Minocycline Prevents Latent T Cells From Activating

[Inchlingblue]

A while back I started a thread wondering if there was any research aimed at maintaining T Cells forever dormant as a way of treating HIV. Ideally without the use of HAART, if there was a compound that could just keep HIV dormant in the reservoirs so that even if a person isn't cured, the virus is never able to reactivate and mount an attack.

Scientists at Johns Hopkins have found that minocycline does in fact target infected immune cells in which HIV lies dormant and prevents them from reactivating and replicating. What I don't get is that they are talking about this as a potential treatment to be used alongside HAART. What's the point of that? I guess less immune activation and inflammation but it would be really amazing if it could be used instead of HAART.

Acne drug prevents HIV breakout
18. March 2010 15:35

Johns Hopkins scientists have found that a safe and inexpensive antibiotic in use since the 1970s for treating acne effectively targets infected immune cells in which HIV, the virus that causes AIDS, lies dormant and prevents them from reactivating and replicating.

The drug, minocycline, likely will improve on the current treatment regimens of HIV-infected patients if used in combination with a standard drug cocktail known as HAART (Highly Active Antiretroviral Therapy), according to research published now online and appearing  in print April 15 in The Journal of Infectious Diseases. "The powerful advantage to using minocycline is that the virus appears less able to develop drug resistance because minocycline targets cellular pathways not viral proteins," says Janice Clements, Ph.D., Mary Wallace Stanton Professor of Faculty Affairs, vice dean for faculty, and professor of molecular and comparative pathobiology at the Johns Hopkins University School of Medicine.

"The big challenge clinicians deal with now in this country when treating HIV patients is   keeping the virus locked in a dormant state," Clements adds. "While HAART is really effective in keeping down active replication, minocycline is another arm of defense against the virus."

Unlike the drugs used in HAART which target the virus, minocycline homes in on, and adjusts T cells, major immune system agents and targets of HIV infection. According to Clements, minocycline reduces the ability of T cells to activate and proliferate, both steps crucial to HIV production and progression toward full blown AIDS.

If taken daily for life, HAART usually can protect people from becoming ill, but it's not a cure. The HIV virus is kept at a low level but isn't ever entirely purged; it stays quietly hidden in some immune cells. If a person stops HAART or misses a dose, the virus can reactivate out of those immune cells and begin to spread.

The idea for using minocycline as an adjunct to HAART resulted when the Hopkins team learned of research by others on rheumatoid arthritis patients showing the anti-inflammatory effects of minocycline on T cells. The Hopkins group connected the dots between that study with previous research of their own showing that minocycline treatment had multiple beneficial effects in monkeys infected with SIV, the primate version of HIV. In monkeys treated with minocycline, the virus load in the cerebrospinal fluid, the viral RNA in the brain and the severity of central nervous system disease were significantly decreased. The drug was also shown to affect T cell activation and proliferation.

"Since minocycline reduced T cell activation, you might think it would have impaired the immune systems in the macaques, which are very similar to humans, but we didn't see any deleterious effect," says Gregory Szeto, a graduate student in the Department of Cellular and Molecular Medicine working in the Retrovirus Laboratory at Hopkins. "This drug strikes a good balance and is ideal for HIV because it targets very specific aspects of immune activation."

The success with the animal model prompted the team to study in test tubes whether minocycline treatment affected latency in human T cells infected with HIV. Using cells from HIV-infected humans on HAART, the team isolated the "resting" immune cells and treated half of them with minocycline. Then they counted how many virus particles were reactivated, finding completely undetectable levels in the treated cells versus detectable levels in the untreated cells.

"Minocycline reduces the capability of the virus to emerge from resting infected T cells," Szeto explains. "It prevents the virus from escaping in the one in a million cells in which it lays dormant in a person on HAART, and since it prevents virus activation it should maintain the level of viral latency or even lower it. That's the goal: Sustaining a latent non-infectious state."

The team used molecular markers to discover that minocycline very selectively interrupts certain specific signaling pathways critical for T cell activation. However, the antibiotic doesn't completely obliterate T cells or diminish their ability to respond to other infections or diseases, which is crucial for individuals with HIV.

"HIV requires T cell activation for efficient replication and reactivation of latent virus," Clement says, "so our new understanding about minocyline's effects on a T cell could help us to find even more drugs that target its signaling pathways."


