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Allogeneic transplantation of CCR5-deficient progenitor cells in a patient with HIV infection: an update after 3 years and the search for patient no. 2 - pdf attached
 
 
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AIDS:
14 January 2011 - Volume 25 - Issue 2 - p 273-274
Correspondence
 
Hutter, Geroa; Thiel, Eckhardb
aInstitute of Transfusion Medicine and Immunology, University Heidelberg, Mannheim, Germany
bMedical Department III (Haematology and Oncology), Charite Campus Benjamin Franklin, Berlin, Germany.
Received 7 July, 2010
Revised 16 September, 2010
Accepted 23 September, 2010
 
In February 2007, the medical team of the Charite Berlin performed an allogeneic haematopoietic stem cell transplantation (HSCT) in an HIV-infected patient with acute myeloid leukaemia (AML) using progenitor cells from a donor, especially selected for homozygosity for the CCR5-delta32 deletion (HIV-resistance gene) [1]. Now, more than 3 years after this treatment, the patient is still off antiretroviral medication and without any evidence of viral replication. Furthermore, the patient's CD4 cell count rose to more than 800/µl and all investigated haematopoietic stem cell derivatives, including macrophages of the gut, became CCR5 negative. This case has inspired new hopes that some kind of gene therapy may become the key to an improvement in HIV treatment and hopefully an HIV cure. Nevertheless, it was just a single case and repeating this approach in a small series of patients would be desirable to make further conclusions. Here, we report our efforts to find a second candidate for allogeneic CCR5-delta32 transplantation and the limitations of this undertaking.
 
The main indication for allogeneic HSCT in adults is the diagnosis of AML. In the last decade, about 3500 new cases of AML have been reported in Germany per year (incidence 3.0-3.9/100 000/year) [2]. Taking into account that only one third of these patients are less than 60 years of age and therefore eligible for allogeneic HSCT, furthermore, that a reasonable proportion of patients pass away before transplantation and, finally, that a human leukocyte antigen (HLA)-matching sibling can be found in 20%, the incidence of appropriate candidates for allogeneic HSCT could be assumed as being approximately 1.0-1.5/100 000 per year. The prevalence of HIV in Germany is about 0.0006% [3]. Taken together, in Germany, we expect to find only 0.5-1.5 patients per year with a coincidence of HIV and AML suitable for transplantation with CCR5-delta32 screened stem cells.
 
Currently, 75% of patients requiring an allogeneic HSCT will find at least one HLA-matched donor. The prevalence of CCR5-delta32 homozygotes in Europe is between 1% and 3%. Therefore, the likelihood of finding an HLA-matched donor is dramatically reduced if we cannot expand the donor pool by a factor of at least 10, requiring the worldwide cooperation of stem cell registries.
 
In spring 2009, our institution organized an international workshop bringing together leading European stem cell registries for a discussion of the possibilities and limitations of a CCR5-based donor screening [4]. The meeting came to the agreement of supporting further attempts to use CCR5-delta32 deleted stem cells in appropriate candidates. To expand the repertoire of donors, prescreened stem cells will be provided by Stemcyte, a company that already charged over 10 000 units of CCR5-tested cord blood units [5].
 
Since the publication of our report, we received several requests from other institutions concerning the possibility of finding CCR5-depleted donors for transplantation in HIV-infected patients with an indication for allogeneic HSCT. Table 1 shows all performed and planned CCR5 donor screening activities carried out by our workgroup. As expected, one limitation in finding appropriate candidates was that, frequently, only few HLA-matched donors were available. Furthermore, statistically, we should have found at least one CCR5-delta32 homozygous donor in patient 3; however, the search was unsuccessful.
 
Table 1. Summary of CCR5 genotyping.
 
