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Cure for AIDS

A scientist conducting HIV gene therapy research at The Gates FoundationThere is currently no cure for AIDS or HIV infection. Although antiretroviral treatment can suppress HIV – the virus that causes AIDS – and can delay AIDS-related illness for many years, it cannot clear the virus completely.

However, there is hope and optimism around the possibility of a genuine cure for HIV being developed within the next few decades. The launch of a new strategy to develop a cure, involving scientists, policy makers, funders and people living with HIV, in July 2012, marked an increased focus on the development of a cure as a potential approach to curbing the HIV and AIDS epidemic. 1

Why is it so difficult to cure HIV and AIDS?

Curing AIDS is generally taken to mean clearing the body of HIV, the virus that causes AIDS. The virus replicates (makes new copies of itself) by inserting its genetic code into human cells, particularly a type known as CD4 cells. Usually the infected cells produce numerous HIV particles and die soon afterwards. Antiretroviral drugs interfere with this replication process, which is why the drugs are so effective at reducing the amount of HIV in a person’s body to extremely low levels. During treatment, the concentration of HIV in the blood often falls so low that it cannot be detected by the standard test, known as a viral load test.

Unfortunately, not all infected cells behave the same way. Probably the most important problem is posed by “resting” CD4 cells. Once infected with HIV, these cells, instead of producing new copies of the virus, lie dormant for many years or even decades. Current therapies cannot remove HIV’s genetic material from these cells. Even if someone takes antiretroviral drugs for many years they will still have some HIV hiding in various parts of their body. Studies have found that if treatment is removed then HIV can re-establish itself by leaking out of these “viral reservoirs”.

A cure for HIV must either: 1) remove every single one of the infected cells (known as a sterilising cure or eradication) or 2) control HIV effectively by keeping the virus dormant, after the discontinuation of treatment (known as a functional cure). 2

Reputable research on curing HIV and AIDS

The possibility of ‘a functional cure’

The results of a study released in 2012, involving fourteen French people living with HIV are one indicator that a ‘functional cure’ for HIV may be possible. The people involved, known as the ‘Visconti cohort’, started taking antiretrovirals very soon after they became infected. After three years of medication, they stopped taking ARVs, which would usually result in the HIV-infection resurging. However, on this occasion they were able to stop taking the medication and yet remain with low levels of virus in their systems for an average of seven years. 3 

More recently, the potential benefits of a 'functional cure' have been seen in two newly born babies. In March 2014, it was reported that a nine-month-old baby born in California with HIV may have been functionally cured as a result of antiretroviral drug treatments that doctors administered just four hours after birth. 4 Similarly, in March 2013, researchers announced a Mississippi baby born with HIV and given high doses of three antiretroviral drugs shortly after delivery, still appeared to be functionally cured two years on. 5

In order to replicate the Mississippi baby results, in June 2014, researchers proposed giving antiretroviral treatment to 54 identified HIV-positive infants from around the world within 48 hours of birth. 6 In July, progress towards a functional cure took a significant blow with detectable levels of HIV found in the Mississippi baby. 7

Purging the HIV reservoir

Many researchers believe the best hope for eradicating HIV infection lies in combining antiretroviral treatment with drugs that flush HIV from its hiding places. The idea is to force resting infected CD4 cells to become active, whereupon they will start producing new HIV particles. The activated cells should soon die or be destroyed by the immune system, and the antiretroviral medication should 'mop up' the released HIV. Chemical agents used to activate resting cells are called antilatency agents.

Early attempts to employ this technique used interleukin-2 (also known as IL-2 or by the brand name Proleukin). This chemical messenger tells the body to create more CD4 cells and to activate resting cells. Researchers who gave interleukin-2 together with antiretroviral treatment discovered they could no longer find any infected resting CD4 cells. But interleukin-2 failed to clear all of the HIV; as soon as the patients stopped taking antiretroviral drugs the virus came back again. 8 9

There is a problem with creating a large number of active CD4 cells: despite the antiretroviral drugs, HIV may manage to infect a few of these cells and replicate, thus keeping the infection alive. Scientists are now investigating chemicals that don’t activate all resting CD4 cells, but only the tiny minority that are infected with HIV.

One such chemical is valproic acid, a drug already used to treat epilepsy and other conditions. In 2005 a group of researchers led by David Margolis caused a sensation when they reported that valproic acid, combined with antiretroviral treatment, had greatly reduced the number of HIV-infected resting CD4 cells in three of four patients. They concluded that:

“This finding, though not definitive, suggests that new approaches will allow the cure of HIV in the future.” 10

Sadly, such optimism was premature; studies later suggested that valproic acid has no long term benefits. 11 12

Another option being investigated to 'activate' resting HIV-infected cells is the use of histone deacetylases (HDAC) inhibitors. Histone deacetylases are enzymes that control the proteins involved in binding DNA. They effectively 'silence' groups of genes, including some HIV genes. Stopping them from doing this would allow for those resting HIV-infected cells to be reactivated. Agents that aim to stop histone deacetylases from 'switching off' or 'silencing' genes are called histones deacetylase inhibitors. SAHA (vorinostat) is a potent histone deacetylase inhibitor which is being tested in cell cultures for HIV. 13