LINKS:

http://www.news-medical.net/news/20100318/Acne-drug-prevents-HIV-breakout.aspx

http://www.youtube.com/watch?v=C_ImNAEpOHY

http://forums.poz.com/index.php?topic=26397.0
 

[veritas]

Inch,

Your quote: "What I don't get is that they are talking about this as a potential treatment to be used alongside HAART. What's the point of that? "

It looks like minocycline only targets resting cd4s in reservoirs. HAART is needed to control freeflowing virus and infected cd4s in the bloodstream.

What is really neat about this therapy, if it pans out, is the freezing of  cd4s doesn't seem to compromise the immune system 's ability to function. neat stuff.

v

[Inchlingblue]

It looks like minocycline only targets resting cd4s in reservoirs. HAART is needed to control freeflowing virus and infected cd4s in the bloodstream.

 

I know, I meant after a person has already become undetectable with HAART. If this is supposed to keep HIV dormant in resting CD4s then theoretically, after getting viral load down to zero using HAART, which can be done, then it would be great if there were a drug (maybe minocycline?) that could keep HIV from reactivating in the reservoirs in the absence of HAART. HAART is able to fully suppress virus in the blood (in a majority of people) and the reason HAART can't be stopped currently is because virus from reservoirs reactivates and is then able to mount an attack.

I guess it's too early to know the extent of what minocycline can do with HIV but I agree that overall it's good news. Even if it only serves to keep inflammation and immune activation lower that would be a good thing.

[Cosmicdancer]

Hopefully this acne drug, minocycline, can be prescribed for people currently on HAART since it has already been in use for decades.  It's anti-inflammatory effects were impressive, and it maintains HIV in a latent non-infectious state in t-cells. 

http://www.sciencedaily.com/releases/2010/03/100319202528.htm

Acne Drug Prevents HIV Breakout

ScienceDaily (Mar. 20, 2010) — Johns Hopkins scientists have found that a safe and inexpensive antibiotic in use since the 1970s for treating acne effectively targets infected immune cells in which HIV, the virus that causes AIDS, lies dormant and prevents them from reactivating and replicating.

The drug, minocycline, likely will improve on the current treatment regimens of HIV-infected patients if used in combination with a standard drug cocktail known as HAART (Highly Active Antiretroviral Therapy), according to research published now online and appearing in print April 15 in The Journal of Infectious Diseases. "The powerful advantage to using minocycline is that the virus appears less able to develop drug resistance because minocycline targets cellular pathways not viral proteins," says Janice Clements, Ph.D., Mary Wallace Stanton Professor of Faculty Affairs, vice dean for faculty, and professor of molecular and comparative pathobiology at the Johns Hopkins University School of Medicine.

"The big challenge clinicians deal with now in this country when treating HIV patients is keeping the virus locked in a dormant state," Clements adds. "While HAART is really effective in keeping down active replication, minocycline is another arm of defense against the virus."

Unlike the drugs used in HAART which target the virus, minocycline homes in on, and adjusts T cells, major immune system agents and targets of HIV infection. According to Clements, minocycline reduces the ability of T cells to activate and proliferate, both steps crucial to HIV production and progression toward full blown AIDS.

If taken daily for life, HAART usually can protect people from becoming ill, but it's not a cure. The HIV virus is kept at a low level but isn't ever entirely purged; it stays quietly hidden in some immune cells. If a person stops HAART or misses a dose, the virus can reactivate out of those immune cells and begin to spread.

The idea for using minocycline as an adjunct to HAART resulted when the Hopkins team learned of research by others on rheumatoid arthritis patients showing the anti-inflammatory effects of minocycline on T cells. The Hopkins group connected the dots between that study with previous research of their own showing that minocycline treatment had multiple beneficial effects in monkeys infected with SIV, the primate version of HIV. In monkeys treated with minocycline, the virus load in the cerebrospinal fluid, the viral RNA in the brain and the severity of central nervous system disease were significantly decreased. The drug was also shown to affect T cell activation and proliferation.

"Since minocycline reduced T cell activation, you might think it would have impaired the immune systems in the macaques, which are very similar to humans, but we didn't see any deleterious effect," says Gregory Szeto, a graduate student in the Department of Cellular and Molecular Medicine working in the Retrovirus Laboratory at Hopkins. "This drug strikes a good balance and is ideal for HIV because it targets very specific aspects of immune activation."

