HTB

Berlin man remains free of detectable HIV 3.5 years after CCR5-negative stem celltransplant

1 December 2010. Related: Basic science and immunology.

Richard Jefferys, TAG

At the 2008 Conference on Retroviruses & Opportunistic Infections, a piece of paper pinned to a poster board conveyed some surprising information: an HIV-positive man who had received two stem cell transplants for acute myelogenous leukemia (and the dauntingly toxic ablation regimens that go with them) had remained off antiretroviral therapy for nearly ten months since, without any evidence of the virus coming back. [1]

The finding did not rest entirely on serendipity; his doctors had intelligently sought out a stem cell donor homozygous for the CCR5 delta 32 mutation, which prevents expression of the HIV co-receptor CCR5 on the surface of cells. Most people, including me, wandered past the poster oblivious to its potential import. But Marty Delaney, the much-missed leader of Project Inform who passed away in January 2009, was more alert. He wrote an article for the PI website describing the case, which was posted February 12, 2008. It concluded: “This is another one of the kind of “one step at a time” approaches that we hope will one day lead to an outright cure of HIV infection, a state in which people who were once actively infected can remain “HIV undetectable” without any ongoing use of therapy. We urge other researchers to replicate or build upon this impressive case study, and we salute the patient and his doctors for taking this bold approach to treating HIV disease.” [2]

Many months later, in November 2008, the story finally broke in the mainstream media when Mark Schoofs authored an article for the Wall Street Journal entitled “A Doctor, a Mutation and a Potential Cure for AIDS;” many other outlets followed his lead. [3] The article was prompted by a September 2008 scientific workshop on the case, sponsored by amfAR, at which the man’s doctor—a cheerful German hematologist named Gero Hütter spoke. A detailed case report followed in the 12 February 2009 issue of the New England Journal of Medicine. [4]

This month, in the first edition section of the journal Blood, the latest update on the individual in question appeared. [5]

Follow-up is now out to 3.5 years and HIV remains undetectable in blood and every tissue studied, including gut and brain. CD4 T cell counts have climbed back into the normal range (the highest they have been since the original HIV diagnosis). There are some immunological deficits reported: the numbers of naive T cells and newly-produced T cells known as recent thymic emigrants remain lower than those of healthy individuals, but are at similar levels to those seen in stem cell transplant recipients without HIV infection. Of concern to the researchers was the fact that, before his transplant procedures, the individual showed evidence of the presence of HIV capable of entering cells via the CXCR4 receptor (X4-tropic HIV).

It was initially assumed that this virus would re-emerge at some point, but that has not occurred despite the documented presence of activated, CXCR4-expressing CD4 T cells in the gut (which would be expected to be prime targets). The paper closes with this sober statement: “From these results, it is reasonable to conclude that cure of HIV infection has been achieved in this patient.”

As Marty Delaney had advocated, an expanding number of projects are aiming to build on this result. The National Institutes of Health will soon be funding a multi-researcher project named after him, the Martin Delaney Collaboratory: Towards an HIV-1 Cure. [6]

Several potentially far safer approaches to abrogating CCR5 expression via genetic modification are in—or will soon enter—human trials. In April of next year, the AIDS Policy Project, amfAR, Project Inform and TAG are sponsoring a workshop to specifically address issues related to advancing cure-related clinical research. What was once written small in a cavernous Boston conference hall now looms large, providing hope that a cure for HIV infection is possible.

The individual has now gone public in Stern magazine; his name is Timothy Ray Brown, a 44 year old US citizen. [7] A rough google translation of the article, which describes the series of difficult medical challenges he faced, including a bout of leukoencephalopathy that he is still recovering from.
[8]

Given the media attention that is likely to follow, it’s important to stress the not-so-good news: the extremely risky procedures that Timothy Ray Brown underwent to treat his cancer carry a very high risk of mortality, and they cannot be used to try and cure HIV in people without acute myelogenous leukemia (AML). Even for people with HIV who have AML and need a stem cell transplant, the likelihood of finding an appropriate (HLA-matched) donor with the CCR5 delta 32 mutation is extremely low due to its rarity.

comment

We also reported this case from the CROI conference when it was first presented and this continued follow-up is impressive. Given how quickly HIV rebounds when treatment is discontinued, usually to detectable levels with a weeks and to pretreatment levels within a month or two, this person appears to be cured.

Source: Source: TAG basic science blog. (06 December 2010). http://www.treatmentactiongroup.org/basicsciblog.aspx

References

  1. Hutter G et al. Treatment of HIV-1 infection by allogeneic CCR5-D32/D32 stem cell transplantation: a promising approach. Poster
    abstract 719. http://www.retroconference.org/2008/Abstracts/31704.htm (abstract) http://www.retroconference.org/2008/PDFs/719.pdf (PDF poster)
  2. Delaney M. Stem cells: Progress towards “the cure”? http://www.projectinform.org/news/08_croi/021208.shtml
  3. Schoofs M. A Doctor, a Mutation and a Potential Cure for AIDS. Wall Street Journal. 7 November 2008. http://online.wsj.com/article/SB122602394113507555.html
  4. Hutter G et al. Long-term control of HIV by CCR5 delta32/delta32 stem-cell transplantation. N Engl J Med 2009; 360:692-698. http://www.nejm.org/doi/full/10.1056/NEJMoa0802905
  5. Allers K et al. Evidence for the cure of HIV infection by CCR5 delta32/delta32 stem cell transplantation. Blood, prepublished online December 8, 2010; DOI 10.1182/blood-2010-09-309591. http://bloodjournal.hematologylibrary.org:80/cgi/content/abstract/blood-2010-09-309591v1
  6. Martin Delaney Collaboratory: Towards an HIV-1 Cure http://grants.nih.gov/grants/guide/rfa-files/RFA-AI-10-009.html
  7. Der Mann, der HIV besiegte. Sterne magazine. 8 December 2010. http://www.stern.de/gesundheit/the-berlin-patient-der-mann-der-hiv-besiegte-1631908.html
  8. Der Mann, der HIV besiegte. Sterne magazine. 8 December 2010. Rough google translation: http://translate.google.com/translate?u=http%3A%2F%2Fwww.stern.de%2Fgesundheit%2Fthe-berlin-patient-der-mann-der-hiv-besiegte-1631908.html&sl=de&tl=en&hl=&ie=UTF-8

Links to other websites are current at date of posting but not maintained.