Your opinion on HIV-1 and AIDS

F

FiReaNGeL

Registered Member
We all know that HIV-1 is a worldwide disaster, and that it must be stopped. I'm a PhD student working on AIDS, and I'm curious about solutions normal people would come up with. Sometimes a fresh look at a 20 years old problem can do miracles. To help, I set up an allegory about the immune system and HIV-1 (see this post on my blog, real world simplified explanation is available 2-3 posts later)

I have my own idea about how to cure it (and I'm working hard on it, don't worry!) but want to get some non-expert input. Don't fear to express weird / novel ideas... anything is accepted.

The blog itself is about bioinformatics, HIV-1, microarrays... all the stuff I'm working on / with basically. It's quickly picking up speed, and posts should be more frequent now that I finished my master's thesis. Hope to see you there ;)
 
What do we know about the function of the CCR5 co-receptor? How vital is it for T-cell function? If it's not too important (people can live without it), we could possibly engineer cells that produce antibodies that bind to the active site of the CCR5 protein, but do not illicit an immune response from the host organism. Perhaps attaching another protein group onto the heavy chain of the antibody, or some such mechanism.

Just an idea of the top of my head. I'm no expert, but I'm no layman when it comes to biology either. Welcome to sciforums!
 
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How about engineering another disease that is perfectly harmless to healthy people but will kill someone with HIV within 24 hours, and spreads airborne but is only incubated in people with HIV. After everyone with HIV is dead, so to will be the other virus. Thus, all uninfected people live happily ever after =]
 
Idle Mind said:
What do we know about the function of the CCR5 co-receptor? How vital is it for T-cell function? If it's not too important (people can live without it), we could possibly engineer cells that produce antibodies that bind to the active site of the CCR5 protein, but do not illicit an immune response from the host organism. Perhaps attaching another protein group onto the heavy chain of the antibody, or some such mechanism.

Just an idea of the top of my head. I'm no expert, but I'm no layman when it comes to biology either.
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First, CCR5 is a chemokine receptor (its ligand is RANTES) involved in chemotaxis, among other things. It is present at the surface of some CD4+ T cells as well as macrophages, both targets of HIV-1. However, some CD4+ T cells express another chemokine receptor, CXCR4 (which can also serve as a coreceptor for HIV-1). So you would have to target both. Antibodies tend to do two bad things in this context : when they bind, they can mimick the ligand and induce signaling in the cell, which can lead to various problems if you over stimulate them. Second, antibodies tend to be a 'destroy me, i'm dangerous' signal to the immune system, so you would target both macrophages and CD4+ T cells ;)

But your idea is far from irrelevant. In fact, it's an important area of research right now. Drugs candidate (small peptides which bind to the coreceptors, T-20 style) are already in clinical trials and seem promising. See this link for an example.

However, all they promise to do is the same thing that current anti HIV-1 drugs can do : stop new infection from occuring. The problem of latent HIV integrated in cells is still the same.
 
cato said:
How about engineering another disease that is perfectly harmless to healthy people but will kill someone with HIV within 24 hours, and spreads airborne but is only incubated in people with HIV. After everyone with HIV is dead, so to will be the other virus. Thus, all uninfected people live happily ever after =]
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Thanks for the idea and lack of humanism. If you had AIDS, would you still see this solution as a good one? I see...
 
Is there a way to limit the antibody's ability to cause an immune response? Do we know for sure that HIV-1 binds to the receptor site of either CCR5 or CXCR4, or is it a random length along the peptide (although it obviously has to be outside the cell)? Like I said, it was a quick idea that came to mind as soon as I read the thread. I'm sure if it were that simple, we would be a little closer to curing it.

After HIV-1 enters the cells, it adds the gp120 protein to the surface, correct? Is there a way to target infected cells based on that? What are the problems, assuming that this does occur?
 
Thanks for the idea and lack of humanism. If you had AIDS, would you still see this solution as a good one? I see...
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Yes, I would. "In order to do good, you may have to engage in evil" (Robert S McNamara) I would hope however that I am not stupid enough to get or spread HIV so it would not be directed at me. However, if in some circumstance I did get it I would sacrifice my self if it meant the complete annihilation of HIV/AIDS.
 
Idle Mind said:
Is there a way to limit the antibody's ability to cause an immune response? Do we know for sure that HIV-1 binds to the receptor site of either CCR5 or CXCR4, or is it a random length along the peptide (although it obviously has to be outside the cell)? Like I said, it was a quick idea that came to mind as soon as I read the thread. I'm sure if it were that simple, we would be a little closer to curing it.

After HIV-1 enters the cells, it adds the gp120 protein to the surface, correct? Is there a way to target infected cells based on that? What are the problems, assuming that this does occur?
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There is a way to limit antibody mediated immune response. If you look at an antibody, you see that it's shaped like a Y. The stem of the Y is what is called the Fc part of the antibody. The other part, the variable region, recognize and bind to the target. The Fc section point outward and is recognized by various components / cells of the immune system. You can do antibodies composed of just the Fab part (called Fab fragments) that are 100% functional, and they don't cause an immune response. But that kinda make them useless to control infection by HIV-1 too... they will bind, maybe causing some sterical hinderance for the incoming virus (competition for binding), but the solution is not ideal. They can't be synthetized chemically; you need cells to produce them, and getting them in large enough quantity to control infection (not even cure!) in individuals would cost a fortune and your first-born child. Small peptides that bind to the target (in this case, CCR5 or CXCR4) are prefered for this reason. A good example, the T-20, is a small peptide that bind to the viral protein involved in fusion with the cell (gp41).

