THE development of antiretroviral therapies (ART) has meant that, where available, people living with the human immunodeficiency virus (HIV) now have a normal life expectancy.

Yet despite this achievement, ART is not a cure for HIV and people living with HIV need to keep taking ART for the rest of their life to prevent the development of acquired immune deficiency syndrome (Aids).

As of this moment, two people have been — or at least appear to have been — completely cured of HIV infection, the virus was eradicated from their body and they no longer needed to take ART.

To understand how this was possible we need to know about the lifecycle of the HIV virus and how a HIV infection progresses over time. HIV is transmitted most commonly through sexual contact without condoms or antiretroviral protection, or through blood-borne transmission due to sharing needles and contaminated blood products. Once in the body HIV infects macrophages and CD4+ T cells, two types of cells belonging to the immune system.

Macrophages look for and consume other cells in the body that are displaying abnormal behaviours that could indicate that they have been invaded by a pathogen or have developed mutations that are preventing their proper functioning.

This behaviour helps to destroy foreign pathogens and cancerous cells and keep the body healthy. CD4+ T cells also try to recognise these sick or infected cells, if they find anything they release chemical signals that induce responses in other immune system cells (such as macrophages) against the threat that they have found.

HIV enters these two cells by binding to a specific receptor on their surface known as chemokine co-receptor 5 (CCR5). This receptor helps the immune cells to respond to chemokines, which are chemical signals produced by other cells in the body to help activate the immune system.

The virus injects a complicated bundle of proteins and viral genetic information into the cell that works in a mirror image of how human cells turn the genetic information in our DNA into proteins to perform bodily functions.

In our cells the tightly wound and hard-wearing DNA undergoes transcription into messenger RNA, which is then read like a set of instructions during the process of translation which turns RNA code into complex proteins.

HIV instead injects a payload of viral RNA into the cell that undergoes “reverse transcription” to turn it into viral DNA, this viral DNA is then inserted into the DNA of the cell by specialised proteins that came packaged with the virus. As a result the genetic code needed to produce new viral particles is now written permanently into the DNA of the immune cell.

The immune cell will read this inserted viral DNA and will unwittingly produce all of the parts needed to create a new HIV virus within itself. The new virus will leave its initial cell and float around in the bloodstream until it finds a new immune cell with the right chemokine receptor that it can infect.

This is why people living with HIV need to continue to take ART medication. It is not possible to cure someone of HIV by destroying all instances of the virus in the bloodstream, since infected cells will just continue to produce new copies of the virus.

The late stage of HIV infection, Aids, the immune system has practically ceased to function because the body has critically low levels of CD4+ T cells. Many infected T cells are eliminated by other parts of the immune system or cause their own programmed cell death (known as apoptosis) if they recognise that they have been compromised.

It is becoming clear that another mechanism causes healthy T cells around an infected T cell to also trigger apoptosis, which leads to huge losses in T cell population numbers.

At this point opportunistic infections begin to emerge by normally harmless bacteria or rare cancers that are usually squashed at an early stage by the immune system .

One of the symptoms that eventually led to the discovery of HIV was the occurrence in New York of a cluster of cases in otherwise healthy young men of a rare cancer called Kaposi’s sarcoma that usually only occurs in people with impaired immune systems.

Preventing the destruction of immune cells is the primary goal of HIV treatment by ART, yet for the two people that have so far been cured of HIV this is no longer the case. Both men — who were known as “the London patient” and “the Berlin patient” until they waived their anonymity — had also been diagnosed with a type of cancer for which the treatment was chemotherapy followed by a bone marrow transplant.

The chemotherapy would destroy the men’s existing immune systems along with the cancerous cells and the stem cell and bone marrow transplants that they received would go on to create new immune cells. However, the donors of these transplants were carefully chosen such that they had a mutation in their CCR5 receptors which means that HIV is no longer able to invade their macrophages and CD4+ T cells.

This mutation, known as CCR5-32, conveys protection from HIV cell entry using the CCR5 receptor if an individual has copies of the gene from both parents (“homozygous”). It is important to note that this modified receptor only resists some strains of HIV, since others can invade cells through other mechanisms.

Fortunately, the patients treated were the perfect match for the donors, who were among the approximately 1 per cent of Europeans that are estimated to be homozygous for CCR5-32.

After the carefully planned transplant, the newly transplanted bone marrow would create stem cells that developed into immune system cells which could not be infected with HIV. The men’s CD4+ T cell counts increased and doctors would eventually find no trace of HIV inside any of their tissues. They had been cured of HIV.

The extreme risks involved in chemotherapy and immune system transplants means that this is not a feasible HIV cure other than for people who already need to undergo the dangerous cancer treatment to save their lives.

However, it does give HIV researchers avenues to follow in the pursuit of general cure for HIV — one idea under consideration is a way to block CCR5 expression in a person’s cells so that they can develop a population of HIV-resistant immune cells.

Perhaps the end to the HIV epidemic will come through behavioural tools such as condom use, pre-exposure prophylaxis (PrEP) and needle exchanges. Perhaps it will be through a vaccine that helps the body to recognise and respond to specific proteins on the viral membrane that are shared by most strains of HIV.

More than likely, it will involve a combination of approaches. Regardless of the specific solutions, it will always involve the patient creativity of research as well as the bravery and determination of people living with HIV like the Berlin and London patients.