Renewed Hope

The Way to a Cure

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.

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