The man received bone marrow from a donor who had naturalresistance to HIV infection; this was due to a genetic profile which led to theCCR5 co-receptor being absent from his cells. The most common variety of HIVuses CCR5 as its ‘docking station’, attaching to it in order to enter andinfect CD4 cells, and people with this mutation are almost completely protectedagainst infection.
The case was first reported at the 2008 Conference onRetroviruses and Opportunistic Infections in Boston,and Berlindoctors subsequently published a detailed case history in the New England Journal of Medicine inFebruary 2009.
They have now published a follow-up report in the journal Blood,arguing that based on the results of extensive tests, “It is reasonable toconclude that cure of HIV infection has been achieved in this patient.”
The case history
The 'Berlinpatient' is an HIV-positive man who developed acute myeloid leukaemia, receivedsuccessful treatment and subsequently experienced a relapse in 2007 thatrequired a transplant of stem cells.
Doctors chose stem cells from an individual who had anunusual genetic profile: a mutation inherited from both parents that resultedin CD4 cells that lacked the CCR5 receptor. This mutation, called CCR5 delta 32homozygosity, is present in less than 1% of Caucasians in northern and westernEurope, and is associated with a reduced risk of becoming infected with HIV.
This is because all new infecting viruses need to use theCCR5 receptor on CD4 cells when infecting an immune system cell of the CD4type.
Later in the course of HIV infection another type of virusemerges that can use the CXCR4 receptor instead.
Before the stem cell transplant the patient receivedchemotherapy treatment that destroyed most immune cells and total bodyirradiation, and also received immunosuppressive drugs to prevent rejection ofthe stem cells.
Antiretroviral therapy was halted on the day of thetransplant, and the patient had to receive a second stem cell transplant 13days after the first one, due to a further relapse of leukaemia.
The patient continued to receive immunosuppressive treatmentto prevent rejection for 38 months, and at 5, 24 and 29 months post-transplantcolon biopsies were taken to investigate possible graft-versus-host disease inthe intestine. At each investigation additional samples were taken to check forsigns of HIV infection in the abundant immune cells of the gut wall.
During the 38 month follow-up period the donor CD4 cellsrepopulated the mucosal immune system of the gut, to such an extent that thefrequency of CD4 cells was almost twice as high as in HIV-negative healthycontrols, and this phenomenon was also seen in a control group of tenHIV-negative individuals who received stem cell transfers.
The repopulation of CD4 cells was accompanied by thecomplete disappearance of host CD4 cells, and after two years the patient hadthe CD4 count of a healthy adult of the same age.
One of the challenges for any approach to curing HIVinfection is long-lived immune system cells, which need to be cleared before apatient can be cured. In the case of the Berlinpatient CCR5-bearing macrophages could not be detected after 38 months, suggesting thatchemotherapy had destroyed these longer-lived cells, and that they had alsobeen replaced by donor cells.
Nevertheless HIV remained undetectable by both viral loadtesting (RNA) and tests for viral DNA within cells, and HIV antibody levelsdeclined to the point that the patient has no antibody reactivity to HIV coreantibodies, and only very low levels of antibodies to the HIV envelopeproteins.
Seventeen months after the transplant the patient developeda neurological condition, which required a brain biopsy and lumbar puncture tosample the cerebrospinal fluid for diagnostic purposes. HIV was alsoundetectable in the brain and the CSF.
An additional indication that HIV is not present lies in thefact that the patient’s CD4 cells are vulnerable to infection with virus thattargets the CXCR4 receptor. If any virus with this preference was stillpresent, the researchers argue, it would be able to swiftly infect the largepopulation of memory CD4 cells that has emerged.
Doctors chose stem cells from an individual who had anunusual genetic profile: a mutation inherited from both parents that resultedin CD4 cells that lacked the CCR5 receptor. This mutation, called CCR5 delta 32homozygosity, is present in less than 1% of Caucasians in northern and westernEurope, and is associated with a reduced risk of becoming infected with HIV.
This is because all new infecting viruses need to use theCCR5 receptor on CD4 cells when infecting an immune system cell of the CD4type.
Later in the course of HIV infection another type of virusemerges that can use the CXCR4 receptor instead.
