When I applied for graduate programs in Microbiology and Immunology last year, I wasn’t planning to work on HIV.  After learning about the many failed vaccine trials and dozens of drugs that treated but didn’t cure the disease, I was convinced that HIV needed to be dealt with by public health measures and not by science.  I figured that if so many people had tried and failed to find a cure, maybe there just wasn’t one to be found.

But here I am, finishing up my first year in graduate school and committed to doing my PhD in an HIV lab.  Why?  Well, it turns out there’s actually a good reason that we can’t yet cure HIV – and it’s probably (hopefully) not an insurmountable problem.

The question

So why isn’t there a cure for HIV?  My aunt-in-law volunteered one plausible reason when I brought up the subject – maybe HAART (highly active antiretroviral therapy, the combination of drugs used to treat HIV) just treats the symptoms of HIV, like Robotussin treats the symptoms of colds.  Seems plausible, right?

Plausible, but completely wrong.  The drugs administered to HIV patients directly attack the virus at many points in its life cycle (see picture).  The drugs completely or nearly annihilate viral replication for years…yet if patients stop taking drugs at any point during those years, the virus comes right back.

I always used to think the answer was drug resistance, and it’s true that drug resistance is a problem.  HIV mutates incredibly quickly – part of the reason it’s so hard to make an HIV vaccine – and the virus doesn’t stop mutating once it’s infected someone.  Although HAART is usually effective for many years, eventually drug-resistant virus appears and replicates, launching the patient from HIV-positivity into full-blown AIDS.

It turns out, though, that drug-resistance can’t be the only problem.  As I mentioned earlier, HAART suppresses HIV replication to undetectably low levels for years before drug-resistant virus appears.  So, the real question is how the virus manages to survive HAART before developing drug resistance.  The answer appears to be latency.

What is latency?

HIV is a retrovirus, which means that after it infects a cell, it turns its RNA genome into DNA and then integrates that DNA into the host cell’s DNA (see diagram above).  Usually, the life cycle continues after that – the viral DNA gets read and turned into proteins, which come together to make more HIV virions, which then go infect other cells.  The thing is, though, the life cycle doesn’t have to continue immediately.  After the HIV DNA has integrated into the cellular DNA, it can just sit there indefinitely – for as long as the cell is alive, which for some cells is a very long time.  Virus in this state is known as latent virus – it’s still there, but it’s not actively doing anything.  It can’t reproduce or kill cells – but it’s also invisible to the immune system and all the drugs we have.

The theory is that we can’t cure HIV because the drugs only kill the virus that’s actively replicating.  They don’t do anything about latent virus because that virus is hidden in the cell’s genome.  But latent virus can also reactivate itself, in ways that are still poorly understood.  Thus if a patient stops taking HAART, some of the latent virus can and inevitably will reactivate, spread, and make the patient sick again.

Where is latent virus hiding?

This is actually a big question in the HIV field right now.  It turns out that there are certain conditions that support HIV latency and others that don’t, so HIV only becomes latent in a small percentage of cells.  One place where latent HIV has been found is in CD4+ T cells (helper T cells).  This isn’t surprising, since helper T cells are the primary target of HIV infection.  It looks like there may be latent HIV in other cells as well, however – everything from macrophages to astrocytes in the brain to blood stem cells in the bone marrow (that last is what I’m studying, FYI).  It’s still not clear where all the HIV is hiding, though, and we need to find the virus before we can figure out how to deal with it.

So what can we do?

Once we figure out where the latent HIV is, what can we do about it?  Actually, the theory is that the best way to deal with latent virus is to figure out how to reactivate it.  It seems almost counterproductive, but it makes sense if you think about it – if you reactivate the virus it’ll start killing cells again, but it will also be visible to the immune system and the drugs we already have.  HAART is actually really good at killing active virus, so if we could just figure out how to get all the latent virus out of latency, HAART might be able to take care of the rest.

There have already been some clinical trials with drugs that reactivate latent virus, but so far even these drugs have not been able to cure the disease.  The problem is that the drugs that have been used so far were developed based on tests in T cells, not in any of the other cell types that are thought to have latent HIV.  Different cells likely require different mechanisms of viral reactivation, so identifying all the latent reservoirs has to be the first step.

Latency – more than just HIV

Latent infection is a problem for other diseases in addition to HIV, though often for different reasons.  Broadly construed, latent infection is any non-symptomatic infection.  For HIV, that means virus that’s integrated into the genome and not expressing viral proteins.  Many other viruses, such as herpes viruses, can also create latent infections; so can some bacteria, like Mycobacterium tuberculosis (causative agent of tuberculosis) and parasites like Toxoplasma gondii (a.k.a the reason pregnant women aren’t supposed to clean cat litter).  These latent infections can be problematic for a variety of reasons.  For some diseases, like HIV, latent infection presents a barrier to disease eradication.  For others, like tuberculosis, we can cure the latent infection – the problem is just that people with latent tuberculosis don’t feel sick, and people who aren’t sick rarely check to see if they’re infected.  Latent infection is thus part of what makes tuberculosis such a challenging public health problem – there are just a ton of people who have latent tuberculosis, and if those people aren’t treated they can later develop active tuberculosis and spread the disease to others.

Finally, my favorite tangent: Toxoplasma gondii.   Toxoplasmosis is a particularly bizarre example of latent disease.  It’s thought that the parasite may actually have effects on infected people even in its latent form – but the “effects” aren’t necessarily making the host sick.  The parasite may instead do strange things like make you friendlier – or if you’re a mouse, make you attracted to the scent of cats.  Check out the wikipedia page on toxoplasmosis if you’re interested – it’s an intriguing if inconclusive read.

Conclusion of sorts

So there’s a quick introduction to HIV latency and what we might be able to do about it.  There’s still a lot of work that needs to be done, of course, but the questions are clear and seem to be addressable.  In conjunction with continued efforts towards vaccine development and implementation of various public health measures, dealing with HIV latency could help us to finally bring the HIV pandemic under control.

This post was written by lucy.mcnamara

This entry was posted on Saturday, July 11th, 2009 at 2:24 pm and is filed under Uncategorized. You can follow any responses to this entry through the RSS 2.0 feed. You can leave a response, or trackback from your own site.