caudoviral

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Here Be Dragons

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One of the more common misnomers flying around the pop-sci publications is this idea of “Junk DNA”. Now to be fair, this label originated with the scientific community. Even Francis Crick was dismissive of its utility, but that was thirty years ago. As it turns out, junk DNA (more accurately called non-coding DNA) contains both a variety of sequences with biological utility and large portions of our genomic history. It is the later that I wanted to bring up today.

One of the major forms of transcriptional control involves histone deacetylase. You can think of histones as essentially spools of DNA. If DNA is wrapped tightly around histones it is unavailable to be transcribed to RNA and then translated to protein. Modification of histones determines the precise manner in which the DNA interacts with them, and acetylation of histones loosens the wrapping of the DNA, making it available. So your cells employ histone deacetylase to make sure that regions of the genome stay nice and silent. Which is good, cause there is some scary stuff hiding in the sea of non-coding DNA.

Recently there has been a push to use histone deacetylace inhibitors to cause expression of genes of interest (e.g. it is suggested they could be used to flush latent virus out of memory T-Cells to destroy latent reservoirs of HIV). Now, these ideas seem really sound on the surface. If we could destroy that reservoir of latency, we could see long-term drug free remission in HIV infection. But what else might you wake up? As far as I know there is no reliable method (if there is indeed a method at all) to target histone deacetylase inhibitors to specific regions of the genome, so this would be a general approach inhibiting all of a cells histone deacetylase, which I can’t but think would lead to A) steps towards tumor transformation as cell cycle controls  were disabled, and B) the activation of unfriendly endogenous elements in the genome. Fishing out integrated HIV provirus is an excellent idea, but what else might we pull in with it?

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Written by Caudoviral

04/07/2011 at 11:29

Posted in Biology, HIV/AIDS

Tagged with

HIV & HSC

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They haven’t managed to kill me with exams yet; however, it’s not from lack of trying. But I found something so interesting yesterday that I just couldn’t keep myself from blogging about it. And by interesting, I mean terrifying. I tend to find life beautiful. Even if it is something most people would find gross, or disturbing, or horrible. I’m a biologist, it’s a documented weakness of our ilk. So when I say that the following engenders in me a feeling of profound wrongness and almost disgust, I want you to take my full meaning.

First, background:

  • HIV comes in two flavors, CCR5 tropic and CXCR4 tropic. You might remember a post on CCR5 tropic HIV from a while back. It basically denotes which co-receptor is necessary for the virus to enter a cell (and yes, there are dual-tropic strains). We generally focus on CCR5 because, for reasons that are not entirely clear, initial infection with HIV is almost entirely CCR5 tropic with the infection shifting to CXCR4 tropic as it progresses.
  • Hematopoietic stem cells (HSC) are the source of all of your blood. ALL of your blood, myeloid and lymphoid. They are a self-renewing pool of multipotent cells, which means that they can be used to make new blood as needed (this is why you can donate blood and bone marrow have it regenerate). Among the offspring of the lymphoid lineage are the T-cells that HIV usually attacks.

Got all that? Good. Sit down. Are you sitting comfortably?

In sum, we have shown that multipotent HSPCs and HSCs can be infected by HIV and that this infection is primarily accomplished by CXCR4-tropic HIVs. The infection and destruction of multipotent HSPCs may contribute to the more rapid decline in CD4 counts associated with CXCR4-tropic HIV isolate emergence. Alternatively, as infected HSCs could create an extremely long-lived reservoir of virus, preferential infection of these cells by CXCR4-tropic virus could provide a reservoir for the emergence of CXCR4-tropic isolates late in disease: as other viral reservoirs are depleted, CXCR4-tropic virus from the HSC and HSPC reservoir could begin to predominate. In addition, our demonstration that HIV can infect cells capable of stably engrafting for months in the xenograft model indicates that HIV can infect HSCs that are capable of self-renewal and, if the integrated viral genome is latent, that it can be maintained and even expanded by cell division.

The above quote comes from an article published in this month’s Cell: Host & Microbe, and I have to say that their work looks pretty solid (at least to my exam addled brain). They performed a series of experiments using viruses generated from a minimal HIV genome and expressing three variant (R5, R4, or dual) envelope proteins. With this they demonstrated that not only could CXCR4 tropic and dual tropic viruses infect hematopoeitic progenitor cells in general, but that they could specifically do so to cells capable of multilineage reconstitution in immunocomrpmised mice. Or to put it another way: XR4 and dual tropic HIV infects HSC.

