(AIDS) Progress towards an HIV cure
Gus Cairns scans the horizon for an HIV cure.
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Different patients, different cures
More transplant cures – but one important failure
‘Functional cures’ after early treatment
Strategies for chronic HIV infection: kick, kill, contain
The last time I wrote a review of the progress researchers are making towards a cure for HIV (see Towards a Cure for All, HTU 203 and HTU 204), it was 2011, in the wake of the first documented cure of someone with HIV.
Timothy Ray Brown, also known as the ‘Berlin patient’, had apparently had every trace of active HIV infection removed from his body by means of a bone-marrow transplant containing T-cells resistant to HIV infection. Brown’s case showed that we could cure HIV: but clearly we will need safer, simpler and cheaper ways of achieving the same goal (the transplant, which Brown needed anyway for leukaemia, nearly killed him).
Different patients, different cures
Since then, there has been exciting progress in some areas – including announcements of a few more cases using the same and other strategies. However, it is becoming apparent that there may be no one single cure mechanism for HIV.
We may start achieving cures earlier in two groups of patients. Firstly, for people like Brown, whose condition ethically allows the sort of ‘nothing to lose’ procedure he underwent. Secondly, in people whose HIV is diagnosed very soon after they are infected, where there are signs that using antiretroviral therapy (ART) from the start may suppress HIV reproduction so fast and so deeply that it never really gets going.
Some of these ‘cures’ might better be termed ‘remissions’, because we do not know whether HIV will reappear at some point in the future: there may remain a tiny number of infected cells in the ‘reservoir’ of long-lived, quiescent T-cells, and it is possible they could be reactivated in the future.
The rest of us, though – those with chronic infection, who may be living healthy lives on ART but who would rather not have to take it – may have to wait considerably longer before a cure comes along.
More transplant cures – but one important failure
In a few people with cancers, similar cures to Brown’s have been achieved. At a 2013 pre-International AIDS Society (IAS) conference symposium, Towards an HIV cure, researcher Dr Timothy Henrich told delegates that two people with HIV in Boston, who received stem-cell transplants for the treatment of lymphoma, had been maintaining undetectable HIV viral loads without medication for 15 and 7 weeks respectively.1 The decision to take them off ART was only made after the most sensitive available tests failed to detect any HIV genetic material in their cells.
The approach taken here was relatively less toxic than that used for Brown. He had his entire immune system effectively deleted with strong chemo- and radiotherapy before receiving a bone-marrow transplant of new immune cells with the so-called delta-32 CCR5 mutation, which occurs in about 2% of northern Europeans and means they are almost completely resistant to HIV infection.
The Boston patients received an immune-suppressant regimen that consisted only of chemotherapy, and the stem cells were from genetically matched donors without the delta-32 CCR5 mutation.
How did this produce a situation where no more than one in 200,000 immune-system cells in the blood were the patients’ original cells and there was no more than one copy of HIV DNA in 15 million cells?
When we receive a transplant – whether of stem cells or of an organ like a liver – our body recognises it as ‘foreign’ and, unless the parts of the immune system that destroy foreign tissue are suppressed, the transplant can fail. Sometimes, however, the graft’s cells start waging war on the native tissue in what is called graft-versus-host disease (GVHD).
That’s what the researchers believe happened in these cases. “For six to nine months after the transplant, we see a mingling of the donor and host cells, and what happens over time is that the donor cells clear out the host cells.” It had been important to keep the patients on ART during this time, Henrich added, as it protected the donor cells from infection with HIV.
However, he warns: "This is not a practical strategy that we can do for most people with HIV. Stem-cell transplantation is dangerous. There can be up to 20% mortality associated with stem cell transfer in the first year after transplantation".
This danger was underlined earlier this year. Doctors in Minnesota used a similar strategy to the one that cured Brown in a twelve-year-old boy with HIV and leukaemia. They used not bone-marrow cells but stem cells – immune system progenitor cells – found in the blood from the umbilical cords of newborn babies, containing a rich supply of foetal stem cells that can be nudged into turning into a wide variety of cell types. The researchers found enough cord blood with the delta-32 mutation to give these to the boy.
Unfortunately the boy, Eric Blue, lived for less than three months after his transplant.2 The GVHD that in the Boston patients had wiped out most of the remaining HIV-infected cells had, as it can sometimes do in transplant patients, turned lethal: the donor cells mounted a devastating attack on Eric’s body.
