Archive for February 2011
When I study retroviruses I always feel a little like I am studying something closely related to myself. Why? Well, because I kind of am. See, the human genome is not exactly virginal, and over our development a number of retroviral hangers-on have integrated but never left.
One of the characteristics of a retrovirus is that it converts its genome from RNA to DNA and then places that genome into our own. So the idea is that we replicate the viral proteins just as we replicate our own cells. However, not all viruses wind up extracting themselves, and those that don’t become what we call endogenous.
They stay with us, for good or ill, and get passed through each generation, becoming part of us. So when we look at something like HIV we also have to realize that retroviral envelope proteins were essential in mammalian placental development. And that it was the retroviral env proteins that kept us alive when our mothers immune system would have otherwise killed us in utero. A discomfiting thought.
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:
- 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.
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
- “The X-files in immunity: sex-based differences predispose immune responses.” Fish Nature Reviews Immunology 8 737-44 (2008)
- “Sex differences in longitudinal human immunodeficiency virus type 1 RNA levels among seroconverters.” Sterling, et al. Journal of Infectious Diseases 180 666-72
- “Sex differences in HIV-1 viral load and progression to AIDS.” Farzadegan, et al. Lancet 352 1510-14 (1998)
So recently the lovely ladies over at Fishnet Bluestockings added me to their blogroll, and I have reciprocated in kind. If you are at all interested in a rational slant of feminism, especially as it concerns the entertainment industry, I highly encourage you to go check them out (and I am not just saying that because one of their writers is a dear friend). This post is inspired by something I started saying in their comment sections, and as it concerns something that influences my view on humanity in general, I thought it would be best to expound on it here.
Sex is a defined, binary, biological distinction. It is a genetic designation based on the possession of a particular genotype. In humans this is the presence or absence of the Y chromosome and even more specifically the gene SRY (Sex-determining Region Y).
In other animals it can get a little more complicated and fun, but that’s beyond the scope of this post. So, the presence or absence of this one thing is the difference between male and female. It’s a pretty tiny piece of genetic material, but then you know what those people with penises say… And (in this case) they are not too far off the mark. The cascade effects of having this are huge and make for a great deal of phenotype variation between males and females (for a good example of this, just check out my article on Estrogen, Leptin, and Obesity). Males and females are biologically and genetically geared towards different things: e.g. males store fat in different areas of their body, males create sperm instead of ova, males tend to have an easier time developing muscle, etc. There is also a great deal of structural change, bone shape, brain shape, there have even been recent studies showing a difference right down to the cytology of certain cell types, etc.
But what does all this mean? It means that biology is damn awesome, and it means that males and females have a number of legitimate differences that need to be taken into account if for no other reason than their medical significance. As a for instance, hip replacement therapy needs to be different for males and females since we have different bone structures in our reproductive regions (ironically there is currently only a single ‘sexless’ hip on the market because doctors have been accused of being evil and sexist for saying that their male and female patients need different prostheses). What this most emphatically does not mean is that one sex is somehow better than the other. This latter idea is part of the myth of gender, and is one that should be expunged.
Gender is a fuzzy, poorly-defined, spectrum with a basis in sociology and psychology. The important thing to take away here: GENDER IS NOT SEX. This would be a lot more clear if our society could stop marginalizing transgender individuals (and stop conflating the larger transgender community with strict transsexualism or any kind of display of sexuality). Now, gender would like to be sex, and for quite a while the enforcement of a narrow gender role based on biological sex has been the status quo (in recent years this has become less true for the concept of ‘woman’ thanks in large part to the feminist movement). The idea of gender is deeply ingrained and wants to survive and so it will often pretend to have a ‘natural’ basis. In recent years this has adopted the language of science and the lie that gender has a biological basis, or that indeed gender and sex are one. Both of these are easily shown to be false due to varied gender roles across culture and race, and especially by the presence of both eclectic third gender individuals (like your humble author and many American transgendered people) and organized third gender groups (like the Hijra). None of us have a fundamentally different biology than any of the normative folk walking around. None of us are not, at a genetic level, male or female. But we are most emphatically not men or women. And given how that false dichotomy has been repeatedly abused as the subject of a patriarchal power play, why would we want to be?
Okay, I know that my readership is small and frail and fluctuating (and I think largely non-American), but this was recently pointed out to me along with a very polite request to repost it. Via Isis the Scientist:
For months the new House leadership has been promising to cut billions in federal funding in fiscal year (FY) 2011. Later this week the House will try to make the rhetoric a reality by voting on HR 1, a “continuing resolution” (CR) that would cut NIH funding by $1.6 billion (5.2%) BELOW the current level – reducing the budget for medical research to $29.4 billion!
We must rally everyone – researchers, trainees, lab personnel – in the scientific community to protest these draconian cuts. Please go to [this link] for instructions on how to call your Representative’s Washington, DC office today! Urge him/her to oppose the cuts to NIH and vote against HR 1. Once you’ve made the call, let us know how it went by sending a short email to the address provided in the call instructions and forward the alert link to your colleagues. We must explain to our Representatives how cuts to NIH will have a devastating impact on their constituents!