Now active HIV infection appears to kill HSC cells outright, and HSC death is really bad, but if you have been following closely you’ll realize that that isn’t the biggest worry here. Latent infection of HSC could lead to a near impossible to purge, continually renewing reservoir of infection, moreover it appears that it is possible for infected HSC to differentiate and produce daughter cells that are already infected. This means that in advanced cases of HIV infection, we might need to start looking for integrated provirus in cells that HIV technically can’t infect.

This is a blow struck to the heart of our immune system. Sure, there are genetic disorders that screw with HSC, cancers even, but a pathogen? I feel like they are breaking the rule about fighting on holy ground. It is still important to see if wild-type HIV is capable of latently infecting HSC instead of killing them outright, but given the versatility of this virus, it wouldn’t surprise me, and if that is the case it is all the more reason to lock down HIV infection as early as possible. We are really close to finding a way to flush latent infection from T-cells, and it would be a serious blow if we succeed in that only to find that HIV has yet another reservoir lying in wait.

(And okay, I admit that my disgust is laced with a teensy bit of: Oh wow that is so awesome.)

Notes & Sources

  1. HIV-1 Utilizes the CXCR4 Chemokine Receptor to Infect Multipotent Hematopoietic Stem and Progenitor Cells (Carter, et al. 2011)
  2. Thats only the second Highlander joke in three months of science blogging. I am falling behind schedule.

Written by Caudoviral

03/25/2011 at 14:13

Posted in Biology, HIV/AIDS

Tagged with ,

HIV Latency 101

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It has been pointed out to me that if I am going to spend time talking about HIV latency, it might benefit my readers to understand what is meant by that. And to understand that, you need a basic understanding of the disease. So here it is, your crash courseon the course of HIV infection and viral latency.

Untreated HIV infection can be split into roughly three phases:

Image lifted from the NIAID's page on AIDS over at http://www.niaid.nih.gov

  • Initial Infection and Acute Symptoms: This phase represents the 1-2 months immediately after infection. The virus integrates into your cells and provokes an immune response. This leads to flu-like symptoms that do not persist.
  • Asymptomatic Phase: During this phase, which can last ~2-10 years, you have a relatively low viral load and demonstrate no symptoms. This is because the immune system is still in control. The virus is not causing CD4 T-cell death at an unmanageable rate and this phase persists until an immune escape event occurs.
  • AIDS: Once the virus dodges immune control, it proliferates rapidly, killing CD4 T-cells and opening the body up to the spectrum of opportunistic infections that will ultimately lead to death.

HAART (Highly Active Anti-Retroviral Therapy) can essentially prolong the asymptomatic phase of the infection indefinitely (or at least for as long as your body can deal with taking the drugs). The problem is that during the asymptomatic phase, your body is not able to eliminate the virus entirely. And even on HAART the drugs only work for as long as you take the drugs. So despite reducing viral load to a minimum, neither your body or our current best therapy can provide a cure. Just a stopgap. And it is a stopgap that has allowed uncountable numbers of HIV patients to live longer and better quality lives, but it is ultimately not a solution to the underlying problem.

So how is it that HIV can hang on long enough to eventually overpower the immune system? And how is it that our effective anti-retroviral regimen can’t manage to destroy the infection entirely? Viral latency. HIV has a number of molecular mechanisms (primarily based on transcription control) that allow it to sit in a cell for a good deal of time before replicating and budding off to go along its merry way. When that quality is coupled with the quirk of certain T-cells to go latent and become memory-T-cells, it makes for a particularly stealthy infection. The body and the drugs can do nothing to a latent virus in a latent cell, but if either of them let their guard down, and that cell becomes active and that virus becomes active, the entire infection can re-profuse.

This is (hopefully) the last hurdle to achieving an effective and practical cure for the disease: find a way to dump the reservoirs. Preferably without killing the patient. If only that were as easy as it sounds.

Written by Caudoviral

02/23/2011 at 13:37

Posted in Biology, HIV/AIDS

While we are on the subject of sex differences…

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Females infected with HIV proceed to AIDS faster than their male counterparts. This is, ironically enough, one of the benefits of being a pre-menopausal female at work. As I explained earlier, there is a recognizable gradation in survival value between pre-menopausal females, males, and post-menopausal females based on reproductive capability. You can’t properly gestate a child for 9 months if you are dead. To this end there are several health benefits exclusive to the pre-menopausal female system.