The success with the animal model prompted the team to study in test tubes whether minocycline treatment affected latency in human T cells infected with HIV. Using cells from HIV-infected humans on HAART, the team isolated the "resting" immune cells and treated half of them with minocycline. Then they counted how many virus particles were reactivated, finding completely undetectable levels in the treated cells versus detectable levels in the untreated cells.

"Minocycline reduces the capability of the virus to emerge from resting infected T cells," Szeto explains. "It prevents the virus from escaping in the one in a million cells in which it lays dormant in a person on HAART, and since it prevents virus activation it should maintain the level of viral latency or even lower it. That's the goal: Sustaining a latent non-infectious state."

The team used molecular markers to discover that minocycline very selectively interrupts certain specific signaling pathways critical for T cell activation. However, the antibiotic doesn't completely obliterate T cells or diminish their ability to respond to other infections or diseases, which is crucial for individuals with HIV.

"HIV requires T cell activation for efficient replication and reactivation of latent virus," Clement says, "so our new understanding about minocyline's effects on a T cell could help us to find even more drugs that target its signaling pathways."

The research was supported by grants from the National Institutes of Health.

Authors of the paper, in addition to Clements and Szeto, are Angela K. Brice, Sheila A. Barber and Robert F. Siliciano, all of Johns Hopkins. Also, Hung-Chih Yang of National Taiwan University Hospital.

[Inchlingblue]

There's a recent thread on this topic:

http://forums.poz.com/index.php?topic=31796.0

[Cosmicdancer]

Oops, sorry about that Inching.  I totally missed the thread you started the other day.  The moderator can delete this one if they want. 

[J220]

Amazing, right under our noses, this drug was. For me what is exciting is that, as the article states, they will study Minocycline's MOA and determine exactly what it is that makes it work, and then use this knowledge to develop other drugs or maybe even a vaccine.

[Cosmicdancer]

We should be able to see fairly quickly what impact it has on preventing resistance to various HAART combinations since patients can ask doctors to add it to their regimens, no?  It also has anti-inflammatory benefits it seems.  I did notice that, for some, there are side effects.  I'm just wondering about the long-term effects of taking an antibiotic since they kill off good and bad bacteria alike. 

[sensual1973]

sorry,my medicine cabinet is full already.

[Hellraiser]

sorry,my medicine cabinet is full already.

Heh. 
"Oh this could make my life better?  I would take it but it's just so damn inconvenient!"

This is what I pretty much imagine people to say when they turn down medicine that could make them live a better life for whatever reason.  Side effects, difficulty in adherence, etc...

[Tempeboy]

The possible benefits are twofold,

With HAART keeping HIV at undetectable levels in blood, brain and genital fluids - the theory is that minoclycline could reduce replication of dormant virus.

If it worked this would not only allow people to recover more CD4's, but would also calm the immune systems 'inflammatory response' - reducing tissue damage and fatigue etc.

The big drawback is that long term use is associated with kidney damage, still I am going to try a months worth to see if I notice any difference,  doc informs I would get better outcomes by quitting smoking.

[Hellraiser]

When I change physicians I am going to look into possibly using this, but combined with tenofivir's renal side effect profile I'm a little bit leery.  I guess I'll just chat the doc up and see how it goes.

[adhoc]

I pointed the story out to my dermatologist and I am taking it now as I have skin issues, So far its working good for the skin. I havent had any side effects so to speak. My numbers have been slow to rise so on my next draw we'll see if anything new as I have been taking it for a month or so now. I was taking 1 150mg 2x daily but have moved beyond the first month and only taking once daily for the next couple months. If anything happens as far as counts Ill follow up on this thread.

[elf]

I am puzzled, sometimes they say contradictory things:

1. this substance is good because (re)activates dormant HIV
2. this substance is good because keeps dormant HIV dormant


 

[hahaha]

I am puzzled, sometimes they say contradictory things:
1. this substance is good because (re)activates dormant HIV
2. this substance is good because keeps dormant HIV dormant
 

Correct me if i' m wrong, but it seems to me
1. if the substance combine with the capacity of killing or eradication of HIV, it shall activate dormant HIV,
2. if not, then keep HIV dormant will be good.
 