Your other idea is a good one too. But we've been there, and at the moment no one had success with this approach. The problems are :

1- Few gp120 molecules will be left at the surface after infection, and they are endocytosed (internalized) relatively quickly, as most surface molecules.

2- Latent HIV-1, once integrated and dormant, does not produce gp120. gp120 accumulate at the surface only in the final stages of viral replication, when new virus massively leave the infected cell. As you can guess, the cell will die pretty soon after that, so it's kinda pointless.

A team had a great idea on this theme : incorporate CD4 (HIV-1 receptor) at the surface of a rhabdovirus (cause rabies, kill cells pretty fast). In vitro, it works extremely well; it target and kills HIV-1 infected cells (well, not the latently infected ones). In vivo however, it has many problems. CD4 cause it to bind to other cells, triggering immune response among other things. It is also recognized by the immune system, being a virus.

Keep going, it's interesting to see ideas you come up with ;)
 
A little background on myself, before I continue. I am an undergraduate in British Columbia, Canada, majoring in Biology. My background is mainly molecular and the closely related fields, but I also have an interest in ecology (aquatic).

Now, another idea on the antibody thing. We are able to produce cells that overexpress genes. We could engineer an antibody that doesn't produce an immune response, and add the gene with an SV-40 promoter several times into a cell's genome (a stem cell, perhaps? Otherwise the normal cells -- B-cells?). This would mean a lot of the antibody is being produced. Do we know what peptide sequence on either of the co-receptors that the virus binds to? If we do, we could make the antibody specific to that site, so that the steric hindrance is very strong and the virus can't compete.
 
I´ve heard that HIV dies at ~43C, is this true? If it 'is' true, then how quickly and is there some possibility to heat up human cells to 43c without damaging them?
 
Idle Mind said:
A little background on myself, before I continue. I am an undergraduate in British Columbia, Canada, majoring in Biology. My background is mainly molecular and the closely related fields, but I also have an interest in ecology (aquatic).

Now, another idea on the antibody thing. We are able to produce cells that overexpress genes. We could engineer an antibody that doesn't produce an immune response, and add the gene with an SV-40 promoter several times into a cell's genome (a stem cell, perhaps? Otherwise the normal cells -- B-cells?). This would mean a lot of the antibody is being produced. Do we know what peptide sequence on either of the co-receptors that the virus binds to? If we do, we could make the antibody specific to that site, so that the steric hindrance is very strong and the virus can't compete.
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It was evident that you had some biology background ;)

We have specialized cells to produce monoclonal antibodies, called hybridomas (fusion of a B cell with a cancerous cell). Even these can't produce truely massive amounts of antibodies, and then you have to purify it on affinity columns from the supernatant... can't compare to chemical peptide synthesis.

Even if you could synthetize enough, you must realize that the immune system does respond to HIV-1, and somewhat control it (using antibodies, among other things). The problem is that HIV-1 mutate REALLY fast; error rate (point mutation) is estimated between 1 in 2000-10000 nucleotides (HIV-1 genome is almost 10 000 bases). This mean that with the massive amount of HIV-1 particles produced and infecting new cells, if left uncontrolled by HAART (Highly Active AntiRetroviral Therapy), each day in an infected individual every single point mutation arise; 1% of each double mutation. gp120 (or other antibodies targeted viral proteins) will mutate enough to escape the immune system and retain their activity (well, not 100% but enough to retain infectivity potential).

To answer the other suggestion (heat), HIV-1 'dies' when you cause its proteins to denature (lose their conformation). It would require a few more degrees than 42, but the problem is that your proteins will denature too, killing you in the process ;) High fever is especially dangerous for this reason (41-42 Celcius is considered dangerous and can cause brain damage or death).
 
my idea is more human than cato's, but follows along the same lines. We make AIDS/HIV camps. since its not airborne(that we know) then all the quarantine would have to do is prevent people from leaving, and from getting body fluids on stuff. Make a mini city, have them make stuff, not food, and that way it wont spread, thus eliminating the disease in a few generations. now undoubtedly something will happen, but vectors can just be eliminated. :m:
 
Hotsexyangelprincess, while more humane than cato's, it's still an unethical proposition. Not everyone who has HIV-1 knows that they do, and we are not allowed to screen people for the disease without their consent.

