HIV depletes the number of CD4+ T cells, and causes AIDS by essentially erasing the immune system. To enter a T cell an HIV viral particle must have correct keys to a door on the surface of a T cell. The door opens only when an HIV viral particle "touches down" and attaches to two receptors on the surface of a CD4+ T cell, CD4 and CCR5. While an HIV viral particle always binds to the CD4 receptor, in a small number of people, especially of European Caucasian descent, CCR5 receptor could be mutated, and the "key" on the surface of the HIV virus does not "fit" the receptor on the surface of the T cell. In this case, CD4+ T cells stay HIV free.
This is what happened in the case of "Berlin patient" Timothy Ray Brown. He has been living with HIV since 1995 controlling it with anti-retroviral drugs. In 2007 he was diagnosed with leukemia. As a part of treatment for leukemia he underwent a hematopoetic stem cell transplant (HSCT, A.K.A. bone marrow transplant,) from an unrelated donor, who actually had a mutation in the genetic code of the CCR5 receptor. As a result of such a transplantation, Timothy's new T cells are impervious to HIV. Whatever HIV he had in his own T cells was presumably wiped out with his entire own immune system in preparation for the transplant. He remains HIV free since 2008.
It did not require a giant intellectual leap to propose blocking CCR5 receptors to make CD4+ T cells resistant to HIV. In this case the door on the surface of T cells stays locked, and a person, HIV free. Based on this premise so called entry inhibitors were developed that prevented an HIV virus touching CCR5 receptor. At the same time, those who already have HIV will likely benefit as well. Those T cells infected with HIV make and release new viral particles. But HIV-free T cells with blocked CCR5 receptors are protected from the viral entry. CD4+ T cells already infected with HIV die, while those with blocked CCR5 receptors remain uninfected. Over time, at least in theory, all HIV infected cells will die, including those that harbor so called "HIV reservoir," that remains dormant on anti-viral medications. The end result, complete HIV cure.
One of problems with this approach is that CCR5 blocking is not 100% efficient, and the virus gets through. How to make this fence impenetrable?
Well, a new study published in NEJM reported building such a fence by editing CCR5 gene in CD4+ T cells. HIV-positive patients with undetectable viral loads and sufficiently high levels of CD4 T-cells had some of their CD4+ T cells removed, genetically edited to introduce a specific mutation into the gene coding for CCR5 receptor, and infused back. Following the transfusion, six out of 12 study participants went off anti-viral treatment for 3 months. In these patients the load of HIV increased, but the decline in modified CD4+ T cells was significantly lower than in those unmodified ones.
This is a very encouraging results, to say the least. If the number of CCR5-modified CD4+ T cells could stay the same or even increase, over time infected CD4+ T cells will die leaving the patient HIV-free. The reason why the number of CCR5-modified cells also decreased is the following. Each cell has two copies of the same gene, one from each parent. Thus one needs to edit both copies in each CD4+ T cells. The gene editing method proposed in the study did not "edit" each copy of the CCR5 gene, resulting in reduced but existing susceptibility to HIV entry.
There was, however, one patient who inherited one copy of CCR5-mutated gene from one of parents. His CD4+ T cells, as all his cells, had one of two copies of CCR5 genes already mutated but it was not enough to protect him from contracting HIV. But he only needed to have one copy of CCR5 gene edited in CD4+ T cells. Therefore for him, effectiveness of gene editing was much much higher, and his viral load remained undetectable after he received the infusion of gene-edited CD4+ T cells and went off anti-viral therapy.
This is a remarkable study shows the proof in principle and safety of the gene-editing approach. It seems to be only a matter of time, and probably not too distant, when someone will effectively edit both copies of the CCR5 gene to make them insensitive to HIV. HIV will become history then.
This is what happened in the case of "Berlin patient" Timothy Ray Brown. He has been living with HIV since 1995 controlling it with anti-retroviral drugs. In 2007 he was diagnosed with leukemia. As a part of treatment for leukemia he underwent a hematopoetic stem cell transplant (HSCT, A.K.A. bone marrow transplant,) from an unrelated donor, who actually had a mutation in the genetic code of the CCR5 receptor. As a result of such a transplantation, Timothy's new T cells are impervious to HIV. Whatever HIV he had in his own T cells was presumably wiped out with his entire own immune system in preparation for the transplant. He remains HIV free since 2008.
It did not require a giant intellectual leap to propose blocking CCR5 receptors to make CD4+ T cells resistant to HIV. In this case the door on the surface of T cells stays locked, and a person, HIV free. Based on this premise so called entry inhibitors were developed that prevented an HIV virus touching CCR5 receptor. At the same time, those who already have HIV will likely benefit as well. Those T cells infected with HIV make and release new viral particles. But HIV-free T cells with blocked CCR5 receptors are protected from the viral entry. CD4+ T cells already infected with HIV die, while those with blocked CCR5 receptors remain uninfected. Over time, at least in theory, all HIV infected cells will die, including those that harbor so called "HIV reservoir," that remains dormant on anti-viral medications. The end result, complete HIV cure.
One of problems with this approach is that CCR5 blocking is not 100% efficient, and the virus gets through. How to make this fence impenetrable?
Well, a new study published in NEJM reported building such a fence by editing CCR5 gene in CD4+ T cells. HIV-positive patients with undetectable viral loads and sufficiently high levels of CD4 T-cells had some of their CD4+ T cells removed, genetically edited to introduce a specific mutation into the gene coding for CCR5 receptor, and infused back. Following the transfusion, six out of 12 study participants went off anti-viral treatment for 3 months. In these patients the load of HIV increased, but the decline in modified CD4+ T cells was significantly lower than in those unmodified ones.
This is a very encouraging results, to say the least. If the number of CCR5-modified CD4+ T cells could stay the same or even increase, over time infected CD4+ T cells will die leaving the patient HIV-free. The reason why the number of CCR5-modified cells also decreased is the following. Each cell has two copies of the same gene, one from each parent. Thus one needs to edit both copies in each CD4+ T cells. The gene editing method proposed in the study did not "edit" each copy of the CCR5 gene, resulting in reduced but existing susceptibility to HIV entry.
There was, however, one patient who inherited one copy of CCR5-mutated gene from one of parents. His CD4+ T cells, as all his cells, had one of two copies of CCR5 genes already mutated but it was not enough to protect him from contracting HIV. But he only needed to have one copy of CCR5 gene edited in CD4+ T cells. Therefore for him, effectiveness of gene editing was much much higher, and his viral load remained undetectable after he received the infusion of gene-edited CD4+ T cells and went off anti-viral therapy.
This is a remarkable study shows the proof in principle and safety of the gene-editing approach. It seems to be only a matter of time, and probably not too distant, when someone will effectively edit both copies of the CCR5 gene to make them insensitive to HIV. HIV will become history then.
