Case report from the first clinical trial of CRISPR-edited stem cells in people with HIV and cancers

Richard Jefferys, TAG

One of the ways TAG keeps track of developments in HIV cure research is by maintaining an online listing of clinical research culled from trial registries (primarily [1]

In May 2017, a research group in China registered the first human HIV trial involving the CRISPR/Cas9 gene editing system – a technology that has generated considerable excitement and attention due to promising results in small animal models. [2]

Last month in the New England Journal of Medicine, the researchers published a case report describing outcomes in a study participant (presumably the first individual enrolled). [3]

The design of the study is similar to several prior gene therapy trials for HIV positive people with cancer diagnoses that require stem cell transplantation as part of the treatment regimen (City of Hope in California has been a notable pioneer of this research). [4]

After appropriate stem cell donors are identified, some of the donated cells are subjected to genetic modification in the laboratory prior to being administered to study participants. Unmodified cells are also delivered to guard against any risk of the genetic modifications compromising the normal therapeutic efficacy of the stem cell transplantation.

The novel aspect is the use of CRISPR/Cas9 to edit the gene for the CCR5 receptor that most HIV strains use to infect cells. The researchers previously published laboratory results demonstrating the feasibility of the approach. The goal is for the gene-edited stem cells to generate a population of HIV-resistant CD4 T cells after transplantation. [5]

The participant described in the NEJM paper is a 27-year-old HIV positive man diagnosed with acute lymphoblastic leukemia, which was successfully driven into remission by chemotherapy regimens prior to the stem cell transplant. After transplantation, tests showed that the stem cells successfully generated a new donor-derived immune system by four weeks post-transplantation (referred to as full donor chimerism) and the cancer remained in remission with a very low predicted risk of relapse. ART was maintained throughout.

Over 19 months of follow up, the proportion of gene-edited cells detectable in bone marrow ranged from 5.20% to 8.28%. Seven months after transplantation, permission was obtained to conduct an analytical treatment interruption (ATI).

At the time of the ATI, the proportion of peripheral blood CD4 T cells showing evidence of CCR5 gene disruption was 2.96%. The proportion increased after treatment cessation, peaking at 4.39% during the ATI. ART was restarted after four weeks due to a very high viral load rebound to 30 million copies/mL; this is not atypical in stem cell transplant recipients because the new donor-derived immune system cells have not been exposed to HIV before, and therefore no virus-specific immunity is present (arguably it would have been prudent to restart ART sooner, if possible). After the ATI, the proportion of gene modified CD4 T cells stabilised at a little over 2.5%.

No adverse events related to the editing of the CCR5 gene were documented. The researchers conducted multiple searches for any evidence of off-target effects (gene edits in the wrong places) but found none. They note, however, that the relatively low efficiency of the gene editing in this study may have limited their ability to detect off-target activity.

The results offer encouragement for further pursuit of CRISPR/Cas9 as a gene editing tool in HIV, but the study authors state in their conclusion: “To further clarify the anti-HIV effect of CCR5-ablated HSPCs [hematopoietic stem and progenitor cells], it will be essential to increase the gene-editing efficiency of our CRISPR–Cas9 system and improve the transplantation protocol.”

In an accompanying commentary, Carl June adds that “additional patients who undergo engraftment with higher frequencies of CRISPR­ Cas9-edited stem cells will have to be followed for longer periods of time in order to ensure the safety of this approach.”

Both the paper and the commentary cite the recently published claim that homozygosity for the CCR5-delta 32 mutation is associated with a reduced lifespan as reason for caution regarding the editing of CCR5, however this concern no longer holds because the work was retracted due to a flaw in the analysis. [7]


Jefferys R. TAG Basic Science Project. (24 October 2019).


  1. TAG. Research Toward a Cure Trials.
  2. Safety of transplantation of CRISPR CCR5 modified CD34+ cells in HIV-infected subjects with hematological malignances.
  3. Xu L et al. CRISPR-edited stem cells in a patient with HIV and acute lymphocytic leukemia. N Engl J Med 2019; 381:1240-1247 (26 September 2019). DOI: 10.1056/NEJMoa1817426
  4. 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. doi: 10.1126/scitranslmed.3000931.
  5. Xu L et al. CRISPR/Cas9-mediated CCR5 ablation in human hematopoietic stem/progenitor cells confers HIV-1 resistance in vivo. Molecular Therapy. (03 May 2017).  DOI:
  6. June CH. Emerging use of CRISPR technology — chasing the elusive HIV cure. Editorial. N Engl J Med 2019; 381:1281-1283. DOI: 10.1056/NEJMe1910754.
  7. Jefferys R. Widely publicized report associating the CCR5-Δ32 mutation with reduced longevity is retracted. TAG. (09 October 2019).

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