Okay, I will continue to give this some more thought. Thanks for your replies.
 
hotsexyangelprincess said:
my idea is more human than cato's, but follows along the same lines. We make AIDS/HIV camps. since its not airborne(that we know) then all the quarantine would have to do is prevent people from leaving, and from getting body fluids on stuff. Make a mini city, have them make stuff, not food, and that way it wont spread, thus eliminating the disease in a few generations. now undoubtedly something will happen, but vectors can just be eliminated. :m:
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Well, I feared that these forums were quite not the right place to get intelligent ideas, and I was (partly) right. Yeah, why not quarantine by force 40 millions persons. And let's do the same thing with other diseases, too. And people with low IQ (you qualify for that one sir), disabilities, ugly people, people with ideas against the power in place, various minorities, and of course, people of color and oh! almost forgot jews!

Another comment of that kind and I'm taking my business elsewhere. Those who are REALLY interested in PRODUCTIVE discution with someone working in the field (that's me!), feel free to visit my blog and post comments.

http://thescientistblog.blogspot.com/
 
Yeah, I feel my idea is more humane than Hotsexyprincess's. Furthermore, I know my way is also immoral. Just because I would volunteer for this does not mean that it is moral. However like I said "how much evil must we do in order to do good" (R.S. McNamara) so you can get into a huge circle of moral logic that will take you nowhere, like-is it moral to have sex out of marriage? (Big spreader of aids), or-is it moral to spend my tax dollars on federal grants to fund aids research, which I will probably never get?

It is easy to see how that could get sticky. I just wanted to give my two cents and voice my disgust for people whose ongoing irresponsibility (unsafe sex) exacerbates the existing problem with the disease. However, I have no medical knowledge, so I will shut up now.
 
Another comment of that kind and I'm taking my business elsewhere.
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Don't you think that's a little extreme? We have to consider every option, good or bad, before we can come up with a solution to most problems. You have been able to point out the problems in all of the proposed solutions so far, which is a good thing. You will also have to remember that not all here have as much experience on this topic as you, so the calibre of ideas may not be what you are expecting.

However, I digress. I see we have the complete sequence of HIV-1. The gene which codes for the p19 protein responsible for preventing the viral RNA from being spliced is subsequently sequenced. I can see problems with what I am about to propose, but maybe there are ways around it. Design a short stretch of anti-sense RNA against the mRNA transcript from this gene, which would prevent translation. With no p19 protein product, the viral RNA would be left on it's own to be spliced, and with no carrier. What do you think of that?

*edit* Also, are there areas of conservation between CCR5 and CXCR4?
 
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Idle Mind said:
Don't you think that's a little extreme? We have to consider every option, good or bad, before we can come up with a solution to most problems. You have been able to point out the problems in all of the proposed solutions so far, which is a good thing. You will also have to remember that not all here have as much experience on this topic as you, so the calibre of ideas may not be what you are expecting.

However, I digress. I see we have the complete sequence of HIV-1. The gene which codes for the p19 protein responsible for preventing the viral RNA from being spliced is subsequently sequenced. I can see problems with what I am about to propose, but maybe there are ways around it. Design a short stretch of anti-sense RNA against the mRNA transcript from this gene, which would prevent translation. With no p19 protein product, the viral RNA would be left on it's own to be spliced, and with no carrier. What do you think of that?

*edit* Also, are there areas of conservation between CCR5 and CXCR4?
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Yeah, my reaction to nazist ideas must have been a little excessive :rolleyes: But you're right, not everyone have experience on HIV-1 here (that's why I came, I wanted to see fresh ideas about it. When you're in the forest, you tend to focus on trees).

For you idea... p19 is called Rev, and is, like you said, implicated in the splicing of HIV-1 genome. You could very well design siRNA (small interfering RNAs, a recent discovery. 22 basepairs double stranded RNA, when introduced in cells, cause the specific degradation of mRNA to which they hybridize).

Even if we don't consider the problem of mutations which would produce virions resistant to the solution eventually (which is a big one), you have to find a way to introduce it in cells. This is not a trivial task; adenovirus and lentiviral vectors (derived from... HIV-1!) are in development to transduce cells with genes (or siRNA); so called 'gene therapy'. It's promising, but suffered a setback in human testing after disaster struck (Jesse Gelsinger died 3 days after receiving adenovirus mediated gene therapy). So we'll have to wait for that.

About the HIV-1 denial craze, if I was you I wouldn't give it much attention. Sure, it can be entertaining ;) If you check this particular piece (because it's not the only one on the web), it's almost composed exclusively of religious babble with no supporting facts, misquoting (Dr. Marc Weinberg among others). Do check however this page which explain the classical arguments of this 'HIV-1 don't exist or don't cause AIDS' group, and some counter arguments. In my opinion, it's not only silly, it's downright criminal. 40 millions people infected worldwide, and let's shut our eyes on the problem. It doesn't exist! And let's mix a little religion with it (I won't get started on religion, I promise!).

Been insomniac for 2 days now, i'll go get some sleep. They say that after 4 days i'm supposed to get hallucinations... can't wait ;)
 
Even if we don't consider the problem of mutations which would produce virions resistant to the solution eventually (which is a big one)
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I'm not so sure about this being a problem. Having many changes in genes can cause malfunction of the product, so there are areas of conservation. We know the sequence of the gene, and know what the protein sequence is, and what it will look like. We could design the siRNA to attach to the part of the mRNA that codes for the RNA-binding site of the protein, which has to remain virtually unchanged if it is to keep functionality.
 
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