December 15th, 2010

[BLOG-LIKE POSTING] On what the HIV cure really means

I noted back in 2008 a curious story suggesting that an American man living in Germany had been cured of his HIV infection as a by-product of his leukemia treatment.

Berlin-based hematologist Gero Huetter claimed on Thursday that he has cured an HIV infection in a 42-year-old man through a bone-marrow transplant.

The patient, a U.S. citizen living in Germany, was suffering from advanced leukemia and HIV two years ago when Huetter treated the cancer with a bone-marrow transplant at Berlin's Charité hospital. As a side experiment, he inserted the bone marrow of a donor naturally resistant to HIV, the virus that causes AIDS. (Researchers have long known that about 1% of Europeans carry a genetic mutation that makes their cells resistant to HIV infection.) Bone marrow produces the cells that HIV attacks. So, the thinking went, inserting marrow that produces HIV-resistant cells might endow the patient with a means to repel the infection. Twenty months after the transplant, Huetter says, the man shows no signs of carrying the virus.


The result, two years later, as described in the paper submitted to Blood?

HIV entry into CD4+ cells requires interaction with a cellular receptor, generally either CCR5 or CXCR4. We have previously reported the case of an HIV-infected patient in whom viral replication remained absent despite discontinuation of antiretroviral therapy after transplantation with CCR5{Delta}32/{Delta}32 stem cells. However, it was expected that the long-lived viral reservoir would lead HIV rebound and disease progression during the process of immune reconstitution. In the present study, we demonstrate successful reconstitution of CD4+ T cells at the systemic level as well as in the gut mucosal immune system following CCR5{Delta}32/{Delta}32 stem cell transplantation, while the patient remains without any sign of HIV infection. This was observed although recovered CD4+ T cells contain a high proportion of activated memory CD4+ T cells, i.e. the preferential targets of HIV, and are susceptible to productive infection with CXCR4-tropic HIV. Furthermore, during the process of immune reconstitution, we found evidence for the replacement of long-lived host tissue cells with donor-derived cells indicating that the size of the viral reservoir has been reduced over time. In conclusion, our results strongly suggest that cure of HIV has been achieved in this patient.


AIDSmap has an extended article that goes into great examining the various tests to which the man--now identified as Berlin resident Timothy Ray Brown--has been subjected to for the last few years, as his doctors try to prove the victory over his leukemia and his HIV.

Antiretroviral therapy was halted on the day of the transplant, and the patient had to receive a second stem cell transplant 13 days after the first one, due to a further relapse of leukaemia.

The patient continued to receive immunosuppressive treatment to prevent rejection for 38 months, and at 5, 24 and 29 months post-transplant colon biopsies were taken to investigate possible graft-versus-host disease in the intestine. At each investigation additional samples were taken to check for signs of HIV infection in the abundant immune cells of the gut wall.

During the 38 month follow-up period the donor CD4 cells repopulated the mucosal immune system of the gut, to such an extent that the frequency of CD4 cells was almost twice as high as in HIV-negative healthy controls, and this phenomenon was also seen in a control group of ten HIV-negative individuals who received stem cell transfers.

The repopulation of CD4 cells was accompanied by the complete disappearance of host CD4 cells, and after two years the patient had the CD4 count of a healthy adult of the same age.

One of the challenges for any approach to curing HIV infection is long-lived immune system cells, which need to be cleared before a patient can be cured. In the case of the Berlin patient CCR5-bearing macrophages could not be detected after 38 months, suggesting that chemotherapy had destroyed these longer-lived cells, and that they had also been replaced by donor cells.

The patient did not resume antiretroviral therapy after the transplant.

Nevertheless HIV remained undetectable by both viral load testing (RNA) and tests for viral DNA within cells, and HIV antibody levels declined to the point that the patient has no antibody reactivity to HIV core antibodies, and only very low levels of antibodies to the HIV envelope proteins.

Seventeen months after the transplant the patient developed a neurological condition, which required a brain biopsy and lumbar puncture to sample the cerebrospinal fluid for diagnostic purposes. HIV was also undetectable in the brain and the CSF.

An additional indication that HIV is not present lies in the fact that the patient’s CD4 cells are vulnerable to infection with virus that targets the CXCR4 receptor. If any virus with this preference was still present, the researchers argue, it would be able to swiftly infect the large population of memory CD4 cells that has emerged.


The article goes on to describe how, inspired by this apparent success, "[scientists were sufficiently intrigued by the Berlin patient that they met in Berlin in 2009 to discuss how they could coordinate efforts to identify CCR5-delta32 homozygous donors and expand the supply of stem cells from these donors, for example through sampling blood cells from the umbilical cord of babies born to mothers who are homozygous for CCR5-delta32, in order to eventually facilitate stem-cell therapy." Apparently gene-therapy techniques have are already in development

Why isn't Brown's success a cure in itself, ready for mass use? It's an incredibly difficult, expensive, and dangerous course of treatment.

"Our phones have been ringing off the hook," said Dr. Margaret Fischl, director of the AIDS clinical research unit at the University of Miami Miller School of Medicine. "We are having patients calling us and asking if they can stop their antiretroviral therapy -- and the answer is uncategorically no."

The theory is that if you could wipe out every infected cell you could cure HIV, Fischl said, but this is a unique case.

The patient had intense chemotherapy and radiation, then relapsed and was given a second transplant from the same donor. The donor was unique in that he had a gene that could fight the most common form of HIV. This mutation is seen in about one in every million people, Fischl explained.

"How much did a second transplant contribute to the slow takeover of the donor cells that are resistant to one form of HIV? The extent that that happened is remarkable," she said.

However, this patient also was infected with another form of HIV as well, Fischl said. "What they are hoping is that the chemotherapy and radiation therapy wiped out that form, too. Could that patient still rebound with HIV in the future? Yes," she said.

This treatment also carries with it a 30 percent risk of death, Fischl added.

"That he was young and got through it is quite remarkable," she said. "I would never give this to a healthy patient. I could never justify it. If you use this therapy, 30 percent of your patients could die from the intervention."


Indeed, the AIDSMap article has a telling paragraph: "On being asked if it would have been better to live with HIV than to have beaten it in this way he says “Perhaps. Perhaps it would have been better, but I don’t ask those sorts of questions anymore."

It's worth noting that the specific mutation that gives a low single-digit percentage of Europeans immunity to HIV infection isn't present among populations of non-European background, limiting the applicability of this technique to the vast majority of HIV-infected people around the world. The hype is, sadly, overstated. The sort of comments that yo0u find in this CNN comment thread explains why people should be careful.

Besides being something very good for Brown, the importance of his medical experience is that it demonstrates that doctors do understand HIV well enough to treat it. They know how it replicates; they know how it can be knocked out of a body. Add this story to a selection of other news items--last year's annoouncement of a partially successful HIV vaccine, the discovery of antibodies effective against HIV in one long-term infected person and the implication for medicine, the extended life spans that people enjoying good medical care can now expect and the discovery that this same treatment can limit the further spread of the virus--which demonstrate that HIV is on its way to being another mastered medical conditions. (Would that it wasn't decades and tens of millions of lives after it appeared.)