Before the stem cell transplant the patient receivedchemotherapy treatment that destroyed most immune cells and total bodyirradiation, and also received immunosuppressive drugs to prevent rejection ofthe stem cells.
Antiretroviral therapy was halted on the day of thetransplant, and the patient had to receive a second stem cell transplant 13days after the first one, due to a further relapse of leukaemia.
The patient continued to receive immunosuppressive treatmentto prevent rejection for 38 months, and at 5, 24 and 29 months post-transplantcolon biopsies were taken to investigate possible graft-versus-host disease inthe intestine. At each investigation additional samples were taken to check forsigns of HIV infection in the abundant immune cells of the gut wall.
During the 38 month follow-up period the donor CD4 cellsrepopulated the mucosal immune system of the gut, to such an extent that thefrequency of CD4 cells was almost twice as high as in HIV-negative healthycontrols, and this phenomenon was also seen in a control group of tenHIV-negative individuals who received stem cell transfers.
The repopulation of CD4 cells was accompanied by thecomplete disappearance of host CD4 cells, and after two years the patient hadthe CD4 count of a healthy adult of the same age.
One of the challenges for any approach to curing HIVinfection is long-lived immune system cells, which need to be cleared before apatient can be cured. In the case of the Berlinpatient CCR5-bearing macrophages could not be detected after 38 months, suggesting thatchemotherapy had destroyed these longer-lived cells, and that they had alsobeen replaced by donor cells.
The German researchers and San Francisco-based immunologistProfessor Jay Levy believe that the findings point to the importance ofsuppressing the production of CCR5-bearing cells, either through transplants orgene therapy.The patient did not resume antiretroviral therapy after thetransplant.
Nevertheless HIV remained undetectable by both viral loadtesting (RNA) and tests for viral DNA within cells, and HIV antibody levelsdeclined to the point that the patient has no antibody reactivity to HIV coreantibodies, and only very low levels of antibodies to the HIV envelopeproteins.
Seventeen months after the transplant the patient developeda neurological condition, which required a brain biopsy and lumbar puncture tosample the cerebrospinal fluid for diagnostic purposes. HIV was alsoundetectable in the brain and the CSF.
An additional indication that HIV is not present lies in thefact that the patient’s CD4 cells are vulnerable to infection with virus thattargets the CXCR4 receptor. If any virus with this preference was stillpresent, the researchers argue, it would be able to swiftly infect the largepopulation of memory CD4 cells that has emerged.
The Berlin patient speaks to the press
The `Berlin patient`,Timothy Ray Brown, a UScitizen who lives in Berlin,was interviewed this week by German news magazine Stern.
His course of treatment for leukaemia was gruelling andlengthy. Brown suffered two relapses and underwent two stem cell transplants,as well as a serious neurological disorder that flared up when he seemed to beon the road to recovery.
The neurological problem led to temporary blindness andmemory problems. Brown is still undergoing physiotherapy to help restore hiscoordination and gait, as well as speech therapy.
Friends have noticed a personality change too: he is muchmore blunt, possibly a disinhibition that is related to the neurologicalproblems.
On beingasked if it would have been better to live with HIV than to have beaten it inthis way he says “Perhaps. Perhaps it would have been better, but I don’t askthose sorts of questions anymore.”
TimothyBrown is now considering a move from Berlin toBarcelona or San Francisco, and, reports Stern magazine, enjoying a drink and acigarette.
Stern also interviewed Dr Gero Hütter, who was in charge of Timothy Brown’s treatment. Dr Hüttertold Stern that as a scientist he was“in the right place, at the right time” and that “for me it is important tohave overthrown the dogma that HIV can never be cured. Something like this isthe greatest thing one can achieve in medical research”.
His course of treatment for leukaemia was gruelling andlengthy. Brown suffered two relapses and underwent two stem cell transplants,as well as a serious neurological disorder that flared up when he seemed to beon the road to recovery.
The neurological problem led to temporary blindness andmemory problems. Brown is still undergoing physiotherapy to help restore hiscoordination and gait, as well as speech therapy.
Friends have noticed a personality change too: he is muchmore blunt, possibly a disinhibition that is related to the neurologicalproblems.
