervention
HAART can suppress replication of the HIV virus and reduce the number of serious infections that people with HIV can get. Data suggest that even with the best available HAART regimen, HIV will not be eradicated during the lifetime of most patients. In fact, HIV persists in reservoirs of chronically infected cells in both peripheral blood and lymphoid tissues.

Recent studies have shown that valproic acid can activate and release HIV from some of these reservoirs, exposing the virus to anti-HIV drugs. It is not known how valproic acid exactly works, only that it acts on the central nervous system on the human brain. It has been used to treat epilepsy, migraine headaches, and certain depressions. Using valproic acid to lure HIV from the hidden reservoirs is a new experimental treatment.

http://www.hivnet.ubc.ca/e/clinicaltrials/A205.html

[J220]

Actually the first part of that Valproic Acid clinical study was disappointing, it just didn't work, unfortunately. ( http://www.advocate.com/news_detail_ektid42183.asp ). But no worries there are many other promising candidates in the pipelline.!

[NYCguy]

I was going to say the same thing - last I heard Valproioc acid hadn't panned out so I'm surprised it's still being studied, hopefully with better results this time.  The macrophage work is extremely interesting and it's good to start seeing some results on ways to counteract those damn 'resting' cells.

[MitchMiller]

Here's another article that expands on the information in the original article posted.  Note that TAT again emerges as a significant factor here.  It seems like a TAT inhibitor would also have the same effect... perhaps giving credence to the "unofficial" results of the Ensoli vaccine posted in an online forum by a subject in the trial last year....
 
Researchers Seek To Deny HIV Its Safe Havens In The Human Body
Main Category: HIV / AIDS
Also Included In: Infectious Diseases / Bacteria / Viruses;  Genetics
Article Date: 01 Feb 2008 - 5:00 PST

A drug already used to treat parasitic infections, and once looked at for cancer, also attacks the human immunodeficiency virus (HIV) in a new and powerful way, according to research published online in the open access journal Retrovirology.

Past research has established that HIV has "learned" to hide out in certain human cells where it is safe from the body's counterattack, cells that come to serve as viral reservoirs. Operating from these havens, the virus slowly builds its numbers over more than a decade until it finally becomes capable of dismantling human immune defenses. In the end stages, this process leaves patients vulnerable to the opportunistic infections of AIDS. The newly published work explains for the first time how the virus makes chemical changes that keep its chosen reservoirs alive long past their normal lifespan. The new study also provides the first evidence that an existing ant-parasite drug can reverse this deadly longevity.

"AIDS continues to take nearly 3 million lives worldwide each year, and novel treatment approaches are urgently needed," said Baek Kim, Ph.D., associate professor in the Department of Microbiology & Immunology at the University of Rochester Medical Center. "We think our results are profound because, in discovering exactly how HIV hides in the body, we think we have learned how to take away its hiding places. Without them, the virus would have a much harder time causing disease," said Kim, lead author of the new study.

Secret to Long Life

Cell division is a process central to life. A parent cell divides into two cells, each containing copies of the same genes. This enables a single-cell human embryo to divide and grow into the vast number of cells that make up the human body. Different cell types divide at various speeds. T cells, for example, sense foreign organisms have invaded the body, and quickly divide and grow into a large, specifically designed army to attack the invader. Macrophages, on the other hand, are designed to roam the body engulfing and digesting dead tissue and bacteria. To assume this special role, they give up the ability to divide.

Unlike most viruses in its family, HIV has the ability to infect both non-dividing macrophages and rapidly dividing T cells, a key to its deadliness. Given its choice, HIV would prefer to infect rapidly dividing T cells, because with each division comes another opportunity for the virus to copy itself using the T cells' genetic machinery. On the other hand, T cells sense they are infected and quickly commit suicide, taking out the virus as well. So quickly do T cells self-destruct that the virus would lose its battle with the human immune system if it did not have long-lived macrophages to hide in during the early years of infection, Kim said.

Many cells can "choose" to die when they sense cancer-causing flaws in their own genes, or when they are being used as a virus factory. Certain biochemical pathways call for cell suicide and others postpone it, with the two forces counterpoised to control lifespan. Cancer and AIDS result in part from problems in these pathways.

Past studies found that HIV-infected macrophages can serve as viral reservoirs because some unknown factor extends their lifespan. In the brain, for example, macrophages secrete toxins produced by the virus they carry, including the transactivator (tat) protein, which causes nearby nerve cells to commit suicide. When enough nerve cells die, patients gradually lose memory, speaking ability and decision-making skills despite the best available treatment. Presumably, such toxicity should cause brain macrophages to self-destruct as well, but that is not the case. Macrophages live on, and no one had known why until the publication of two papers by Kim's team, one in January 2008 and the other in January 2007.

The earlier paper reported that macrophages infected with HIV live abnormally long, and that the long life may be related to the presence of the HIV protein tat. In the current study, researchers found the exact mechanism by which HIV turns on a series of cell survival signals in human macrophages: tat-related manipulation of the PI3K/Akt kinase pathway. Phosphatidylinositol 3 kinases (PI3K) are enzymes that turn on another enzyme, Akt, to prevent cell suicide and extend cell lifespan. Akt has been implicated in cancer, where cells live too long.

