Towards a cure for all (part one)

This article originally appeared in HIV Treatment Update, a newsletter published by NAM between 1992 and 2013.
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For the first time, someone has been cured of HIV infection. It was a brutal and expensive procedure but, as Gus Cairns reports, in the first of a two-part feature on curing HIV infection, it may signal the way to a cure for everyone.

The Berlin patient

On 13 December, NAM’s website aidsmap.com published a news story1 which, thanks largely to circulation on social media like Facebook and Twitter, received 50 times the usual hits.

It concerned the ‘Berlin patient’, who we now know as Timothy Ray Brown, an American living in Berlin. He will go down in history as the first person ever to be cured of HIV. His doctors had already published two papers on his case2,3 (see HTU issues 182 and 192) but it was only in a third paper, summarising late results, that they allowed themselves to say: “It is reasonable to conclude that cure of HIV infection has been achieved in this patient.”4

Glossary

cure

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 person’s 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. 

CCR5

A protein on the surface of certain immune system cells, including CD4 cells. CCR5 can act as a co-receptor (a second receptor binding site) for HIV when the virus enters a host cell. A CCR5 inhibitor is an antiretroviral medication that blocks the CCR5 co-receptor and prevents HIV from entering the cell.

immune system

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

bone marrow

Cells in the middle of bones which are responsible for producing blood cells.

reservoir

The ‘HIV reservoir’ is a group of cells that are infected with HIV but have not produced new HIV (latent stage of infection) for many months or years. Latent HIV reservoirs are established during the earliest stage of HIV infection. Although antiretroviral therapy can reduce the level of HIV in the blood to an undetectable level, latent reservoirs of HIV continue to survive (a phenomenon called residual inflammation). Latently infected cells may be reawakened to begin actively reproducing HIV virions if antiretroviral therapy is stopped. 

The extraordinary explosion in interest hints that, however well we are doing on our antiretrovirals (ARVs), however normal a life people manage to live with HIV, most people still long to be rid of it.

Kill or cure

The cure Brown underwent was not one you’d wish on anyone, though. It only happened because he developed something else: leukaemia. This is cancer of the immune system, a wild overproliferation of the blood cells originating in the bone marrow. When Brown’s chemotherapy failed and his leukaemia returned, his doctors decided on the last resort - a bone marrow transplant.

To do this, doctors destroy a large part of the immune system to kill off the cancerous cells. They then introduce a graft of bone marrow from a healthy donor who’s as closely matched genetically as possible, so the host’s body doesn’t attack the new cells. These should then become the patient’s new immune system.

What this also means, in a person with HIV, is that if the original immune system is wiped out thoroughly enough, so are the CD4 cells that harbour the virus.

Brown’s doctor, Gero Hütter, had an idea. He knew that about 1% of Caucasians have a genetic mutation called the delta-32 double-delete mutation. ‘Double-delete’ means they inherited a copy of the same defective gene from both parents. In these people, certain classes of immune cell lack a cell-membrane protein called CCR5.

The majority of human immunodeficiency viruses, and 99% of those transmitted, need to grab on to a CCR5 molecule in order to infect a cell; indeed one of the newer HIV drugs, maraviroc (Celsentri), works by blocking the CCR5 molecule.

People with this mutation are almost completely resistant to HIV infection and, more importantly in this case, to HIV proliferation: no CCR5 means no new cells to infect. So what would happen if Brown’s immune system was replaced by one from a donor with no CCR5? Would his HIV disappear?

To cut to the chase, the answer was yes, and fast (for the full report, see www.aidsmap.com/page/1577949). Despite being taken off ARVs the day before his bone marrow transplant, Brown only had one more detectable viral load before it disappeared entirely. Two months after his first transplant, all his bone marrow cells had become CCR5-negative. Five months after, his CD4 cells were acting as if there was no HIV in his body. At this point, however, the researchers could still find CCR5-expressing cells in his gut, so they hesitated to announce a cure. Two years later, they could find none anywhere, and the antibody responses which define whether someone is ‘HIV-positive’ or not were dwindling away to near-zero.

They also found no HIV in Brown’s brain. They were certain of this because 17 months after his first transplant (he had to have a second at 13 months), Brown developed a brain impairment and had a brain biopsy. Hütter’s team can’t absolutely rule out this having been caused by a flare-up of HIV lurking in the brain, but the biopsy and analysis of Brown’s cerebrospinal fluid revealed no evidence of HIV. They suggest it was probably due to immune deficiency caused by the transplant procedures and the chemotherapy. He suffered temporary blindness, memory problems and loss of muscular co-ordination.