On beingasked if it would have been better to live with HIV than to have beaten it inthis way he says “Perhaps. Perhaps it would have been better, but I don’t askthose sorts of questions anymore.”
TimothyBrown is now considering a move from Berlin toBarcelona or San Francisco, and, reports Stern magazine, enjoying a drink and acigarette.
Stern also interviewed Dr Gero Hütter, who was in charge of Timothy Brown’s treatment. Dr Hüttertold Stern that as a scientist he was“in the right place, at the right time” and that “for me it is important tohave overthrown the dogma that HIV can never be cured. Something like this isthe greatest thing one can achieve in medical research”.
Implications for future approaches to curing HIV infection
If a cure has been achieved in this patient, it points theway towards attempts to develop a cure for HIV infection through geneticallyengineered stem cells.
The German researchers and San Francisco-based immunologistProfessor Jay Levy believe that the findings point to the importance ofsuppressing the production of CCR5-bearing cells, either through transplants orgene therapy.
Scientists were sufficiently intrigued by the Berlin patientthat they met in Berlin in 2009 to discuss how they could coordinate efforts toidentify CCR5-delta32 homozygous donors and expand the supply of stem cellsfrom these donors, for example through sampling blood cells from the umbilicalcord of babies born to mothers who are homozygous for CCR5-delta32, in order toeventually facilitate stem-cell therapy.
Gene therapy techniques which can transform stem cells – andall their descendents – into cells resistant to HIV entry may be a morepractical option than looking for matching donors.
Several USresearch groups announced in October 2009 that they had received funding toexplore techniques for engineering and introducing CCR5-deficient stem cells.
If these approaches prove successful they will be expensive,so in the early stages it is likely that they would be reserved for people withno remaining treatment options or a cancer requiring bone marrow or stem celltransfer.
As Timothy Brown’s experience shows, curing HIV infectionthrough ablative chemotherapy, immunosuppressive drugs and stem cell transferis not a course of treatment for the faint-hearted. It has required courage,determination and a lot of support to become the first person to be pronounced`cured` of HIV infection.
The German researchers and San Francisco-based immunologistProfessor Jay Levy believe that the findings point to the importance ofsuppressing the production of CCR5-bearing cells, either through transplants orgene therapy.
Scientists were sufficiently intrigued by the Berlin patientthat they met in Berlin in 2009 to discuss how they could coordinate efforts toidentify CCR5-delta32 homozygous donors and expand the supply of stem cellsfrom these donors, for example through sampling blood cells from the umbilicalcord of babies born to mothers who are homozygous for CCR5-delta32, in order toeventually facilitate stem-cell therapy.
Gene therapy techniques which can transform stem cells – andall their descendents – into cells resistant to HIV entry may be a morepractical option than looking for matching donors.
Several USresearch groups announced in October 2009 that they had received funding toexplore techniques for engineering and introducing CCR5-deficient stem cells.
If these approaches prove successful they will be expensive,so in the early stages it is likely that they would be reserved for people withno remaining treatment options or a cancer requiring bone marrow or stem celltransfer.
As Timothy Brown’s experience shows, curing HIV infectionthrough ablative chemotherapy, immunosuppressive drugs and stem cell transferis not a course of treatment for the faint-hearted. It has required courage,determination and a lot of support to become the first person to be pronounced`cured` of HIV infection.
Reference
Allers K et al. Evidencefor the cure of HIV infection by CCR5Δ32/ Δ32 stem cell transplantation.Blood, advance online publication December 8, 2010.
Hutter G et al. Transplantationof selected or transgenic blood stem cells – a future treatment for HIV/AIDS.J Int AIDS Soc 12: 10, 2009.
Hutter G et al. Long-termcontrol of HIV by CCR5 CCR5Δ32/ Δ32 stem-cell transplantation. N Engl JMed. 360: 692-8, 2009.
Thanks to Greta Hughson for translation.
Hutter G et al. Transplantationof selected or transgenic blood stem cells – a future treatment for HIV/AIDS.J Int AIDS Soc 12: 10, 2009.
Hutter G et al. Long-termcontrol of HIV by CCR5 CCR5Δ32/ Δ32 stem-cell transplantation. N Engl JMed. 360: 692-8, 2009.
Thanks to Greta Hughson for translation.