William T. Talman, MD
I really shouldn’t need to explain why this sort of shit is a very bad thing. Congress is, at the moment, very much like a cornered animal. They are under great pressure to cut spending wherever they can, and a large percentage of the electorate is probably willing to let them get away with hacking at science funding to preserve tax cuts. There are two problems here: (1) research funding is not nearly a big enough portion of the budget to fix any problem by cutting it, so this is more of a symbolic sacrifice rather than a practical one; and (2) if allowed to do it now, it will happen again in the future. We can’t let hacking away at research become (even more of) a fallback plan whenever they want it to look like they are doing something.
This is not a partisan issue. A number of people are trying to make it one, but look beyond that. Yes, Republicans started this, but if Democrats stand idly by they are just as guilty. And the consequences of this will be measurable in a body count. So, if you have any stake at all in the future of biomedical research (and yes, this will extend beyond America, science is a species level issue, especially these days), please raise hell and spread the word.
So, this week is going to be kind of rough. Due to inclement weather, some exams that were supposed to have been last week were postponed. This would normally be fine, if not for the fact that the exams scheduled for this week stayed right where they were. So basically I am caught in the middle of a midterm train wreck. Delightful.
Since I highly doubt anyone wants to hear me ramble on about cell bio trivia (and really that’s all most exams are, trivia contests, which seems especially short-sighted in a field this dynamic) I am afraid y’all are stuck without a proper article today.
I am going to leave a link to something I stumbled across this morning however, cause I found it kind of cute: Esther Inglis-Arkell over at io9 has put together a list of Ten Things Bacteria Can Do That You Can’t. It might not be exactly rigorous, but since it made me smile as I sipped my morning tea and glared at the stack of textbooks on my desk, I thought it worth sharing.
Regularly scheduled articles should be back on by Friday at the latest. If I somehow wind up with a handle on things mid-week maybe we will see some Wednesday activity, maybe not.
Someone recently said to me that telomerase wasn’t oncogenic. And in one sense, they were exactly right: the gene that produces telomerase is not recognized as an oncogene. In the other sense however, they were wrong: the reactivation of telomerase (or ALT) is a necessary step in the route to a malignant neoplasm, known as oncogenesis. This is one of the reasons I have never liked the “oncogene” designation. It’s fuzzy and a little misleading. Moreover, I think this fuzzyness is related to some of our misconceptions about cancer.
When we look at disease, we tend to look at it in terms of cause and effect. E.g. influenza causes flu, pneumocystis causes pneumonia, etc. And this schema works really well when you a are dealing with pathogens. Charge in, antibiotics and antivirals blazing, remove the cause, and the disease goes away (usually, although if it doesn’t then you probably have just not removed the cause well enough, as is the case with latent HIV). However, cancer and genetic diseases are often a different story. People ask: “Why haven’t we cured cancer yet?” and I have seen at least one paranoid documentary claiming we could obviously cure cancer at any time and just don’t because evil corporations profit off of it. Ideas like these are the result of the misconception that cancer has simple causes and simple solutions.
Misconception concerning oncogenes is a primary culprit in the current confusion, and (as I talked about in an older post) why we tend to hear a lot these days about “the X cancer gene”. These ideas are absurd. There are two mistakes working together here: (1) That oncogenes are genes whose only purpose is to cause cancer; (2) That oncogenes are sufficient to cause cancer.
(1) In truth, oncogenes have a variety of roles in the body, it is their constitutive over-expression that drives the growth component of cancer. Many oncogenes are lethal if knocked out, which is to say they are vital to development and survival of the whole organism. It is just that there is actually to much of a good thing.
(2) This is where things really begin to go off the rails. An oncogene alone is no more a cause of cancer than active telomerase or the lack of a tumor suppression gene. The development of a neoplasm is a stepwise process and no one step is sufficient while all of them are necessary. Generally it requires three mutations for a benign neoplasm and five for a malignant one (certain conditions, like a genetic predisposition for retinoblastoma or infections with an oncovirus take this number down by one). And while these mutations need to perform similar functions (cause growth, remove reproduction limits, direct angiogenesis, alter metabolism, etc), they can occur in any of a multitude of individual genes.
With a system so complex, it should be apparent why the old schema doesn’t work. There is no one single cause of cancer and no one single cure. There is no one “X cancer gene”. Cancer is a large spectrum of conditions the battle against which will rage on well into the future. While we might find ways to cure specific cases and deal with specific oncoviruses and genetic predispositions we will never cure ‘cancer’. To do so would mean to remove all mutation and make ourselves essentially genetically static. I hope I don’t have to explain why that would be a bad thing.
Sources & Further Readings
- I don’t really have a whole lot on oncogenes lying around at the moment, but a nice place to get an introduction might be Geoffrey M. Cooper’s textbook on the subject. It’s short and pretty straightforward.