‘Functional cures’ after early treatment
In people with chronic HIV, then, we have only achieved cures in a few people where high-risk, complex measures are ethically possible. This year, however, a number of cases of apparent cure or long-term remission from HIV turned up in people subject to a more benign technique – antiretroviral therapy.
In the first report, the talk of the Conference on Retroviruses and Opportunistic Infections (CROI) in Atlanta in March 2013, US researchers identified a case of a functional cure in a baby girl infected with HIV (the ‘Mississippi baby’), who began ART within two days of birth.3 The child has now been off treatment for 18 months, and although HIV DNA (genetic material) has been detected at very low levels in her cells, she has no detectable viral RNA in her blood and her virus is not reproducing – the definition of a functional cure.
The apparent suppression of the girl’s HIV to levels below which it could start replicating – either because there was no fully functional HIV DNA left, or because her own immune system was controlling any remnants – was initially greeted with some scepticism. Was the HIV truly an infection, or residual maternal virus? Would HIV eventually reappear? There was nervousness about the claim of researcher Deborah Persaud that “This is our Timothy Brown moment”. Even if this was not an isolated case and could be repeated, few people get the chance to start ART within days of infection.
However, a study published soon after CROI confirmed not only that long-term off-treatment remission of HIV was possible, it might even be quite common – and that ART did not necessarily have to be started within the first day or two. French researchers4 found 14 (now 26) adult patients from a group called the VISCONTI cohort who also started ART soon after infection, subsequently stopped it, and had not had to re-start because they had largely – and in eight cases completely – maintained undetectable viral loads for four to ten years after stopping therapy.
Furthermore, the researchers suggested that the only reason such cases are not more common is simply because, once having started ART, few people stop. They claimed that 15% (later revised downwards to 5 to 10%) of people with HIV, if ART was started within six months of HIV infection and maintained for at least a year, could subsequently become so-called ’post-treatment controllers’.
Their estimate is a stark contrast to findings from studies conducted between 1996 and 2000, soon after the introduction of highly active ART, which found no evidence that people who began treatment in primary infection soon after acquiring HIV could control HIV after stopping treatment. The key difference is that earlier studies looked at HIV control in people who had only received treatment for 12 to 18 months. The French patients had been on treatment for an average of three years before stopping, and all started treatment within ten weeks of infection, compared to within six months in previous studies.
A further study, presented at the IAS conference, came up with another patient – a 67-year-old German man - who had started ART within —three months of infection and stayed on it for five years, but who stopped his HIV therapy in 2004 and, apart from a small initial viral ‘rebound’, has not had a detectable viral load result since.5
This patient’s CD4 and CD8 cells had strong anti-HIV responses, meaning his immune system was actively preventing viral replication. This is also characteristic of ‘elite controllers’, people who maintain undetectable viral loads without therapy and, essentially, generate their own long-term remission from active HIV.
Being an elite controller might not be good for you. Another presentation at the IAS cure symposium found that HIV responses in elite controllers were characterised by increased activation of virus-fighting proteins such as interferon alpha which, as anyone who has taken it as hepatitis C treatment knows, creates symptoms of its own.6 Another found high levels of a second immunomodulator with known harmful effects called galectin 9.7 Elite controllers don’t just experience physical malaise: it had already been shown that they have higher levels of cardiovascular disease than average, similar to other people with HIV not on ART.8
The VISCONTI researchers found that the viral control seen in their patients (and the Mississippi baby) had almost an opposite explanation from that seen in the majority of elite controllers, whose immune cells tended to be rather unresponsive to HIV. Infection spread slowly through the body, which allowed the immune system time to recognise HIV and mount a vigilant response to it.
In contrast, the VISCONTI patients’ immune cells were unusually sensitive to HIV infection and their acute HIV infection period was characterised by high viral load. HIV invaded so fast, it gave their immune systems no time to react. Normally, this would result in the body being ‘seeded’ with a large reservoir of HIV-infected CD4 cells that would start pumping out virus as soon as viral suppression with ART was removed.
The theory goes that, if ART is started quickly enough and maintained for long enough, the viral reservoir remains small. In normal HIV infection, even in people on ART, residual HIV - burning away like a pilot light - remains; as soon as ART is removed it ‘lights the fire’ again, stimulating cells into producing a new burst of HIV.
In the VISCONTI patients, on the other hand, there was so little HIV around that, when ART was taken away, the immune system – which, remember, had never been given time to ‘recognise’ HIV – simply acted as if it was not there at all.