An interview with Gero Hütter, Institute of Transfusion Medicine and Immunology, Mannheim, Germany
Following on his recent paper published in Blood on December 8, 2010, we are pleased to offer you an interview with Dr Gero Hütter.
An intriguing HIV-positive patient was first reported at the 15th CROI in 2008 involving a 40-year-old man who received 2 bone marrow transplants for acute myeloid leukemia.
Gero Hüetter, MD, and his colleagues opted to perform the transplants with cells from a donor having the CCR5 delta-32 deletion, known to confer some sort of HIV resistance. Before that, the patient was 'conditioned' by intensive chemotherapy and radiation.
On the day of his first transplant, he discontinued his antiretrovirals. The same procedure was repeated twice about 13 months later due to leukemia relapse.
In February 2009, a preliminary report (1) in The New England Journal of Medicine showed that at no point during the initial 20-month follow-up period did the Patient HIV viremia rebound.
On December 8, 2010, in a paper published in Blood, (2) the authors conclude that 3.5 years after the initial transplant, this patient has been cured from HIV infection. The German team observed successful reconstitution of CD4+ T cells in blood and gut, and replacement of patient's long-lived cells by donor's cells without any trace of HIV.
This is currently the only case of HIV that has been cured in the world.
Dr Gero Hütter kindly agreed to answer our questions:
Q1: In your last Blood paper you decided to use the term ‘cure’ rather than long-term drug-free control, can you tell us why?
GH: In February 2011 this patient will be off any antiretroviral medication since 4 years. The last direct evidence of HIV was detectable on day 60 after transplantation. After that, multiple testing regarding HIV-RNA and DNA in blood, bone marrow, and solid organs was negative. Furthermore, additional tests like bio assay or single copy assay were negative. Corresponding to these findings, the CD4 T-cell count increased to normal values. Finally, we observed a partial sero-deconversion concerning HIV-antibodies.
Q2: What is the difference between ‘functional cure’ and ‘sterilizing cure’, and where does your patient stand?
GH: 'Functional cure' is achieved when the patient has no signs of disease and doesn’t need any specific medication or treatment. In our case, 'sterilizing cure' is probably achieved because meanwhile all infected reservoir cells have been replaced by non-infected and R5-resistant immune cells including gut macrophages and microglia of the brain. The question whether there is at least one infected cell left in the patient is only philosophical. Practically, this patient will not be able to infect other people with HIV and he will not suffer from HIV-related complications anymore.
Q3: What does this case tell us in terms of the role of HIV CCR5 and CXCR4 strains?
GH:The predominant role of R5 strains in transmission is incontrovertible. Anyway, this case tells us, that R5 is necessary in maintaining HIV infection. This could implicate that a complete (?) disruption of CCR5 during HIV infection would offer a therapeutic approach in the future.
Q4: Your results are great hope for lot of patients but how could they have wider implications than being an isolated terrific case?
GH: This case has supported and sometimes initiated intensive investigations in translating the knowledge of CCR5-delta32 transplantation into a more feasible way of treatment. I believe that the potential of any kind of gene therapy is still in development. Nevertheless, the main problem is that current techniques are not able to knock-out CCR5 in all stem cells for transplantation.
Q5: Do you think that the future of new anti-HIV therapeutic approaches is more in stem cell therapy than in drugs ‘purging’ the reservoir?
GH: In my opinion, the question why CCR5-delta32 transplantation worked so well in this patient is still not finally cleared. I believe that not only the CCR5 disruption was substantial for this success but also important the purging of the reservoir by the conditioning regimen. Therefore, probably both therapeutic approaches will be necessary for a new anti-HIV treatment in future.
1-Hütter G, Nowak D, Mossner M et al. Long-term control of HIV by CCR5 Delta 32/Delta 32 stem-cell transplantation. N engl J Med 2009; 360 (7): 692-8
2-Allers K, Hütter G, Hofmann J et al. Evidence for the cure of HIV infection by CCR5 delta 32/delta 32 stem cell transplantation. Blood 2010, prepublished online Dec 8.
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Key words: bone marrow transplant, delta 32 deletion, hiv cure, hiv eradication, hiv reservoir, hiv reservoirs