The simplest proposed scenario for eradicating HIV involves giving a person an experimental treatment that causes the cells that comprise the latent HIV reservoir to wake up and start producing virus (see sidebar below). Ideally, this person will be someone who started on ARV medications soon after infection and has remained undetectable ever since. It seems likely (though we don't know for sure) that people who start treatment very early may have a smaller number of latently infected cells harboring hidden HIV.
One type of treatment would act like an alarm clock to wake the cell up. Another type would enter the cell's DNA and unlock the HIV genes and allow them to produce virus. It's likely a combination of these kinds of drugs may be needed.
Because the individual will continue taking ARV drugs, any virus produced will be stopped from spreading and infecting cells in other parts of the body. After the latent reservoir has been activated by the experimental treatment, it is thought that the immune system will clean house and destroy the infected cells. This general approach has already been tested in people, but the drugs tried so far have not been effective.
So, what are some of the basic science questions that research must address in the coming years to make this scenario a reality? First, we want to find out where the latent HIV is hidden in people who are taking ARV drugs. Where are the reservoirs? How much viral DNA is stored away? Is the virus replicating? Or is it lying completely dormant in resting immune cells? What happens to these cells when they begin to produce viruses or HIV proteins? Will the immune system really recognize them as foreign and destroy them?
That is a key question, because the simplest strategy for eradication envisions "waking up" the infected resting cells and getting them to announce themselves to the immune system, which then destroys them. We think that is what happens, but we're not sure. If the immune system won't clean house, then we will need to develop medicinal torpedoes to destroy the infected cells.
But to find out where the latent reservoir cells are in the body, scientists will need to develop better ways of testing whether HIV is actually present in these cells and if they are producing viable, infectious virus or not. Only one in a million immune cells may harbor viral DNA in a person taking ARV drugs. How can scientists tell if the treatments they are using to flush out those cells have worked or not? There are a lot of cells infected with HIV DNA that only produce broken, noninfectious virus. How can we tell if we're getting to the cells that matter?
But most urgently, a test must be developed that can be used to identify potential drugs to activate the latent HIV in these cells.
The drugs tested so far for unlocking HIV in a latently infected cell have been fairly crude. A class of drug used in cancer chemotherapy called HDAC inhibitors has been used at lower doses in people with HIV to activate the HIV reservoir. The problem is that these cancer drugs do not act specifically to unlock HIV.
Scientists need a way to test large numbers of compounds and molecules to find those that will make a good drug. It must be safe for use in people and must have a strong and specific effect on the target, in this case, activating latently infected cells. It may be that more than one drug will be needed to address different types of cells if we find that the HIV reservoir is more widely distributed than we hope.
The ultimate challenge will be to test these new compounds in people and to prove that they work. At first, human testing is likely to go slowly and be aimed at answering the scientific questions facing cure researchers. Hitting a home run with the first molecules to be tested is very unlikely.
One of the key problems is learning how to tell if the treatment has had an effect or not. The test subjects for this early research will be taking antiretrovirals and will have undetectable viral loads by the most sensitive tests available -- less than one copy per milliliter of blood. One way to test for a cure in someone who had taken an experimental treatment is to stop the ARV drugs and wait to see if the viral load bounces back or remains undetectable. This is a risky way to go, since the rebounding virus can cause an immune reaction, re-seed new cellular reservoirs, and possibly develop resistance to the drugs remaining in the body after the last dose. The SMART study showed that people who stopped and started ARVs had a somewhat greater risk of inflammation-related diseases, such as heart and vascular problems. So stopping someone's HIV meds is not a step to be taken lightly. But, as with the HIV-positive leukemia patient, showing that the virus remains undetectable after ARVs have been stopped is the best proof that a cure for HIV has been achieved.
It may never be possible to prove that every single cell containing HIV has been removed by a curative treatment, but the promise of a lifetime free of HIV and HIV drugs is compelling scientists and people with HIV to finally imagine what was only recently thought impossible: A cure for AIDS.
|Reservoir Dogs: A Virus Goes Into Hiding|
When combination antiretroviral (ARV) therapy was first shown in the mid-1990s to reduce HIV in the blood to undetectable levels, some of the first questions to arise were: What will happen if the drugs are stopped? Will the virus remain undetectable? Will the patient be cured?
Unfortunately, it soon became clear that the ARV drugs that suppress HIV so effectively are not a cure and that the viral load can bounce back once they begin to leave the bloodstream. As more and more people started ARV medications -- and as the death rate from AIDS plummeted -- most HIV research focused on improving treatment, and the quest for a cure took a back seat.
The reason why the HIV viral load comes back when ARV meds are stopped is the same reason why permanently curing HIV infection will be such a difficult problem to solve.
A virus is not a self-sufficient living creature like a bacterium or a parasite. A virus is basically a container for a small strand of DNA -- the genetic code for the virus itself. For HIV to cause an infection, it must enter a host body (that's you), enter a host cell (such as the immune system's CD4 T-cell), then deliver its DNA payload to the nucleus of the cell, where the body's own DNA is stored.
DNA is a chemical code in the form of a long chain that tells the body's machinery how to make all of the proteins and parts it needs to live and grow. Every cell in your body (and you have trillions) contains a complete copy of your unique DNA, even if the cell only uses part of it for its own purposes.
While the body's DNA chain is long (about six feet, stretched out), only a tiny strand of DNA is needed to hijack the cell's machinery into making new copies of the virus. This process is called replication, and when an infected cell begins cranking out new HIV particles, it is like a Xerox machine, spitting out copies, each of which can travel through the bloodstream and infect new cells, creating new viral copy machines. Fortunately, ARV drugs can effectively shut down the viral replication copy machine -- but they can't remove the viral infection.
Some viral infections, like hepatitis C virus (HCV), can be cured if replication can be stopped long enough. Among viruses, HIV is unusual because it carries integrase, a special protein tool that guides the small thread of viral DNA into the infected cell's DNA. Integrase makes a break in the human DNA, then inserts the HIV genetic material seamlessly. This means that HIV actually becomes part of the cell, and has access to the same cellular machinery that the human DNA has. This is also one of the key reasons why HIV infection will be so difficult to eradicate.
Having the HIV DNA become a permanent part of a cell's DNA would not be so bad if the cells died off on a regular basis and were replaced by new, uninfected cells, as happens with most cells in the body. You could simply stop new cells from becoming infected by taking ARV drugs, then wait for the infected virus to be retired and recycled.
But HIV infects cells of the immune system, and some of the infected cells become part of the system of immune memory, which helps the body respond quickly to infections it has experienced in the past.
Some of these infected immune memory cells -- perhaps one in a million -- become dormant, and may remain quiet and hidden away for decades. Scientists call these sleeper cells the "latent reservoir" of HIV. When awakened by an immune challenge or other stimulus, the memory cells begin to spit out new HIV particles, which go out into the body to infect new cells -- unless they are stopped by ARV meds.
This persistence of HIV in the body is why taking ARVs consistently for a lifetime is necessary, and why curing HIV will be such a great challenge.
-- Bob Huff
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