Any antilatency agents combined with ART aiming to 'reactivate' resting HIV-infected cells and then 'purge' these cells should reach all HIV-infected cells, including those in the difficult to reach areas like the gut-associated lymphoid tissue and the brain. 14 However, this is where the real difficulty lies. Some researchers argue that this 'complete reactivation' could be unnecessary because those cells that are really hard to reach may be so dormant that the body will be able to control them anyway. 15 However, whether or not this is true is unknown. 16

Discouragingly, a 2013 report following a study at the Howard Hughes Medical Institute found that the ‘reservoir’ of inactive viruses could be up to 60 times larger that previously suspected. This means that the potential for ‘reactivating’ resting HIV-infected cells could be severely limited. 17

Bone marrow transplants

In November 2008, a pair of German doctors made headlines by announcing they had cured a man of HIV infection by giving him a bone marrow transplant. 18 The transplant - given as a treatment for leukemia - used cells from a donor with a rare genetic mutation known as Delta 32 that confers resistance to HIV infection. Twenty months after the procedure, researchers reported they could find no trace of HIV in the recipient's bone marrow, blood and other organ tissues. Other experts at the time called for more tests to verify the cure claim. 19

In a journal article published in December 2010, the doctors concluded that the patient had indeed been cured of HIV infection. Their evidence showed a successful reconstitution of CD4 T cells at both the systemic level and in the gut mucosal immune system. 20

However, bone marrow transplantation is too dangerous and costly for widespread use as a cure. Many patients die as a result of chemotherapy or reactions to the transplant, which is usually a last resort in treating life-threatening diseases. As Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, put it:

“It’s very nice, and it’s not even surprising. But it’s just off the table of practicality.” 21

Nevertheless the German transplant does raise hope for related approaches, such as gene therapy. 22

Gene therapy

More recently, gene therapy has been viewed as having the potential to engineer HIV control by introducing cells resistant to the virus.

In 2014, a clinical trial using gene-editing techniques successfully targeted and destroyed a gene in the immune system of 12 people living with HIV, increasing their resistance to the virus. However, because of the invasive nature of stem cell treatment, it is not viable for the majority of people living with HIV as the body is likely to attack the donor cells. 23

Antibodies

All people living with HIV naturally respond to the virus by producing antibodies. Most people's antibodies are unable to kill HIV, however, the immune systems of a small minority produce 'broadly neutralising antibodies', which can kill or neutralise a wide range of HIV strains. 24

In 2014, one study detailed how a research team found and identified these antibodies in a South African woman before cloning them in a laboratory. Despite providing hope for gene therapy in other people, these antibodies were unable to destroy the HIV virus within her own body because HIV mutates too quickly, so she is on antiretroviral treatment. Abdool Karim, one of the scientists working on the study said:

“When a person develops broadly neutralising antibodies it actually has no benefit to the individual who develops it; [they are] not able to neutralise their own virus." 25

A multi-stage approach

It has been argued that combining different treatments may hold the key to finding a cure for AIDS.

Reservoir-purging drugs, which flush HIV out of hiding, are unlikely to drive the virus out of the immune system or produce a functional cure on their own. However, combining them with treatment, which targets HIV-infected cells with toxins, or a vaccine that intercepts the remaining HIV-infected cells, may prove more effective. 26

Though vaccines can help contain HIV infection, often the virus mutates too quickly for the immune system to respond effectively. For this reason, an antibody component has been suggested as a means of alerting the immune system more quickly to HIV-infected immune cells. 27

The danger of a multi-stage approach is that by manipulating the immune system, a slowly progressing infection may develop into a faster one. 28 Indeed, much more research is needed in this area.

Funding for research into a cure

Some of the world’s top research institutions are currently engaged in studies to learn more about infected resting cells and the behaviour of HIV. But this field does not receive a lot of funding. Of the $1.54 billion spent by the National Institute of Allergy and Infectious Diseases (NIAID) on AIDS in 2009, only $40 million was spent on AIDS cure research. 29 This represents only 3 percent of the total NIAID AIDS budget.

One researcher has pointed out that "money for HIV cure research is scarce, especially for risky new ideas that might not pan out". 30 Drug companies, in particular, would prefer to market their antiretroviral drugs. In a difficult economic climate, investing in something which might not be successful could simply seem too risky.

Yet there are still those who remain hopeful, including activist Martin Delaney who is among those calling for an end to defeatism:

“Far too many people with HIV, as well as their doctors, have accepted the notion that a cure is not likely. No one can be certain that a cure will be found. No one can predict the future. But one thing is certain: if we allow pessimism about a cure to dominate our thinking, we surely won’t get one… We must restore our belief in a cure and make it one of the central demands of our activism.” 31

Further information

References

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