Medical science is starting to license and use drugs and procedures that change the genetic code inside the bodys cells, and to correct the bad code that can give rise to conditions such as cancer and the auto-immune diseases. Since HIV is a disease that results from a virus inserting such a piece of bad code into our genes, such therapies could be used to snip out that code and effect a cure.

This was what attendees at last months International AIDS Society Conference on HIV Science (IAS 2021) heard at the workshop on curing HIV. The workshop opened with two introductory talks by Professor Hans-Peter Kiem, the chair of gene therapy at the Fred Hutchinson Cancer Research Center in Seattle in the US (the Fred Hutch) and, in a joint presentation, by the Fred Hutchs Dr Jennifer Adair and Dr Cissy Kityo of the Joint Clinical Research Centre (JCRC) in Kampala, Uganda.

The latter talk was a sign of acknowledgement that, while the prospects for genetic medicine are brighter than ever before, their expense and sophistication do not fit well with the global epidemiology of HIV, which mainly affects the worlds poorest and most disadvantaged communities. Despite this, Fred Hutch and JCRC have embarked upon a joint research programme to develop within the next few years a genetic therapy treatment for HIV that could be realistically scaled up for use in lower-income settings.

A unit of heredity, that determines a specific feature of the shape of a living organism. This genetic element is a sequence of DNA (or RNA, for viruses), located in a very specific place (locus) of a chromosome.

A type of experimental treatment in which foreign genetic material (DNA or RNA) is inserted into a person's cells to prevent or fight disease.

To eliminate a disease or a condition in an individual, or to fully restore health. A cure for HIV infection is one of the ultimate long-term goals of research today. It refers to a strategy or strategies that would eliminate HIV from a persons body, or permanently control the virus and render it unable to cause disease. A sterilising cure would completely eliminate the virus. A functional cure would suppress HIV viral load, keeping it below the level of detection without the use of ART. The virus would not be eliminated from the body but would be effectively controlled and prevented from causing any illness.

The body's mechanisms for fighting infections and eradicating dysfunctional cells.

In cell biology, a structure on the surface of a cell (or inside a cell) that selectively receives and binds to a specific substance. There are many receptors. CD4 T cells are called that way because they have a protein called CD4 on their surface. Before entering (infecting) a CD4 T cell (that will become a host cell), HIV binds to the CD4 receptor and its coreceptor.

HIV cure research pioneer Dr Paula Cannon of the University of Southern California, chairing the session, said: After several decades of effort and false starts, gene therapies now hold out promise for diseases that were previously untreatable.

Hans-Peter Kiem acknowledged the pivotal role of community advocacy in supporting cure research, noting that his project, defeatHIV, was one of the first beneficiaries of a grant from the Martin Delaney Collaboratories, named after the celebrated US treatment activist who died in 2009.

The other factor that gave impetus to HIV cure research was, of course, the announcement that someone had been cured: Timothy Ray Brown, whose HIV elimination was first announced in 2008 and who came forward publicly in 2010. He died in 2019 from the leukaemia whose treatment led to his HIV cure but by then had had 13 years of post-HIV life. He had survived long enough to talk with Adam Castillejo, the second person cured of HIV, and encourage him to come forward too.

Timothy and Adams stories showed that HIV could be cured, and with a crude form of gene therapy too: cancer patients, they were both given bone marrow transplants from donors whose T-cells lacked the gene for the CCR5 receptor, which is necessary for nearly all HIV infection.

But there have only been two cures for two reasons: firstly, bone marrow transplant is itself a very risky procedure involving deleting and replacing the entire immune system of already sick patients. In 2014 Browns doctor, Gero Hutter, reported that Timothy Ray Brown was only one of out of eight patients on whom the procedure had been tried, but that all the others had died.

