HIV cure remains elusive
We've hit a dip on the rollercoaster search for an AIDS cure but not all hope is lost. Elizabeth Finkel reports.
Over the past two years the startling word “cure” has been heard buzzing through the halls at HIV conferences. But that hopeful buzz was distinctly muted at AIDS 2014, the 20th International AIDS Conference, held in Melbourne last week.
“A cure applicable to everyone in the world? Many smart people now think it will never be possible,” Steven Deeks, an HIV researcher at the University of California said.
Back in the mid-1990s, researchers had hopes of a cure. With newly available anti-retroviral drugs (ARVs) to hammer down the virus it was conceivable that patients' own immune systems might clear it completely. But whenever patients took a “treatment holiday” from their ARVs the virus would come galloping back, and researchers gave up on the idea.
But a series of recent events had put “cure” back on the radar.
When HIV infects cells of the immune system, most die quickly as hordes of newly minted viruses burst their way out. But in some cells, like long-lived T-cells, the virus slips into the DNA and sleeps. These “sleeper” cells are the obstacle to a cure. While ARVs stop the virus from multiplying and infecting new cells, they cannot clear the virus from sleeper cells. If treatment stops the virus can reawaken at some point to reseed the infection. Which got researchers wondering – could they rid the body of the virus by acting before the sleeper cells became established? Most people infected with HIV are not treated with drugs till years after infection when their immune system begins to suffer, by which time the sleeper cells are well and truly established. What if treatment started earlier?
Initial signs were hopeful as results from groups of patients in Thailand and France showed that the earlier people were treated the smaller the number of sleeper cells. But the poster child for the idea was the so-called “Mississippi baby”. She showed traces of the virus at birth, transmitted to her by her infected mother. Within 30 hours the newborn was treated with ARVs at the University of Mississippi Medical Center. The treatment lasted for 18 months until the mother stopped it, but the child appeared to be virus free – not even antibodies to the virus were detectable. Apparently she was cured, researchers reported in the New England Journal of Medicine in 2013.
The finding fired up hope. At meetings over the last year speaker after speaker would describe experiments aimed at eradicating the virus. Researchers like those at the US National Institute of Allergy and Infectious Disease announced a trial in March to replicate what had been achieved with the Mississippi baby.
But just 10 days before the Melbourne conference began the idea began to unravel. Reports emerged that the baby’s virus had returned, 27 months after apparently disappearing from her tissues. And another piece of research, presented at the conference by Dan Barouch of Harvard Medical School and colleagues (published in Nature the same week) seemed to show why.
Barouch wanted to find out just how soon treatment would have to start to prevent the establishment of sleeper cells. In tests with rhesus monkeys adult animals were infected with HIV and then started on ARVs three to 14 days later. They were kept on treatment for six months. None of these monkeys was cured. Even three days after infection was too late. The virus forms sleeper cells “much earlier than anyone expected”, said Barouch.
But not all hope is lost. In the same press conference that Barouch reported his results, Ole Schmeltz Søgaard from Aarhus University Hospital in Denmark announced more positive news. He had successfully flushed the hiding virus out from sleeper cells by taking advantage of a drug already used for cancer
Søgaard was using romidepsin, an “HDAC inhibitor”, that works by loosening up stretches of DNA which, like sewing thread, is normally tightly spooled. In the case of cancer, releasing the DNA frees up anti-cancer genes. In HIV it releases the virus bundled up in the DNA of sleeper cells.
In Søgaard’s study six patients who had been on ARV therapy for nearly ten years with no detectable virus in their bloodstreams were treated with the drug for two weeks. Researchers were cheered to discover that the drugs did indeed kick the virus out of the sleeper cells and into the bloodstream. Others including Sharon Lewin, the co-chair of the conference and Director of the Infectious Diseases Unit at Melbourne’s Alfred Hospital, had previously shown that a similar but much weaker drug called vorinostat could waken the virus but it remained inside cells. No virus was detected in the bloodstream. “Because of that there were doubts that the virus had truly become active,” explains Lewin. “The fact that Ole could wake up the virus enough to leave the cells is significant – it’s the first step in a cure.”
Surprisingly, although the treatment woke the virus it did not eradicate any of the sleeper cells. Their number was unchanged, estimates Søgaard. The most likely explanation is that although the virus awoke, multiplied inside the cells and released newly minted copies into the bloodstream, it nevertheless left master copies inside the sleeper cells, says Lewin. The sleeper cells were also clearly not killed. So kicking the virus out of cells is not enough and researchers are now pinning their hopes on a “kick and kill” strategy.
Once woken the sleeper cells will reveal the presence of virus fragments on their surfaces and that will make them visible to the patrolling forces of the immune army. But killing them needs those forces to be well-primed and waiting to go. Researchers have much of the arsenal ready. Neutralising antibodies and a T-cell vaccine known as the Louis Picker vaccine have already been shown to clear the virus in infected monkeys, according to studies published in Nature magazine last year.
The idea now is to combine all the weaponry: HDACs, ARVs and vaccines. “We will be doing just such a trial,” says Barouch.