Generally, those diagnosed with HIV are prescribed antiretroviral therapy (ART) for life to stop it replicating.
The study published in the journal Nature focused on 64 members of a small subset of patients with HIV-1, the most common form of the virus, known as “elite controllers.” Such people can keep the virus at bay without taking drugs, and are thought to make up 0.5 percent of people with HIV.
The team sequenced the DNA of the elite controllers and 41 people taking ART, and compared the results.
The life cycle of HIV sees it copy its genetic material, known as RNA, into DNA then places it in the genome of the human host. This process is called integration. An integrated HIV virus is called proviral.
The provirus makes the host create copies of itself using the body’s machinery. But some parts of our DNA are inactive, and bound up so tightly the machinery is unable to reach it.
The authors compared proviruses in millions of cells from the two groups. As they predicted, the elite controllers had fewer copies of the HIV genetic material in their DNA than those on ART. But they did have more intact proviruses, meaning they had the ability to produce virus particles.
The team believe that the elite controllers have HIV integrated in de-activated regions of their DNA, and therefore don’t need medication to stop it replicating. They hypothesize this is because the immune system killed off host cells where HIV was integrated at active sites when they were first infected.
This amounts to a “functional cure” of HIV in the elite controllers, co-author Dr. Xu Yu, associate professor of medicine at Harvard Medical School, told Newsweek. This is where a virus is still in the body but can be controlled without medication.
Yu said: “What the study showed is that the intact proviruses in elite controllers were integrated in parts of the human genome where they cannot be expressed—they are what we call ‘blocked and locked’—thus cannot cause any diseases any more.”
The work “gives us a blueprint [for] what a functional cure of HIV looks like,” he said. “For inducing a cure of HIV in larger numbers of HIV-1-infected individuals, we don’t have to get rid of all intact HIV sequences in their genomes—we only need to target those viruses that are located in active parts of the human genome where they can be actively expressed.”
Next, the team will consider how to harness the immune system to eliminate integrated HIV in active parts of the human genome in the hope of creating treatments, Yu said. “The remaining sequences that are integrated in inactive parts of the human genome do not seem to cause disease and it looks like they can largely be ignored.”
One elite controller was not found to have intact HIV at all, even though the team analyzed more than 1.5 billion of their cells. Yu said this may be because the patient’s immune system tackled the virus, which he described as “a provocative idea” given that a sterilizing cure of HIV has previously only been seen after stem cell transplantation, an aggressive treatment which can have serious side effects. A sterilizing cure is where proviruses are eliminated from the body. He said: “We are currently searching for elite controllers who also may have achieved a sterilizing cure of HIV. If so, HIV infection may in the future be regarded as a disease that can naturally heal in rare instances.”
Dr. Mark Connors, chief of the HIV-Specific Immunity Section at the Laboratory of Immunoregulation of the National Institute of Allergy and Infectious Diseases who did not work on the paper, told Newsweek: “It is a large effort to perform this analysis on so many cells, and the authors should be commended.
“The major limitation is that it is hard to see a clear path to harnessing this into inducing control. However, insights often come from unexpected places and so in my opinion the more we know the better.”
Connors said the authors’ interpretation that the infected cells of elite controllers are under immunologic pressure is likely correct. “That is, whenever a cell actively expresses HIV gene products in an elite controller, it is killed. So what you are left with is cells that are less likely to do that.”
Dr. Manon Ragonnet a fellow in the faculty of medicine at Imperial College London, U.K., who also did not work on the paper, told Newsweek the study represents “a major finding in terms of understanding how some people are able to control their HIV infections without medication.”
She said: “I am extremely surprised by the individual with a completely naturally controlled infection and no intact active virus at all. This patient has been ‘functionally-cured’ from HIV by his own immune response.”
