Signs of progress in gene therapy for HIV

Richard Jefferys, TAG

Until recently, the idea of genetically modifying a person’s immune system to make it resistant to HIV was generally viewed as extremely appealing, but so dauntingly impractical that it belonged in the realm of science fiction. Over the past year or so, an accumulation of new data has offered hope that it may eventually be possible to translate the idea into science fact.

Central to these developments is the widely reported case of an HIV-positive individual in Berlin who remains off antiretroviral therapy and free of detectable HIV after receiving a bone marrow transplant from an individual lacking the CCR5 co-receptor due to the delta32 genetic mutation. [1]

The bone marrow transplant was received (twice) during a difficult and complicated course of treatment for acute myelogenous leukemia, so the case is not seen as something that can easily be replicated in other people, but rather as a “proof-of-concept” that modifying the immune system can be a means to extinguishing HIV infection.

Complementing this remarkable case report, several studies have described improvements in techniques that may facilitate genetic modification of the immune system. A company called Sangamo Biosciences has developed a technology that allows inactivation of specific genes using enzymes called zinc finger nucleases (ZFNs); the approach is described in detail in the current issue of Nature Reviews Genetics and was also the subject of a New York Times article by Nicholas Wade at the end of last year. [2] An ongoing human trial is using Sangamo’s ZFNs to delete the CCR5 gene in CD4 T cells sampled from HIV positive individuals; the CCR5-negative CD4 T cells are then expanded in number and re-infused into the donor (a very preliminary report from this trial was covered in TAGline earlier this year). [3]

In the current issue of Nature Biotechnology, a research team led by Nathalia Holt describes using the Sangamo technique to successfully modify hematopoietic stem/progenitor cells (HSPC) in mice. [4] The advantage of using HSPCs is that they are the “mother of all cells” and can potentially provide a permanent source of modified immune cells, circumventing the need for altering CD4 T cells in the lab and re-infusing them. Holt’s team was able to show that, in mice, the CCR5-negative HSPCs generated immune cells of multiple types, all lacking CCR5. In “humanised” mice challenged with HIV, these CCR5-negative cells expanded in number and reduced viral load compared to untreated mice with normal CCR5 expression. In an accompanying editorial, Steve Deeks and Mike McCune from UCSF highlight the potential importance of Holt’s findings and outline the implications for future research in humans. [5]

The other recent study that is part of this evolving story was published back in June in the journal Science Translational Medicine. The research group of John Zaia at City of Hope in Duarte, California described results of an experiment in which HSPCs from four individuals with HIV and AIDS-related lymphoma were modified with three anti-HIV genes and re-infused. [6, 7] The modified HSPCs were given along with the infusions of unmodified HSPCs that are a standard part of the protocol for lymphoma treatment. Although it was a small exploratory study, the researchers were encouraged to find evidence that the modified HSPCs had given rise to cells of multiple lineages (e.g. T cells, B cells, macrophages) carrying the anti-HIV genes, albeit at very low numbers.

On 21 August the LA Times published an excellent story by Rachel Bernstein that ties these various gene therapy developments together. [8] It turns out that John Zaia’s group at City of Hope will be the first to use Sangamo’s CCR5-deletion approach to modify human HSPCs, likely also in people with AIDS-related lymphoma initially. The ultimate hope – “reaching for blue sky,” as Deeks & McCune describe it – is that a single shot of souped-up HSPCs may one day be able to equip the immune system with enough HIV-resistant cells to vanquish the virus.

Source: TAG Basics Science web log (23 Aug 2010)


  1. Hütter G et al. Long-term control of HIV by CCR5 delta32/delta32 stem-cell transplantation. N Engl J Med 2009; 360:692-698February 12,
  2. Wade N. In new way to
    edit DNA, hope for treating disease. New York Times, 28 December 2009.
  3. Jefferys R. NIAID workshop: elimination of HIV
  4. Holt N et al. Human hematopoietic stem/progenitor cells
    modified by zinc-finger nucleases targeted to CCR5 control HIV-1 in vivo. Nat Biotechnol. 2010 Aug;28(8):839-47. Epub 2010 Jul 2.
  5. Deeks SG,
    McCune JM. Can HIV be cured with stem cell therapy? Nature Biotechnology 28, 807–810 (1 August 2010) | doi:10.1038/nbt0810-807.
  6. DiGiusto DL et al. RNA-based gene therapy for HIV with lentiviral vector-modified CD34(+) cells in patients undergoing transplantation for
    AIDS-related lymphoma. Sci Transl Med. 2010 Jun 16;2(36):36ra43.
  7. Shah PS, Schaffer DV. Gene
    therapy takes a cue from HAART: combinatorial antiviral therapeutics reach the clinic. Sci Transl Med. 2010 Jun 16;2(36):36ps30.a
  8. Bernstein R.
    HIV-resistant cells work in mice. Can they help humans? Los Angeles Times (21 August 2010).,0,2873266.story

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