Why it’s hard to do

So we can’t do for everyone as we did for Brown. Rowena Johnston is vice-president and director of research for amfAR, the American Foundation for AIDS Research, which last year launched ARCHE – the amfAR Research Consortium on HIV Eradication,5 a network of researchers investigating a cure (see www.amfar.org/cure).

“With Brown they used a more intense and toxic regimen to prepare him for the transplant than is ever used in the United States,” says Johnston. “But even if all the procedural details were worked out, you’d never find enough donors with the delta-32 mutation.”

Something along the lines of Brown’s cure has been discussed since the dawn of the epidemic. One research paper6 documented 32 attempts between 1982 and 1996 to eradicate HIV using bone marrow transplantation. In one in 1989,7 doctors succeeded in wiping out HIV from the T-cells of a man dying of non-Hodgkin’s lymphoma within a month of a bone marrow transplant from a negative donor. He died two weeks later of the cancer, but autopsy specimens from brain, bone marrow, gut and other organs could find no HIV.

The reason HIV is so hard to eradicate is twofold. Firstly, a tiny proportion of cells infected with HIV become ‘resting memory’ cells. These are cells whose job it is to stay secreted away in tissues like the brain, lymph nodes and gut, like sleeper cells in a resistance organisation, until a new infection comes along that resembles the one in which they were originally created.

Secondly, ARVs seem to block most, but not all, virus replication so there are still very low levels of virus replication in patients on treatment – although its significance is an area of hot debate.

The problem with HIV is that one in every thousand to every million resting memory cells is a double agent. Instead of being equipped to fight HIV, it actually contains within its DNA, HIV’s genetic code. As soon as you relax the police state enforced by ARVs, these cells set off a whole new wave of infection.

Cells that produce virus soon die, but putting people on ARVs means that the memory cells may never be activated. They can lurk in the body life-long, as a ‘reservoir’ of HIV.

If you take someone off ARVs for a short while, some reservoir cells die but other memory cells are infected, so you just replenish the reservoir. This is why structured treatment interruptions (‘drug holidays’) didn’t work.

Steven Deeks is professor of medicine at the University of California. He puts it this way: “The fundamental problem is that you’re trying to stimulate the output of part of the immune system while dampening down another part.”

What we need is some fiendishly clever way to get the HIV-infected lurking cells to come out of hiding and blow themselves up, while at the same time protecting uninfected cells from infection. They managed this with Brown – but only by replacing his immune system with someone else’s.

Several other attempts to cure HIV didn’t work either – although they may in the end contribute to a cure.

Very early treatment. If you know someone has acute HIV, within the first three weeks of infection, and give them ARVs right away, the number of infected resting memory cells (the ‘reservoir’) is 10 to 100 times less than in patients treated during chronic infection. In a few patients treated like this, after stopping ARVs the viral load stayed low.8 In another study, however, HIV returned 50 days after therapy in a patient treated early who only had one in every 1.7 billion resting memory cells infected.9 In any case, this strategy would only work for the small minority of people who test for HIV when they have acute infection.

Treatment intensification. If you added more drugs to someone’s ARV regimen, would it drive their viral load down to a point below which there was too little HIV left for it to come back? A tall order if it requires fewer than one in two billion cells to be infected, but there were high hopes when the integrase inhibitor drug raltegravir (Isentress) came along, as it lowers viral load faster than other drugs. A trial found, however, that it had no significant effect on the residual replicating virus in the body.10 Similarly, maraviroc, the first drug of the CCR5 inhibitor class, failed to drive viral load down to any useful extent when added to a regimen11 even though, as we have seen, CCR5 may hold the key to a cure.

