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Author Topic: Question about CXCR4 inhibitor antidrug  (Read 2893 times)

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Offline HALOO

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Question about CXCR4 inhibitor antidrug
« on: November 18, 2008, 04:58:50 PM »
I hope I put this Topic in the right place


I dont understand something.
IF HIV do attach to CD4 by 2 ways that is CCR5 inhibitor (or antagonist), and CXCR4 inhibitor.
We already have  CCR5 inhibitor Antidrug(T-20 and MVC).
If in the future(3-4 years) we have antidrug for CXCR4 inhibitor

Then how can HIV attach to cell(CD4), if there is no another way to attach to the CD4 then I guess we can control this disease(forever with meds).

This sound too easy, I guess that I must misunderstand something.My knowledge about this disease is still very little.

Offline David Evans

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Re: Question about CXCR4 inhibitor antidrug
« Reply #1 on: November 18, 2008, 05:19:36 PM »
Haloo,

Your instincts are right on the mark. It is a good idea to explore the possibility of blocking CXCR4 receptors. That said, it's also turning out to be a difficult task and it's hard to make a realistic guess for how long it might take us to learn everything we need to know.

Remember that both receptors (CCR5 and CXCR4) sit on the outer surface of CD4 cells for a reason. They have functions. We just don't know what all of those functions are. With CCR5 we lucked out. There are people who were born without the ability to make those receptors. Generally, they are just as healthy as the average person, though some infections like West Nile virus may hit them harder. So we knew right from the start that blocking those receptors probably wouldn't hurt people - except for the possibility that it might make HIV strains that preferred CXCR4 become dominant - and therefore possibly lead to faster disease progression. So far this hasn't turned out to be the case.

The same isn't true with CXCR4. In fact, when they knock out the gene responsible for making CXCR4 in mice, the babies don't live, because they have heart defects. So blocking CXCR4 might have serious consequences. Some companies are still looking in this direction, so it's not a dead issue, but it is proving to be a challenge to find compounds that are safe enough for larger human studies.

-David


Offline freewillie99

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Re: Question about CXCR4 inhibitor antidrug
« Reply #2 on: November 18, 2008, 05:38:36 PM »
Haloo and David:

Thats a really interesting point and I'm glad you brought it up. 

David, haven't I read about a school of thought that speculates that the virus might not be able to easily mutate around a blocked CCR5 whether due to small molecule therapy, siRNA interference or gene therapy approaches because very few new viral particles would then be produced? This (again, in theory) would greatly decrease the chance of a mutant form being created that doesn't use the CCR5 portal.

Of course, this would assume an R5-tropic strain, not mixed, in the patient.

Thoughts?
Beware Romanians bearing strange gifts

Offline hotpuppy

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Re: Question about CXCR4 inhibitor antidrug
« Reply #3 on: November 23, 2008, 04:26:30 PM »
Fortunately, most infections are R5 (CCR5).  The virus seems to switch to X4 is what I'm told.  While I'm not an "expert" I am in a R5 inhibitor study and I've read everything I can find and asked alot of questions.  That makes me very knowledgeable and personally committed.

Schering-Plough has had study patients on Vicriviroc for 4 years now with no adverse events, side affects, etc.  This was stated in a 29 Oct (appx) press release. 

If the mutation theory held enough water, we would see infections in people who genetically are lacking the R5 receptor.

It's also important to remember that HIV is not just about CD4 cells.  The common practice is to think that HIV only targets CD4 cells.  However, we know it also targets other types of immune cells such as macrophages, lymphocytes, etc.  Basically anything with an R5 receptor.

The interesting question..... which is not being asked:
If R5 inhibitors can treat HIV, and 70% of HIV infections involve the R5 tropism, can R5 inhibitors be used as a prophylatic to prevent HIV transmission? 
Don't obsess over the wrong things.  Life isn't about your numbers, it isn't about this forum, it isn't about someone's opinion.  It's about getting out there and enjoying it.   I am a person with HIV - not the other way around.