Or rather, they would be benefits were it not for the nature of this virus. Now, in HIV’s defense, this is not actually of selective benefit to it. Viruses aren’t out to kill us and in fact doing so prevents them from going about their merry business of infecting more hosts. What happens is that the HIV latency period relies on its ability to go dormant in inactive immune cells, but in these female patients there is a generally higher level of immune activity. This means fewer inactive cells overall, fewer places for HIV to hide, yet unfortunately not enough immune activity to actually eradicate the infection. The end result is that the patient’s immune system takes more wear and tear than her male counterpart’s, the higher rate of cellular activity leads to higher viral activity, and she progresses to AIDS significantly faster.

Notably this sort of thing is also implicated in the higher rate of auto-immune disease in the female population.

Just as a note, you can probably expect a lot more HIV latency articles throughout the rest of the semester. Have just started research on it, I should be dredging up all kinds of interesting stuff from the literature.

Sources & Further Reading

Written by Caudoviral

02/21/2011 at 09:06

Blood on their hands

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Individual science fiction stories may seem as trivial as ever to the blinder critics and philosophers of today — but the core of science fiction, its essence, the concept around which it revolves, has become crucial to our salvation if we are to be saved at all.
-Isaac Asimov

The above was written by Isaac Asimov in 1978. Five years later, in 1983 he would undergo a bypass surgery. The older and/or more attentive of you might see where this is going. Asimov died in 1992. It would be ten years before his family would make public that he had died of AIDS. Not only did HIV rob us of one of the greatest writers of the 1900s, but it was ten years before his family felt that they might be safe from the stigma attached to the disease. I find the above quote fascinating and haunting because of how pertinent it seems to the manner of Mr. Asimov’s death. He, and so many many others, quite simply did not have to die. They died because simple minded people could not expand their thinking into areas that they didn’t want to.

Infections from tainted blood supply are an often overlooked subset of HIV infections. Why? Certainly not for any good reason, this information could only help understand the current crisis. I feel that in all likelihood society is so embarrassed by how horribly it handled the early days of the HIV epidemic that they try to pretend it never happened. And almost nothing from those days is more starkly horrific than the way we handled the blood supply.

See, blood is more than just a nutrient delivery system, it’s a very lucrative industry. Put yourself in the shoes of an executive of that industry circa 1983. So there is this “gay cancer” going around and everyone is up in arms about it, well…everyone except the current presidential administration which is just ignoring the problem and hoping it will go away. Who knows how you feel about it? Maybe you think that it is a tragedy, maybe you think that it is God’s judgement. Regardless, you get called into a meeting with some guys down at the CDC in January 1983. All of a sudden you are introduced to a new idea: gay cancer might be transmittable by blood. Moreover the CDC actually wants you and your company to take some minimum of responsibility. The horror.

If you were to actually screen your blood it could cost as much as 5 million (1983) US dollars! And how come if this is true, only expert virologists at the CDC know it? Aren’t all those guys just alarmists elites anyway? And hey, they only have clear evidence that three people have contracted the disease from tainted blood so far. That whole thing about 10% of all haemophiliacs being infected by transfusion is rubbish, isn’t it? And it isn’t like a public outcry is likely. Moreover, what gives big government the right to poke its nose into your business anyway? They’re the bad guys here. The government needs to get the CDC under control. So what if about 5% of diagnosed AIDS sufferers had donated blood within the past year, there just is too much of a financial stake for you to bother listening, to bother believing, or to even bother imagining that these experts might be right.

In the meantime, Isaac Asimov would undergo bypass surgery and be supplied blood from a donor with AIDS. That donor had given that blood in good faith, with the intent of saving a life, but the pathogen hiding within would instead claim another victim. And a host more would follow in the wake.

The status quo is often assumed to be good. The first response to troubling information that would change it is generally disbelief. And we have seen this before and will see it again on a grand scale. Sometimes that disbelief leads to inconvenience, sometimes that disbelief leads to no consequence, this time it led to an ever escalating body count. This time it was just one more step in letting a horrifying pathogen rage out of control. And all but for the sake of a little thinking about what could be. All for the sake of a little open-mindedness, a little evidence based speculation and extrapolation on the future, the blood banks voted to willingly go on acting as a vector for HIV. The irony that these institutions earned their keep by saving lives is not lost on me.