Kim's team discovered that a molecule called PTEN (phosphatase and tensin homologue deleted on chromosome 10) normally interferes with Akt signaling, and thus, limits cell lifespan. That is unless something interferes with PTEN. In a series of experiments, Kim's team observed that the presence of HIV tat in infected macrophages lowers PTEN levels by 40 percent, enabling the PI3K/Akt pathway to kick back on and keep macrophages alive. The study also found that an existing drug, miltefosine (Impavido®), inhibits PI3K/Akt pathway, and thus, promises to counter the effect of HIV tat on PTEN, Kim said. The treatment was first identified in Germany in the early 1980s as a potential treatment for breast cancer, but is used today to treat a common, parasitic infection called leishmaniasis.

Furthermore, researchers found that HIV-infected macrophages survive longer only when exposed to stress (e.g. toxins secreted by the virus infecting them). Most cells are expendable, and are ordered to self-destruct if exposed to enough stress. The PI3K/Akt pathway, however, kicks on when cells are designed to survive despite surrounding toxicity (e.g. immune cells). Thus, the toxic environment created by HIV ensures the long-term production of HIV within long-lived macrophage reservoirs.

The current study was conducted jointly by the Medical Center and the University of Utah School of Medicine. Along with Kim, joining the effort in Rochester were Pauline Chugh, Birgit Bradel-Tretheway, Sanjay B. Maggirwar and Stephen Dewhurst. Carlos Maximiliano and Vicente Planelles led the effort in Utah. Retrovirology publishes peer-reviewed, high-impact articles on basic retrovirus research. The journal is edited by Kuan-Teh Jeang, M.D., Ph.D., head of the Molecular Virology Section at the National Institute of Allergy and Infectious Diseases, with the help of a respected editorial board, and has an impact factor of 4.32.

"Miltefosine puts an end to the long lives of HIV-infected macrophages," Kim said. "The fact that it is already used in humans could accelerate the process of seeking government approval for a new, anti-HIV use for miltefosine, or something like it. In the next phase, we will conduct studies seeking to show that Akt inhibition ends the survival of HIV-infected macrophage reservoirs under real-life conditions."

[Patrick]

I think this is wonderful news, of course.  If scientists can find a way to rid HIV from the long-living memory T-cells, then that, coupled with Haart and this drug to kill off the macrophages would effectively clear HIV from our bodies.  It seems audacious to think of that but I am hopeful that this is another important step closer to a cure.

However, this new treatment against the macrophage hideout alone I feel would provide rather useless unless scientists can find a way to clear HIV from the long-living T cells.  Otherwise, they'd kill our macrophages and the HiV hiding within it, but then hiv would repopulate the macrophages again eventually because the virus would still exist in our bodies. 

Unless we killed our macrophages entirely and kept them dead (i.e. kept taking the drug that kills the macrophages).  But I cannot imagine that would be good for us as macrophages are an important part of our immune system.  Treatment like this would have to have everyone on some sort of antibiotic to make sure we didn't start getting bacterial infections and the like. 

So while this new finding is great, it is essentially useless unless its used in conjunction with haart and another yet to be found treatment to remove hiv from long-lived t-cells.  It sounds like we have two out of the three here, one day a cure, one day a cure...............

[John2038]

So while this new finding is great, it is essentially useless unless its used in conjunction with haart and another yet to be found treatment to remove hiv from long-lived t-cells.  It sounds like we have two out of the three here, one day a cure, one day a cure...............

Fortunately, you are wrong

The treatment cause the suicide of infected macrophages (Akt inhibited), not the healthy cells:
This study is seeking to show that Akt inhibition ends the survival of HIV-infected macrophage reservoirs under real-life conditions.

[J220]

I think what Patrick was referring to were infected T-cells, not healthy cells. He's right in that the article states that this new technique targets infected macrophages only. That leaves the second pool of infected T-cells intact, or so we presume at this time. There could be some kind of secondary mechanism that does target those as well, we can only hope.


"...drugs don't eliminate HIV because they can't reach the two known pools of cells where the virus can lie dormant, ever ready to resurface. So-called memory T cells form one such pool....Macrophages, another type of immune cell, form the second pool."

[Patrick]

Yes, I think I misread the article a bit.  If the drug does indeed only target infected macrophages (assuming HIV hasn't infected the majority of them anyway in most of us) then this is indeed a good thing.  Killing infected macrophages could help with keeping viral load down.  Then, presumably, if you could rid the infected long-lived T cells of HIV then you could achieve eradication since you'd be destroying HIV in the reservoirs plus the circulating blood.

I can't imagine that scientists won't figure out a way to target the HIV in the long-lived T cells soon.  It doesn't seem like too far of a jump in science from what is going on currently.  If they can figure that one out, than eradication is possible.  I remain hopeful that one day I will be free of this virus.

[J220]

I am very hopeful as well, not a week goes by that we don't see some great piece of news about further advances. I think they are getting close, very close! Cheers, J.