14 February 2018
How clever biochemistry is tackling HIV
Just 30 years ago, an HIV diagnosis was a death sentence. Today, thanks to a scientific partnership of epic proportions, it is manageable with a single daily pill
IN 1981, doctors in the US became aware of a strange phenomenon. An unusual number of healthy young men in Los Angeles and other cities were falling ill and dying from rare infections and cancers. Their symptoms suggested that something was weakening their immune systems, leaving them vulnerable to diseases they would normally fend off. More mysterious still, the condition appeared to be most prevalent among the gay community, intravenous drugs users and people who had frequent blood transfusions.
Similar cases emerged in other countries and it soon became clear that the world was facing an epidemic of a new disease for which there was no cure. Doctors called the illness Acquired Immune Deficiency Syndrome (AIDS) and within three years had found it was caused by a retrovirus. This virus could be passed on in several different ways: through unprotected sex, blood transfusions, sharing needles, and through pregnancy, childbirth or breastfeeding. But how it could be stopped wasn’t clear.
This was the start of an epic journey to find a treatment for one of the biggest killers of the last half-century. For years, the virus that causes AIDS, the human immunodeficiency virus or HIV, had the upper hand. By 2000, 33 million people were infected, 14 million had died, and in Africa it had become the number one cause of death through infectious disease.
Today, thanks to a series of biomedical breakthroughs and the painstaking work of thousands of researchers around the world, the tables have turned. Those with HIV can now live longer, fuller lives by taking a single daily dose of antiretroviral medicine.
“Today, HIV is a chronic illness,” says Professor Chloe Orkin, a consultant physician at the Royal London Hospital and Chair of the British HIV Association. Indeed, the outcomes are better than for many chronic illnesses. “Those diagnosed early are likely to have a normal life expectancy, which isn’t always the case with long-term illnesses like diabetes,” she says.
In September, the US Centers for Disease Control and Prevention declared that people with minimal amounts of the virus in their blood have “effectively no risk” of passing it to their partner through unprotected sex. That’s one reason why the future for someone diagnosed with HIV in 2018 is a great deal brighter than it was 30 years ago.
At that time, researchers had little idea what made HIV so difficult to beat. We now know the virus attacks a person’s T lymphocytes, a type of white blood cell that plays a central role in the immune system.
“The quest for new HIV treatments has produced some remarkable progress”
Once inside a T-cell, the virus starts to reproduce. First, it transcribes its single-stranded RNA sequence (its genetic blueprint) into a double-stranded DNA sequence using an enzyme called reverse transcriptase. The viral DNA then fuses with the T-cell’s own DNA, allowing it to replicate and create HIV proteins whenever the T-cell is activated. New HIV particles are released into the bloodstream, where they target other T-cells, and the process starts all over again.
The first success in the search for HIV treatments was a class of antiretroviral drugs called reverse transcriptase inhibitors (see full diagram). These disrupted the early stages of the virus’s life cycle by preventing the reverse transcriptase enzyme from synthesising DNA from viral RNA. That made it impossible for the HIV to reproduce.
Some of the first reverse transcriptase inhibitors emerged from collaboration in the early 90s between the Institute of Organic Chemistry and Biochemistry in Prague, the Rega Institute for Medical Research in Leuven, Belgium, and Gilead Sciences. The three-way partnership led to the development of several antiretroviral approaches that are still relevant in HIV treatment today.
By the mid-90s, AIDS had become the leading cause of death among young adults in the US. At this time, medical authorities licensed a second class of antiretroviral drugs called protease inhibitors. These target another of the virus’s enzymes responsible for cleaving the long chains of viral DNA into individual proteins. With protease disabled, the virus cannot reproduce.
Later, researchers chalked up another small victory with a set of drugs that attack the middle part of the virus’s reproductive cycle. Integrase inhibitors disrupt a viral enzyme that integrates the HIV DNA with that of the T-cell.
Each of these was an important step, yet it was clear early on that no single treatment used in isolation can keep HIV at bay for long. This is because the virus has a remarkable ability to mutate as it replicates and this allows it to become resistant to a drug quickly. “HIV actually makes a lot of mistakes when it replicates, generating a lot of mutations,” explains Peter Borg, Medical Director at Gilead Sciences. “If you don’t significantly inhibit the replication, you can end up getting a lot of resistant virus.”
The big breakthrough came in 1996, when researchers realised that the best way to suppress HIV replication was to use a combination of drugs – an approach known as highly active antiretroviral therapy (HAART). The only way the virus could become resistant to this approach would be to develop several mutations at the same time, which is highly unlikely to happen.
The most recent HAART treatments contain two reverse transcriptase inhibitors and a third drug from another class, usually a protease inhibitor or an integrase inhibitor. Together these can reduce the amount of virus in the blood to undetectable levels and allow the immune system to recover, provided they keep taking the treatment. When HAART was introduced, people had to take handfuls of drugs several times a day, and the side effects were often terrible. Today the drugs are far easier to take and can be combined into one or two daily pills.
That approach has had a huge impact. Combination therapy has turned what used to be a death sentence into a chronic illness.
However, the HIV epidemic is far from over. One of the biggest problems, says Borg, is that between a quarter and half of people with HIV are diagnosed when their immune systems are already depleted and so are at risk of other potentially fatal diseases and overall poorer prognosis. “A major challenge is to get people diagnosed and linked to care and on to treatment in a timely fashion.”
In the meantime, there is an urgent need to make the latest therapies and diagnostic tools more available in certain developing countries. In some areas, people with HIV are still treated with old-generation medications associated with more side effects. And the stigma around the disease is dissuading people who may be infected from coming forward for early testing. Finally, there is the issue of ensuring the long-term health of people living with HIV as life expectancy continues to increase.
The quest for new HIV treatments has produced some remarkable progress and these are now beginning to spread. The next article in this series will explore how modern HIV treatments are becoming more widely available across the planet.
For more see: @GileadSciences
Date of preparation: January 2018
Job code: 999/IHQ/18-01//1004(1)
This article appeared in print under the headline “Tackling HIV”