At the end of the meeting, CDC’s Jeffrey Koplan, who was chairing it, began proposing consensus recommendations. Bruce Voeller suggested a resolution opposed to deferral of high-risk donors; the proposal was defeated soundly on a voice vote. Other proposals met similar fates or were modified so extensively that they were rendered meaningless. The meeting adjourned with no recommendation or agreed-upon course of action. Things would simply go on as they were, as if nothing was happening.
-Randy Shilts; “And the Band Played On”

Anyone who seriously has to ask: “How much will it cost me not to kill people? Is it worth it?” Fuck you. I know some of those blood bank execs that attended that meeting are still alive and probably still working today. I just hope they realize the extent of the blood on their hands. And I hope all of you realize just how important the questioning wonder of speculative fiction is if we are to be saved at all.

Sources & Further Reading

Written by Caudoviral

01/31/2011 at 20:46

If only it were as simple as curing HIV.

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The following is old news, yet I am constantly surprised at how few people seem aware of it.

We have a cure for HIV. We have had one since 2007.

One thing that life is good at is living. The species would be in a pretty sorry state if we stood a chance of being wiped out by every passing epidemic. Certain immune individuals naturally arise  in any epidemic, and, as horrible as the HIV epidemic is, it is hardly our first rodeo. A long, long time ago, something (there is contention over whether it was bubonic plague, smallpox, or something else entirely) selected for a T-cell mutation in certain populations in Northern Europe. These populations proved more fit against whatever risk they were facing, and so were able to pass on their genes while their contemporaries passed away. These genes disseminated through the population and currently 5-15% of Europeans posses at least one allele coding for the mutation. As it so happens, possessing one copy of this allele slows the progression of HIV to AIDS by up to two years. Having two copies provides immunity.

This mutation is known as CCR5Δ32. Let’s parse that: C-C Chemokine Receptor 5 Deletion (which we use the Greek letter Delta as a shorthand for) of 32 bases. That deletion of 32 bases is so crippling that the CCR5Δ32 gene is incapable of making functional CCR5. This provides protection from HIV based on the manner in which the virus goes about infecting our cells.

Now, we are all familiar with the fact that HIV selectively infects so called ‘helper’ T-Cells. It does so through interactions between proteins on the surface of the virus and the CD4 molecule on the surface of the T-cell. What people often neglect to mention is that the presence of CD4 is necessary but not sufficient. HIV needs a secondary binding site in order to infect the cell. To this end, it uses CCR5 (and occasionally something else called CXCR4, but only in the late stage of infection). People who are heterozygous for the CCR5Δ32 mutation make less CCR5. People who are homozygous make none.

Beginning to see how this works? “But Caudoviral”, you say, “surely the presence of immunity isn’t in itself a cure!” And you would be right, if we were talking about anything but blood.

The advantage of blood is this: It all springs from a common well: the hematopoietic stem cell. So all we would have to do is take an HIV patient, use radiation to kill his immune system, and do a hematopoietic stem cell transplant from a donor who is homozygous for CCR5Δ32, and stand back and marvel as we have basically transplanted immunity to a disease. It’s absurdly simple. So simple it almost seems like it shouldn’t work. But it does.

In 2007, a 40-year-old, white male presented to a German hospital with a case of acute myeloid leukaemia. The patient had been diagnosed with HIV ten years earlier. Due to the leukaemia, a hematopoietic stem cell transplant was indicated. In addition to screening the donor bank for HLA matches, his doctors also screened for CCR5Δ32 homozygosity. They found a match. The procedure was carried out as planned and to this day the patient is HIV free. Cured.

But don’t take my word for it! The original article is available for free through the NEJM.

They are already looking for a second patient to replicate the results. So why aren’t we celebrating? Why isn’t the war over? Well, one of the great problems with any epidemic is that the medicine is only half the battle. Despite this being a dramatic and surprising result, despite this opening up a new door in the treatment of blood pathogens, the fact of the matter is that hematopoietic stem cell transplant is a complicated, dangerous, painful, and inherently unreliable procedure. Not to mention that it is expensive. We can’t use first world medicine to eradicate an epidemic in some of the poorest nations on the planet (if we could, so many more diseases would be a thing of the past, tb for example).

There is a bitter irony in having the power to cure a disease, but lacking the power to get that cure to everyone who needs it.

However, I can’t be entirely pessimistic. This has brought a great deal of attention to CCR5 as a potential target of therapy for HIV and several chemical CCR5 inhibitors are currently in testing. This might just be the breakthrough that leads to a better future, but I am not crossing my fingers.

Written by Caudoviral

01/10/2011 at 15:43

Posted in Biology, HIV/AIDS