Allogeneic transplantation of CCR5-deficient progenitor cells in a patient with HIV infection: an update after 3 years and the search for patient no. 2 - pdf attached
 
AIDS:
14 January 2011 - Volume 25 - Issue 2 - p 273-274
Correspondence
 
Hutter, Geroa; Thiel, Eckhardb
aInstitute of Transfusion Medicine and Immunology, University Heidelberg, Mannheim, Germany
bMedical Department III (Haematology and Oncology), Charite Campus Benjamin Franklin, Berlin, Germany.
Received 7 July, 2010
Revised 16 September, 2010
Accepted 23 September, 2010
 
In February 2007, the medical team of the Charite Berlin performed an allogeneic haematopoietic stem cell transplantation (HSCT) in an HIV-infected patient with acute myeloid leukaemia (AML) using progenitor cells from a donor, especially selected for homozygosity for the CCR5-delta32 deletion (HIV-resistance gene) [1]. Now, more than 3 years after this treatment, the patient is still off antiretroviral medication and without any evidence of viral replication. Furthermore, the patient's CD4 cell count rose to more than 800/µl and all investigated haematopoietic stem cell derivatives, including macrophages of the gut, became CCR5 negative. This case has inspired new hopes that some kind of gene therapy may become the key to an improvement in HIV treatment and hopefully an HIV cure. Nevertheless, it was just a single case and repeating this approach in a small series of patients would be desirable to make further conclusions. Here, we report our efforts to find a second candidate for allogeneic CCR5-delta32 transplantation and the limitations of this undertaking.
 
The main indication for allogeneic HSCT in adults is the diagnosis of AML. In the last decade, about 3500 new cases of AML have been reported in Germany per year (incidence 3.0-3.9/100 000/year) [2]. Taking into account that only one third of these patients are less than 60 years of age and therefore eligible for allogeneic HSCT, furthermore, that a reasonable proportion of patients pass away before transplantation and, finally, that a human leukocyte antigen (HLA)-matching sibling can be found in 20%, the incidence of appropriate candidates for allogeneic HSCT could be assumed as being approximately 1.0-1.5/100 000 per year. The prevalence of HIV in Germany is about 0.0006% [3]. Taken together, in Germany, we expect to find only 0.5-1.5 patients per year with a coincidence of HIV and AML suitable for transplantation with CCR5-delta32 screened stem cells.
 
Currently, 75% of patients requiring an allogeneic HSCT will find at least one HLA-matched donor. The prevalence of CCR5-delta32 homozygotes in Europe is between 1% and 3%. Therefore, the likelihood of finding an HLA-matched donor is dramatically reduced if we cannot expand the donor pool by a factor of at least 10, requiring the worldwide cooperation of stem cell registries.
 
In spring 2009, our institution organized an international workshop bringing together leading European stem cell registries for a discussion of the possibilities and limitations of a CCR5-based donor screening [4]. The meeting came to the agreement of supporting further attempts to use CCR5-delta32 deleted stem cells in appropriate candidates. To expand the repertoire of donors, prescreened stem cells will be provided by Stemcyte, a company that already charged over 10 000 units of CCR5-tested cord blood units [5].
 
Since the publication of our report, we received several requests from other institutions concerning the possibility of finding CCR5-depleted donors for transplantation in HIV-infected patients with an indication for allogeneic HSCT. Table 1 shows all performed and planned CCR5 donor screening activities carried out by our workgroup. As expected, one limitation in finding appropriate candidates was that, frequently, only few HLA-matched donors were available. Furthermore, statistically, we should have found at least one CCR5-delta32 homozygous donor in patient 3; however, the search was unsuccessful.
 
Table 1. Summary of CCR5 genotyping.

Several strategies have already emerged from our current understanding of persistent HIV infection and, in 1988, David Baltimore, Nobel Laureate, suggested that gene therapy could provide a possible HIV/AIDS treatment. Furthermore, techniques of gene delivery and gene knockdown have been progressed considerably today as instruments for future HIV treatment strategies. Our report, from a successful way of a 'natural' kind of HIV gene therapy, has kindled discussion about whether this patient is sterilizing cured [6,7]. This can be assumed more and more given the fact that, meanwhile, all infectable targets and reservoir elements have been replaced by a new generation of cells with CCR5-negative status. However, in our opinion, an important additional proof-of-concept would be that we were able to reproduce this approach in other patients.
 
 
 
 
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