Offline tash08

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Re: Question about CXCR4 inhibitor antidrug
« Reply #4 on: November 23, 2008, 05:56:25 PM »
Ibalizumab (previously known as TNX-355) is a non-immunosuppressive monoclonal antibody. It is being investigated as an HIV entry inhibitor with the ability to block both CCR5- and CXCR4-tropic viruses, and is currently undergoing a Phase II clinical trial with an estimated study completion date in October 2010.
« Last Edit: November 23, 2008, 06:06:01 PM by tash08 »
01/04/06-HIV-
03/09/06-HIV+
05/07-Atripla
04/01/10 CD4-681, VL-UD
07/10/10 CD4-450, VL-UD
10/10/10 CD4-473, VL-UD
01/21/11 cd4-522, VL-UD
05/02/11 CD4-638, VL-UD <20 copies Hell yeah!
08/3/12 CD4-806, VL-UD

Offline freewillie99

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Re: Question about CXCR4 inhibitor antidrug
« Reply #5 on: November 24, 2008, 10:15:16 AM »
hotpuppy:

Thanks for the info.  Good luck and continued success with your Vicriviroc trial. 
Beware Romanians bearing strange gifts

Offline David Evans

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Re: Question about CXCR4 inhibitor antidrug
« Reply #6 on: November 24, 2008, 11:04:08 AM »
Hotpuppy - good luck with the trial and your Vicriviroc therapy.

FreeWillie - we don't actually know a lot about viral kinetics when the R5 receptor is blocked. Here's what we do know. Though people born without the ability to produce R5 receptors (called Delta 32 homozygotes) are very difficult to infect - they do, occasionally, become infected with X4 virus. And when they are infected, they do have disease progression. Also, in the Selzentry and vicriviroc trials, there are people in whom the X4 virus does become dominant and who then fail those treatments and produce lots of virus.

What some (maybe most) researchers suspect, is that nearly everyone has at least a tiny amount of X4 virus being produced all the time, but for a variety of reasons the X4 virus only emerges as a larger percentage later in the disease progression process - and only in about half of people w/HIV. Understanding the man reasons that the X4 virus remains a tiny minority population will help us better understand the potential of these new drugs.

That said, there are some very early signs that drugs like Selzentry and vicriviroc may do some really beneficial things besides simply blocking viral replication. They also appear to boost CD4s more than other antiretroviral drugs and they may also block inflammation - what many feel may be leading to more heart disease and non-AIDS cancers in people with HIV. That research is either ongoing or just getting started now - so stay tuned - we're actually going to be doing a web exclusive on that in the near future.

-David

Offline John2038

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Re: Question about CXCR4 inhibitor antidrug
« Reply #7 on: November 24, 2008, 11:15:14 AM »
Despite the restrictions of blocking the 2 co-receptors, I'm wondering if taking for e.g. the Ibalizumab for a limited period of time could not still help anyway.

For e.g. for those in salvage regimen and virological failure.

For normal use, the problem is the time it take to purge the latent reservoir.
If the treatment is started quickly after the infection, it takes around 3-4 years to be undetectable with the most sensitive test, anywhere in the body, but up to 15 years or more in some others case (see Fauci study about that).

Now no one know if continuing taking the treatment after the undetectability in the latent reservoir can lead to a purge of them, and ultimately to a cure.

Let says the answer is yes after 10 years, if the treatment is started soon after the infection, the question become: can we block for so long both co-receptors ?

The researchers developing the Ibalizumabsaid have said they might be interrupt their research due to the limited market such drugs might have. But I can't accept this idea, as it's a better than nothing solution for those with no others options. And as far as I know, each of us might potentially need it a day or another. Maybe it can also be use with interruptions, or just to wait the next available drug to be released, or for a chemio or whatever.

Now it's true that its domain of application still need to be better defined, especially for earlier use than a salvage regimen (despite the fact that so far, accordingly to the intermediate results, blocking both receptors doesn't seems to cause any observable problems).
For that, the importance of the cxcr4 co-receptor need to be better studied I guess.

In any case, this drugs will have allows to answers important questions.