Secondly, compatible bone marrow donors are hard to come by as it is, and restricting them to the 1% or so of people who lack the CCR5 receptor, all of them of northern European ancestry, means very few people could benefit from this approach. Attempting transplant with T-cells that do not lack CCR5, in the hope that replacing the immune system with cells from a person without cancer will also get rid of their HIV anyway, has produced temporary periods of undetectable HIV off therapy, but the virus has always come back.

(People like Brown and Castillejo, whose HIV infection was cured by medical intervention, need to be distinguished from people who seem to have spontaneously cured themselves, such as Loreen Willenberg: such people are of course of great interest to cure researchers, but the trick is to make it happen consistently in other people.)

Brown and Castillejos cures, as transplants, were so-called allogenic, meaning that the HIV-resistant cells came from another person. Better would be autogenic transplants, in which immune system cells are taken from a person with HIV, genetically altered in the lab dish to make them resistant to HIV, and then re-introduced. This type of procedure written about for aidsmap as long ago as 2011 by treatment advocate Matt Sharp, who underwent one.

The repertoire of gene therapies is not restricted to CCR5 deletion. Gene therapy is immensely versatile, and could be used in a number of ways.

Instead of using gene therapy to make cells resistant to HIV, it could directly repair defective genes in cells by means of cut-and-paste technology such as CRISPR/Cas9. This is already being used in trials for some genetic conditions such as cystic fibrosis and sickle-cell anaemia. Given that HIV-infected cells are also defective in the sense that they contain lengths of foreign DNA that shouldnt be there, they are amenable to the same molecular editing. Early trials have produced promising results but the challenge, as it has been in a lot of gene therapy, is to ensure that the cells containing DNA are almost entirely eliminated.

One way of doing this is not to delete the HIV DNA from infected cells but to preferentially kill off the cells themselves by creating so-called chimeric antigen receptor (CAR) T-cells. These are T-lymphocytes whose genes have been modified so that their usual receptors such as CD4 or CD8 have been replaced with receptors attuned very specifically to antigens (foreign or unusual proteins) displayed by infected cells and cancer cells. A couple of CAR cell therapies are already licensed for cancers; the problem with HIV is that the reservoir cells do not display immune-stimulating antigens on their surfaces. This means that CAR T-cells would have to be used alongside drugs such as PD-1 inhibitors that stop the cells retreating into their quiescent reservoir phase, an approach demonstrated at IAS 2021.

A couple of other approaches could be used to produce either vaccines or cures. One is to engineer B-cells so they produce broadly neutralising antibodies. A way of tweaking them to do this, called germline targeting, is covered was also discussed at IAS 2021, but if we manage to generate B-cells that can do this, we could then in theory directly edit their genes to make them do the same thing.

"Timothy Ray Brown and Adam Castillejo were both given bone marrow transplants from donors whose T-cells lacked the gene for the CCR5 receptor."

The other way is to induce cells to make viral antigens or virus-like particles that the immune system then reacts to. Scientists have been working on this technique for 20 years and it triumphed last year when the Pfizer and Moderna vaccines against the SARS-CoV-2 virus had over 90% success in suppressing symptomatic COVID-19. These vaccines are not genetic engineering in the sense of altering the genome of cells; rather, they introduce a product of the genetic activation in cells, the messenger RNA that is produced when genes are read and which is sent out into the rest of the cell to tell it to make proteins.

However because HIV is more variable and less immunogenic than SARS-CoV-2, the vaccine induced by the RNA would have to be something that looked much more like a whole virus than just the bare spike protein induced by the Pfizer and Moderna vaccines. If there was such a vaccine could be used both therapeutically as well as in prevention, by stimulating an immune reaction to activated HIV-infected cells. Moderna have announced they will now resume the HIV vaccine research they were working on when COVID-19 hit.

The problem with all these more gentle procedures is that it has proved difficult to replace all the HIV-susceptible cells with the HIV-resistant or HIV-sensitised ones: although engraftment takes place, meaning that the autologous cells are not rejected by the body and are able to establish a population for some time (in some animal experiments, replacing as much as 90% of the native immune cells), eventually the unaltered immune cells tend to win out because the introduced cells lack the deep reservoir of replenishing cells.

