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From Medscape Medical News
Transplant of CCR5-Mutated Stem Cells May Cure HIV
Emma Hitt, PhD

December 20, 2010 — Replacing host stem cells with donor-derived cells homozygous for the CCR5 gene variant Δ32 (CCR5Δ32/Δ32) resulted in the HIV viral reservoir being reduced over time, strongly suggesting that the patient is cured of HIV.

Kristina Allers, PhD, from the Campus Benjamin Franklin, Charité University Medicine in Berlin, Germany, and colleagues reported their findings online December 8 in Blood.

According to background information in the article, the cellular chemokine receptor CCR5 is one of the most common ways that HIV enters CD4+ cells. Individuals homozygous for the CCR5 gene Δ32 allele appear to naturally resist infection with CCR5-tropic HIV strains (R5) because they lack cell surface expression of CCR5.

Stem Cell Transplant With CCR5Δ32/Δ32 cells

The HIV-infected patient underwent stem cell transplantation with a graft containing CCR5Δ32/Δ32 cells in February 2007 because of a relapse of acute myeloid leukemia. Antiretroviral therapy was discontinued on the day of transplantation. The patient had a second relapse 13 months later and received a second stem cell transplant from the same donor.

The current report indicates that the patient's systemic recovery of CD4+ T cells after the stem cell transplantation and discontinuation of antiretroviral therapy was similar to that of 10 control patients who also had stem cell transplants but who were not infected with HIV.

The expansion of activated CD4+ T cells after stem cell therapy usually enriches targets for HIV infection in HIV-infected patients, causing HIV to rebound after stem cell transplantation. However, this individual's CD4+ T cell numbers returned to normal, and HIV remained undetectable.

"Poor recovery of CD4+ T cells in the mucosal immune system is...an important risk factor for the development of HIV disease progression," the authors pointed out. However, the patient's donor-derived CD4+ T cells gradually increased in the gastrointestinal mucosa, with his mucosal CD4+ T cell numbers normalized relative to those of the HIV-uninfected stem cell transplantation control patients.

Increased Numbers of Mucosal CD4+ T cells

In addition, HIV remained undetectable in both gut tissue specimens and mucosal HIV target cell populations of the previously HIV-infected patient. "These findings argue for the absence of HIV disease progression in the largest component of the lymphoid organ system," they conclude.

Both the previously HIV-infected patient and the stem cell transplantation control patients had increased mucosal CD4+ T cell numbers compared with healthy control patients. The authors suggested that this could be explained by the high prevalence of activated/effector memory CD4+ T cells in circulation and by the recovered CD4+ T cells having been efficiently directed to the peripheral lymph nodes.

Patient Remains Susceptible to X4 HIV Infection

The patient's peripheral and mucosal CD4+ T cells remained susceptible to infection with X4 HIV; thus, exogenous HIV reinfection still appears to be a risk, and host cells that survived the chemo-irradiation therapies remained potential sources for the rebound of X4 HIV. However, host-originating CD4+ T cells appeared to be completely removed from the patient's immune system during immune reconstitution; HIV was undetectable in the brain during a neuropathological episode, and no CCR5 expression could be detected in liver tissue sections, indicating the replacement of microglial and Kupffer cells by donor-derived cells.

HIV Eradication Ongoing

The patient remains without any evidence for HIV infection. "Although the recovered CD4+ T cells are susceptible to infection with X4 HIV infection, the patient remains without any evidence for HIV infection since more than 3.5 years after discontinuation of [antiretroviral therapy]," Dr. Allers and colleagues conclude. "From these results, it is reasonable to conclude that cure of HIV infection has been achieved in this patient," they add.

According to Dr. Allers, probably the most important message is that an HIV cure is not completely impossible. "Our study findings are encouraging for the development of new treatment strategies that target the complete inhibition of interaction between HIV and CCR5," she told Medscape Medical News. "It remains to be seen whether this outcome can be replicated in other patients, and in my opinion, the possibility of a 'universal' cure for HIV infection will still need many years."

"We've known about this case for some time" said Paul Sax, MD, from Harvard Medical School in Boston, Massachusetts, "as it was originally presented at the Conference on Retroviruses and Opportunistic Infections in 2008. The findings were published in the New England Journal of Medicine last year," Dr. Sax told Medscape Medical News. "The key is now they have additional length of follow-up and certain other lab findings, such as restoration of gut-associated lymphoid tissue...and a declining titer of HIV antibody," he said.

Transplant Not a Practical Approach for HIV

According to Dr. Sax, a bone marrow transplant from a CCR5Δ32/Δ32 donor is not a practical approach for HIV cure for the millions who have HIV. "The up-front toxicity and risk of death are too high, especially given how safe antiretroviral therapy is now," he said. "Additionally, the proportion of people who have CCR5Δ32/Δ32 as potential donors is very small (especially in non-Caucasians). However, just the fact that it was achieved shows that there might be other strategies that can be more practically deployed — it's very tantalizing."

Certainly the clinicians, the investigators, and the patient who tried this approach in Germany are to be credited for their foresight (and courage) in electing to stop antiretroviral therapy to see whether HIV would not, in fact, rebound. "I'm hopeful that soon there will be additional reports of this or a similar strategy being tried to see if the results can be duplicated," he said.

According to John G. Bartlett, MD, from the Johns Hopkins University School of Medicine in Baltimore, Maryland, the importance of this report is to show it could be done, but the method used cannot be duplicated in others.

"About 2% of people have the CCR5Δ32/Δ32 phenotype and cannot get HIV infection," Dr. Bartlett told Medscape Medical News. "They had to find a donor who was compatible with the patient by routine methods and then find one from that group of 82 who had the Δ32 homology. This was done because the patient had leukemia, but it will not be done for HIV alone, because of the lack of donors and the risk," he explained.

Paving the Way for a "Cure"

The findings have prompted renewed interest in a cure, however. According to Dr. Bartlett, there are several different methods being pursued: emptying the reservoirs with highly active antiretroviral therapy to eliminate HIV, development of a therapeutic vaccine, and methods other than transplant to block receptors. "Many think a cure for HIV is impossible, but they also thought treatment could not be successful for a retrovirus 15 years ago."

The study was supported by the German Research Foundation. The authors and commentators have disclosed no relevant financial relationships.

Blood. Published online December 8, 2010.
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Authors and Disclosures
Journalist
Emma Hitt, PhD