« Last Edit: November 24, 2008, 11:27:34 AM by John2038 »

Offline freewillie99

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Re: Question about CXCR4 inhibitor antidrug
« Reply #8 on: November 24, 2008, 11:19:41 AM »
Thanks, David.  Very informative!  Great stuff.
Beware Romanians bearing strange gifts

Offline freewillie99

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Re: Question about CXCR4 inhibitor antidrug
« Reply #9 on: November 24, 2008, 11:21:51 AM »

That said, there are some very early signs that drugs like Selzentry and vicriviroc may do some really beneficial things besides simply blocking viral replication. They also appear to boost CD4s more than other antiretroviral drugs and they may also block inflammation - what many feel may be leading to more heart disease and non-AIDS cancers in people with HIV. That research is either ongoing or just getting started now - so stay tuned - we're actually going to be doing a web exclusive on that in the near future.

Another reason I'm looking forward to hearing more about the phase 2b and 3 trials of Pro 140...
Beware Romanians bearing strange gifts

Offline hotpuppy

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Re: Question about CXCR4 inhibitor antidrug
« Reply #10 on: November 24, 2008, 11:40:20 AM »
What I currently understand about R5 and X4 is this.  It's coming from both Docs I see, and I believe it to be unprivelaged info.

appx 70% of infections involve R5.  At some point the disease switches to X4.  X4 is lethal to t-cells and is typically associated with advanced HIV infection.  The mechanism for the switch is not known at this time.

they do believe that some people have both tropisms and thus in R5 inhibitor trials they have seen a few cases where suppresion of the R5 tropism allows for an explosion of the X4 tropism.  These cases were attributed to early tropism tests that were not as sensitive as the new tests that are currently in use.  thus it is believed that individuals with mixed tropic infections were admitted to the trials when they should have been excluded.

The information on tropism is sketchy at best and what I consider to be "emerging" knowledge.  I.e. many in the community are unaware of tropism.

My unqualified opinion is that entry inhibitors will change the way we combat the virus.  My reasoning is that if we can keep HIV out of the CD4 there is a real chance it can do it's job.  The reason HIV ultimately ransacks our immune system is because it destroys the alarm system. 
Don't obsess over the wrong things.  Life isn't about your numbers, it isn't about this forum, it isn't about someone's opinion.  It's about getting out there and enjoying it.   I am a person with HIV - not the other way around.

Offline John2038

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Re: Question about CXCR4 inhibitor antidrug
« Reply #11 on: November 24, 2008, 11:48:28 AM »
Thanks hotpuppy !

If I might just add a precision coming from these studies (Vicriviroc Phase II/III Studies)

Approximately 50-60 percent of treatment-experienced patients have virus that uses the CCR5 co-receptor.

Approximately 80-90 percent of treatment-naive patients have virus that uses the CCR5 co-receptor

Offline hotpuppy

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Re: Question about CXCR4 inhibitor antidrug
« Reply #12 on: November 24, 2008, 12:05:00 PM »
Thanks... I was quoting my study doc and ID doc.  They were probably averaging the numbers across the populations.  Either way it's encouraging to use entry inhibitors on HIV infected people.
Don't obsess over the wrong things.  Life isn't about your numbers, it isn't about this forum, it isn't about someone's opinion.  It's about getting out there and enjoying it.   I am a person with HIV - not the other way around.

Offline HALOO

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Re: Question about CXCR4 inhibitor antidrug
« Reply #13 on: November 24, 2008, 05:30:25 PM »
I still really think that Scientist should do Intense Research on this part.

This is really very simple concept, Imagine CD4 and macrophages, lymphocytes, etc as a house.If you close all the doors( CCR5 receptor and CXCR4 receptor) , there is no way the guest(HIV) can enter the house.
     If HIV cannot replicate , the number will of HIV will drop to very low amount(also with the help of other ARV drug).I really dont see how resistance can happen, (IF, aussuming) there is only 2 ways that HIV can contact CD4 and macrophages, lymphocytes, etc.
   If this concept work, we will be able to FOREVER CONTROL(NOT ERASE)l HIV to very low amount and they will  wll not have any affect on the body(since the number is very low).Let hope that in the future ,Scientist will find way to  kill latent reservoir cell.
       Who think this dream can become true???

 


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