Kiem said that the way scientists have been trying to get round this is to only select and alter so-called haematopoeic stem cells (HSCs). These rare and long-lived cells, found in the bone marrow, are the replenishing reservoir of the immune system. They differentiate when they reproduce and give rise to all the immune cells that do different things: CD4 and CD8 T-lymphocytes, B-cells that make antibodies, macrophages that engulf pathogens, dendritic cells, monocytes, natural killer cells, and others.

Altering HSCs genetically so that they are able to fight HIV in one way or another could in theory give rise to a persistent, HIV-resistant immune system. They could in theory lie in wait and be ready to produce effector cells of various types. They would be ready when a new HIV infection comes along (if used as a vaccine) or when HIV viral rebound happens and there is detectable virus in the body (if used as part of a cure). If a person with CAR-engineered stem cells could have repeated cycles of treatment interruption, their HIV reservoir could in theory slowly be deleted.

"Gene therapies are astonishingly expensive."

As mentioned above, although genetic medicine shows enormous promise, the complexity and expense of its techniques means that at present it is unlikely to benefit most people who really need it.

Hans-Peter Kiem said that currently about 60 million people have conditions that could benefit from gene therapy. The vast majority of these either have HIV (37 million) or haemoglobinopathies blood-malformation diseases such as sickle-cell anaemia and thalassaemia that are also concentrated in the lower-income world (20 million).

Dr Jennifer Adair, one of the first researchers to have proposed collaboration on gene therapies for HIV with African institutes, said that gene therapies have already been licensed for conditions such as thalassaemia, spinal muscular atrophy, T-cell lymphoma and a form of early-onset blindness.

But they are astonishingly expensive. The worlds most expensive drug tag goes, depending on which source you read, either to Zynteglo, a genetic medicine correcting malformed beta-haemoglobin and licensed in the US for thalassaemia, or Zolgensma, a drug licensed in Europe and given to children to correct the defective gene that results in spinal muscular atrophy.

Both cost about 1.8 million for a single dose. The price is not just due to the cost of the complex engineering used to make them, but because they are used to treat rare diseases and so have a small market.

At present the technology need to engineer autogenic genetically engineered cells is, if anything, even more expensive and complex than that needed to introduce allogenic cells. It can involve in the region of ten staff and a workspace of 50 square metres per patient. Recently a so-called gene therapy in a box has been made available that can reduce the area needed to produce autogenic genetically-engineered cells from 50 to less than one square metre, and the staff need to one or two, But what is really needed is genetic engineering in a shot; a therapy similar to a vector or RNA vaccine that can be introduced as an injection and produces the genetic changes needed within the body.

Undaunted by the challenges, the US National Institutes of Health are collaborating with the Bill and Melinda Gates foundation to work on a combined programme of HIV and sickle-cell-anaemia genetic therapy (given that something that works for one could be adapted to work with the other).

And the Fred Hutchinson Center has teamed up with the Joint Clinical Research Centre in Uganda with the very ambitious goal of making a genetic therapy that would be at least ready for human testing within two years in an African setting, and that could be scaled up to be economical for Africa if successful.

Dr Cissy Kityo of JCRC in Uganda told the conference that as of 2020, there were 373 trials of gene therapy products registered, of which 35 were in phase III efficacy trials. The global budget for regenerative medicine, which includes genetic therapy and related techniques, was $19.9 billion, having jumped by 30% since the previous year. The US Food and Drug Administration projects that based on the current rate of progress and the development pipeline, they may be licensing around 100 gene-therapy products a year by 2025.

This branch of medicine is no longer exotic, she said. Now steps have to be taken to trial gene therapies in the people who needed them most, and to turn the exotic into the affordable, she added.

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Could gene therapies be used to cure more people with HIV? - aidsmap