October 26, 2015
The recent case of Scottish nurse Pauline Cafferkey, who relapsed nine months after "clearing" her Ebola infection, has raised concerns that the virus could cause relapsing disease in other survivors.
Ebola's clever trick -- to lie dormant inside a cell or to hide in a particular organ -- is not unfamiliar. Lots of viruses can do it. Some common examples include the chicken pox virus, which can hide inside nerves and then reappear decades later as shingles.
Genital herpes, a close relative of the chicken pox virus, can come and go over years by also hiding inside nerves.
However, the master virus with a toolbox of tricks to hide and then reappear is human immunodeficiency virus (HIV). Understanding where and how HIV goes into hiding has recently garnered huge scientific interest in the search for a long-term cure.
Combination antiretroviral therapy (ART) to treat HIV infection was introduced in the mid-1990s and has been one of the most remarkable achievements in modern medicine.
ART rapidly brings HIV under control -- going from millions of copies of virus per millilitre of blood to undetectable levels -- and essentially transformed a fatal disease into a chronic infection.
People who start ART at the right time now have a normal life expectancy. But ART is not a cure. As soon as it's stopped, the virus rapidly returns within weeks.
Understanding where and how the virus hides on treatment is now one of the biggest questions facing scientists working on HIV.
So what secret weapons does HIV have to allow it to persist for years in hiding and then to return so forcefully within weeks?
In short, the answer is HIV latency. In latent infection, HIV integrates its genetic material into the DNA of the patient and becomes "silent."
A brilliant added tool is the use of a long-lived critical cell of the immune system, the resting T cell, as its preferred hiding site. These latently infected resting T cells can slowly divide and, given HIV is now part of the patient's DNA, the HIV is passed down to the daughter cells too.
HIV usually replicates in activated T cells and can efficiently kill those cells in several ways. First, the virus directly damages the outer membrane of the cell. This membrane usually keeps the cell intact.
Following infection of a cell, bits of the virus are quickly revealed to the immune system which, once activated, can zoom in and eliminate the infected cell.
However, if the virus manages to get inside a resting cell, in contrast to an activated T cell, all the machinery needed to produce new viruses is not available and the virus life cycle essentially shuts down.
If things shut down after the virus has already entered the patient's DNA it gets stuck there -- forever.
A recent study in monkeys showed long-lived latently infected cells were established within the very first few days of infection.
When treatment was started as early as three days after infection in these monkeys, the virus couldn't be found.
But when ART was stopped, it still returned. The virus returned after a longer period of time than when treatment was started at seven days, but still returned.
In the rare cases of people lucky enough to get treated very early after infection, it is possible to dramatically reduce the amount of latent virus that persists. But how commonly this translates to being able to stop ART with a delay in return, or even long-term suppression of the virus, remains unknown.
HIV has many other tricks to persist in addition to latency. HIV can infect special types of T cells that live in lymph nodes, called T follicular helper cells. In the lymph node, these cells group together in follicles which are protected from killer T cells that are primed to hunt out infected cells.
HIV can also infect cells other than T cells, including macrophages and specialised cells in the brain called astrocytes. Macrophages also don't move through the blood but reside in tissue and slowly divide. Therefore, once infected, they are much harder cells to clear, even on ART.
Finally, there are specific tissues where both the drugs and immune fighting cells don't penetrate as well as in blood. This includes the brain, gut and the genitals/urinary tract. These are also potential long-lived reservoirs and allow HIV to hide, very similar to what we have recently seen with Ebola.
The recent reports of the Mississippi baby who started ART at birth and the Boston patients who received bone marrow transplants for blood cancer while on ART, showed that even when the virus couldn't be detected in either blood or tissue despite using our most sensitive tests, when ART was stopped, the virus eventually returned. For the Mississippi baby, this was a whopping two-and-a-half years later.
These cases painfully demonstrate the extreme durability of HIV and that we still lack tools that are sensitive enough to detect very low levels of infectious virus on ART.
Current HIV cure research is focused on developing new ways to detect and eliminate the viral reservoir. The ultimate aim is to eradicate HIV entirely or achieve a state of remission. This means a way to stop ART with the virus staying under control.
A successful strategy will likely need two components -- reducing the amount of virus that persists to very low levels and also ensuring a robust immune surveillance system that can catch and eliminate any random virus that might pop out years after stopping ART.
Currently, the best strategy to manage HIV is to keep the virus in permanent hiding and continue life-long ART. There is no question about that.
But by refining our scientific tools of hide and seek to successfully target and then eliminate virus reservoirs, we hope one day to truly see the end of HIV.
Thomas Aagaard Rasmussen, clinical research fellow, The Peter Doherty Institute for Infection and Immunity and Sharon Lewin, consultant physician, Department of Infectious Diseases, Alfred Hospital; and director, The Peter Doherty Institute for Infection and Immunity
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