[Tempeboy]

This is certainly interesting news,

Has anyone heard of any plans to replicate the research on people?

One important issue that these reports have not mentioned is that Minocyline taken in the long term is toxic to the Kidney's.

[vt5john]

Several months ago - I had a major case of Acne on my face and upper chest after started taking HAART.     I was so depressed and stressed out about this :-(....  I have since started using topical cream (Benzoyl Peroxide and Clindamycin) - this does make the acne go away quickly especially on my face, but it's a constant battle.   Someone on the forum did suggest taking Minocycline - but it's not available here in Thailand.   A friend of mine is currently in the US and returning in the near future and is willing to bring back some minocyline for me.  Can this drug be purchased over the counter or can I order it online?  What dosage should I get?  Thank you.

[Inchlingblue]

   Someone on the forum did suggest taking Minocycline - but it's not available here in Thailand.   A friend of mine is currently in the US and returning in the near future and is willing to bring back some minocyline for me.  Can this drug be purchased over the counter or can I order it online?  What dosage should I get?  Thank you.

Maybe you can ask Papillon:

http://forums.poz.com/index.php?topic=33913.msg420209#msg420209

[roy100]

Long term use of this AB can cause thyroid tumor,and or pituitary and adrenal glands cancer.
Also risk to liver and kidney.

Use with caution, I would wait until more research is done.

[vt5john]

Long term use of this AB can cause thyroid tumor,and or pituitary and adrenal glands cancer.
Also risk to liver and kidney.

Use with caution, I would wait until more research is done.

and the HAART meds you and I are currently taking are as safe as lolly pops right?   How about answering my questions?

[J220]

and the HAART meds you and I are currently taking are as safe as lolly pops right?   How about answering my questions?

Why such an agressive response to Roy100's post?? He simply pointed out valid data....and it's not like he (nor anyone here) are obligated to answer your questions. We're all here to help each other, and we are happy to share information. But you should not demand answers to your questions, my friend, nor post sarcastic responses to other's bona-fide replies.

[vt5john]

Why such an agressive response to Roy100's post?? He simply pointed out valid data....and it's not like he (nor anyone here) are obligated to answer your questions. We're all here to help each other, and we are happy to share information. But you should not demand answers to your questions, my friend, nor post sarcastic responses to other's bona-fide replies.

Excuse me!  Yes I was being sarcastic as I believe his reponse is NOT valid data - I was only pointing out the truth i.e: our HAART meds are very toxic to our body with many unknown long-term side effects.   I am not demanding anyone to answer my questions - but if anyone is going to response - might as well read the questions asked?

[tennisplayer56]

Excuse me!  Yes I was being sarcastic as I believe his reponse is NOT valid data - I was only pointing out the truth i.e: our HAART meds are very toxic to our body with many unknown long-term side effects.   I am not demanding anyone to answer my questions - but if anyone is going to response - might as well read the questions asked?

here's a response. HAART has improved dramatically in the last decade so that many have less toxic side effects. so if long term use of minocycline has cancer as a potential side effects, you really cant compare the two groups of drugs now can you? thus, i think roy's response is actually very valid.

[newt]

Based on the recorded side effect profile, I would rather take any modern HAART combo than minocycline long-term. It's especially bad for women, who frequently (generally) get vertigo and tinnitus when taking it (so rather an unfair solution to the reservoir problem). It's a tetracycline, nasty drugs if you take them for more than 4 weeks.

The idea that ARVs used in modern combinations are "very toxic" is not borne out by the data available. I expect the data available in future will get worse. But even nevirapine is kinder to your liver than paracetamol.

Plus it's kinda barking up the wrong tree, the premise of the discovery, ie sending sleeping HIV virons into a coma rather than trying to eliminate them. HAART effectively controls viral replication, it's hard, and perhaps pointless, to improve on this once your viral load is under 50 copies.

- matt

[elf]

You know what, at least minocycline (a relative of doxicycline) is good for treating many parasitic, zoonotic and sexually transmitted diseases.  

Joking apart...

Tetracyclines should not be used for more than 3 months continuously (at least this is what thay say for malaria prophylaxis in travelers) because they basically destroy all ''good'' bacteria in your digestive system and make you more prone to severe fungal infections.