Immune stimulation. You can use cytokines (naturally occurring immune modulators like IL-2 or IL-7) to activate resting cells to produce HIV and destroy themselves. But IL-2 had no effect on the number of resting infected cells,12 and the type of cells it stimulated do not replace HIV-infected cells as a bone marrow transplant does. Also, IL-2 and IL-7 may cause resting infected cells to divide and replenish the reservoir.13 Immune stimulant drugs can be very toxic: many patients found IL-2 hard to tolerate and a previous study using IL-2 and another immune modifier called OKT-3 left some in intensive care.14

Therapeutic vaccine. Studies show that most of the minority of people who control HIV without drugs have CD8 cells (the ones that kill HIV-infected cells) with unusually high activity against HIV. You could try to enhance CD8 cell responses with a therapeutic vaccine made from immune-stimulating bits of HIV. But therapeutic vaccines by themselves have no great record of success. They do seem to stimulate the anti-HIV activity of CD8 cells, but are ineffective at controlling HIV replication, probably because the virus can mutate to evade the surveillance of the CD8 cells.15 If it does, it can come back stronger than ever.16

And yet…the point about Timothy Ray Brown’s cure is that, as Steven Deeks says, “For the first time ever, something worked.”

Rowena Johnston adds: “What’s important is that it focused attention that an HIV cure is possible and realistic and that this is a worthy research area to fund.”

So how might we cure HIV infection in ways that are safer and less toxic than what happened to Brown? Clearly, if we knew, we’d be doing it. But researchers are engaged in the early stages of a number of promising strategies.

To find out what they are, you’ll have to read part two next month…

References
  1. Alcorn K Stem cell transplant has cured HIV infection in ‘Berlin patient’, say doctors. aidsmap.com, 13 December 2010. (See www.aidsmap.com/page/1577949)
  2. Hütter G et al. Long-term control of HIV by CCR5 delta-32/delta-32 stem-cell transplantation. N Engl J Med. 360: 692-8, 2009.
  3. Hütter G et al. Transplantation of selected or transgenic blood stem cells – a future treatment for HIV/AIDS? J Int AIDS Soc 12: 10, 2009.
  4. Allers K et al. Evidence for the cure of HIV infection by CCR5Δ32/Δ32 stem cell transplantation. Blood, advance online publication, December 8, 2010.
  5. See www.amfar.org/cure
  6. Huzicka I Could bone marrow transplantation cure AIDS?: review. Medical Hypotheses 52(3):247-257, 1999.
  7. Holland HK et al. Allogeneic bone marrow transplantation, zidovudine, and human immunodeficiency virus type 1 (HIV-1) infection. Studies in a patient with non-Hodgkin lymphoma. Ann Intern Med 111(12):973-981, 1989.
  8. Hocqueloux L et al. Long-term immunovirologic control following antiretroviral therapy interruption in patients treated at the time of primary HIV-1 infection. AIDS 24(10):1598-1601, 2010.
  9. Chun TW et al. Rebound of plasma viremia following cessation of antiretroviral therapy despite profoundly low levels of HIV reservoir: implications for eradication. AIDS 24:2803-2808, 2010.
  10. Gandhi RS et al. The effect of raltegravir intensification on low-levelresidual viremia in HIV-infected patients on antiretroviral therapy: a randomized controlled trial. PloS Medicine 7(8): e1000321. doi:10.1371/journal.pmed.1000321
  11. Gutiérrez C et al. Effect of the intensification with a CCR5 antagonist on the decay of the HIV-1 latent reservoir and residual viremia. 17th Conference on Retroviruses and Opportunistic Infections San Francisco, abstract 284, 2010.
  12. Losso M et al. Effect of Interleukin-2 on clinical outcomes in patients with a CD4+ cell count of 300/mm3: primary results of the ESPRIT study. 16th Conference on Retroviruses and Opportunistic Infections, Montreal, abstract 90aLB, 2009.
  13. Thiebaut R et al. Understanding and Predicting the Effect of Interleukin-7 in HIV-1 Infected Patients: A Mathematical Analysis of a Phase I/IIa Study. 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), abstract H-931, 2010.
  14. Van Praag RM et al. OKT3 and IL-2 treatment for purging of the latent HIV-1 reservoir in vivo results in selective long-lasting CD4+ T cell depletion. J Clin Immunol. 21(3):218-26, 2001.
  15. Yang O. CTL and the Control of HIV-1 Replication: Or Lessons learned from mixing HIV-1 and CTL. HTVN Conference, 2007. See www.hivvaccineenterprise.org/conference_archive/2007/pdf/OYang.pdf
  16. Autran B et al. Greater viral rebound and reduced time to resume antiretroviral therapy after therapeutic vaccination with ALVAC-HIV vaccine (vCP1452). AIDS 22(11):1313-1322, 2008.