Stem cell transplantation

Stem cell transplantation

In 2007, a 40-year-old HIV-positive man was given a stem cell transplant as part of his treatment for acute myelogenous leukemia (AML).[203] A second transplant was made a year later after a relapse. The donor was chosen not only for genetic compatibility but also for being homozygous for a CCR5-Δ32 mutation that confers resistance to HIV infection.[204][205] After 20 months without antiretroviral drug treatment, it was reported that HIV levels in the recipient's blood, bone marrow, and bowel were below the limit of detection.[205] Virus remained undetectable over three years after the first transplant.[203] Although the researchers and some commentators have characterized this result as a cure, others suggest that the virus may remain hidden in tissues[206] such as the brain (a viral reservoir).[207] The treatment is not considered widely applicable because of its anecdotal nature; the disease and mortality risk associated with stem cell transplants; and the difficulty of finding suitable donors.[206][208]

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What is CCR5-Δ32
CCR5-Δ32

CCR5-Δ32 (or CCR5-D32 or CCR5 delta 32) is a genetic variant of CCR5.[6][7]

CCR5-Δ32 is a deletion mutation of a gene that has a specific impact on the function of T cells[citation needed]. At least one copy of CCR5-Δ32 is found in about 10% of people of Northern Europe and in those of Northern European descent. It has been hypothesized that this allele was favored by natural selection during the Black Death. This coalescence date is contradicted by purported evidence of CCR5-Δ32 in Bronze Age samples, at levels comparable to the modern European population.[8] Smallpox may be another candidate for the high level of the mutation in the European population.[6]

The allele has a negative effect upon T cell function, but appears to protect against smallpox and HIV. Yersinia pestis was demonstrated in the laboratory not to associate with CCR5. Individuals with the Δ32 allele of CCR5 are healthy, suggesting that CCR5 is largely dispensable. However, CCR5 apparently plays a role in mediating resistance to West Nile virus infection in humans, as CCR5-Δ32 individuals have shown to be disproportionately at higher risk of West Nile virus in studies,[9] indicating that not all of the functions of CCR5 may be compensated by other receptors.

While CCR5 has multiple variants in its coding region, the deletion of a 32-bp segment results in a nonfunctional receptor, thus preventing HIV R5 entry; two copies of this allele provide strong protection against HIV infection.[10] This allele is found in 5-14% of Europeans but is rare in Africans and Asians.[11] Multiple studies of HIV-infected persons have shown that presence of one copy of this allele delays progression to the condition of AIDS by about 2 years. CCR5-Δ32 decreases the number of CCR5 proteins on the outside of the CD4 cell, which can have a large effect on the HIV disease progression rates. It is possible that a person with the CCR5-Δ32 receptor allele will not be infected with HIV R5 strains. Several commercial testing companies offer tests for CCR5-Δ32.[12]

A genetic approach involving intrabodies that block CCR5 expression has been proposed as a treatment for HIV-1 infected individuals.[13] When T-cells modified so they no longer express CCR5 were mixed with unmodified T-cells expressing CCR5 and then challenged by infection with HIV-1, the modified T-cells that do not express CCR5 over time take over the culture as HIV-1 kills the non-modified T-cells. This same method might be used in vivo to establish a virus resistant cell pool in infected individuals.[13]

This hypothesis was tested in an AIDS patient who had also developed myeloid leukemia, and was treated with chemotherapy to suppress the cancer. A bone marrow transplant containing stem cells from a matched donor was then used to restore the immune system. However transplant was performed from a donor with the CCR5-Δ32 mutation gene. After 600 days, the patient was healthy and had undetectable levels of HIV in the blood and in examined brain and rectal tissues.[14][15] Before the transplant, low levels of HIV X4, which does not use the CCR5 receptor, were also detected. Following the transplant, however, this type of HIV was not detected either, further baffling doctors.[15] However, this is consistent with the observation that cells expressing the CCR5-Δ32 variant protein lack both the CCR5 and CXCR4 receptors on their surfaces, thereby conferring resistance to a broad range of HIV variants including HIV X4.[16] After three years, the patient has maintained the resistance to HIV and has been pronounced cured of the HIV infection.[17]

Enrollment of HIV-positive patients in a clinical trial was started in 2009 in which the patients' cells were genetically modified to carry the CCR5-Δ32 trait and then reintroduced into the body as a potential HIV treatment.[18][19]


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