By Jerome Groopman
Stunning success in medicine can be born from abject failure. This week, researchers reported in the journal Nature what they hope will be a triumph: a man in London who had H.I.V. and may have been cured of the infection. This promising outcome is the direct result of earlier, unsuccessful attempts at a cure. The London Patient, as he is being called, first contracted H.I.V. and then later developed Hodgkin’s lymphoma. The cancer was resistant to standard chemotherapy, so his doctors advised more intensive chemotherapy, along with a bone-marrow transplant.
Bone-marrow transplant is a drastic treatment that originated for humans in the nineteen-fifties. At the time, the spectre of Hiroshima and Nagasaki and atomic warfare filled the public consciousness. People exposed to radiation died because their bone-marrow stem cells were destroyed, and their bodies could no longer make blood. Researchers thought that bone-marrow cells from healthy donors could be a remedy and, by extension, that they could potentially help people with leukemia, lymphoma, and other cancers, the treatments for which also damaged marrow cells. By 1970, bone-marrow transplants had been attempted in two hundred patients around the world. But the transplants failed to take, and most of the patients died terrible deaths from bleeding or infection. The treatment itself is toxic, and some critics demanded that it be abandoned. Determined researchers, however, such as E. Donnall Thomas, were not ready to give up. Thomas retreated to his laboratory and, working with dogs, figured out the barriers that were preventing successful transplantation. Although the treatment is still toxic, over the years it has advanced to a greater level of safety and, with it, a high level of success. The lives of innumerable people with cancer have been restored by transplanting healthy marrow stem cells. Thomas was awarded the Nobel Prize for this work, in 1990.
The second setback that led to success with the London Patient involves an attempt to cure H.I.V. I was involved in that work, collaborating with the biotech company Genentech. (In parallel, David Ho, now at the Rockefeller Institute, was collaborating with Biogen, another biotech company.) At the time, it was thought that H.I.V. infected the body by attaching itself to a protein, called CD4, on the surface of immune cells, which defend the body against pathogens.
The idea was to produce decoy forms of CD4 that would be infused into the bloodstream of people with aids. The virus would attach to the decoy and become stuck, unable to free itself to move through its normal portal of entry. Studies in the laboratory and in subhuman primates were wildly positive, and were published in Nature and Science, and featured on the front page of the Times. Then, in parallel with Ho, I conducted the first clinical trials of decoy CD4 in patients. We expected that the levels of the virus would plummet in short order, and that eventually the pathogen would disappear entirely. But the decoy treatment had no impact whatsoever. Our failure showcased the fact that we did not fully understand how H.I.V. entered immune cells. Further research ultimately revealed that the virus also uses other proteins on the surface of cells. One of them is called CCR5. To highlight its role, epidemiological studies identified individuals who had been repeatedly exposed to H.I.V. but never contracted it. It turned out they had inherited a mutation, so CCR5 was not present on their immune cells. The mutation was innocuous, having no deleterious health consequences. But the discovery of why we had failed sparked the idea that the mutation could be exploited to benefit people with H.I.V.
That is what was done for the London Patient. He received bone-marrow stem cells from a healthy donor who had the CCR5 mutation. When the London Patient’s immune system regrew after the transplant, it lacked the protein and was impervious to the H.I.V. he had contracted. Unable to take root in his cells, the virus appears to have passed.
The London Patient is now the second such case, after the so-called Berlin Patient, Timothy Brown, who was infected with H.I.V. and then developed leukemia, and received a transplant in 2007. The treatment at the time was enormously costly and dangerous, and Brown nearly died, but by 2009 his H.I.V. was in remission. It has taken a decade to replicate that success. The London Patient, fortunately, did not require radiation or repeated transplantation, as Brown did, only chemotherapy to eradicate his lymphoma and then donor stem cells to restore his depleted bone marrow.
No one is suggesting that people with H.I.V. who do not also have cancer should risk a bone-marrow transplantation, with its toxic side effects. But these two cases provide a proof of principle about the potential of stem cells that lack CCR5. How might this be further pursued? There are recent breakthroughs in methods, such as crispr, to alter genes in cells. Those techniques may be used to genetically alter the cells of people with H.I.V., inactivating the CCR5 gene. Those people should then become resistant to the virus, and hopefully recapitulate the outcomes of the Berlin and London patients.
While this week’s news speaks to how failures can give birth to success for individuals, there is also news about how incremental success may translate into benefits for a broader population. Last month, Anthony Fauci, of the National Institutes of Health, and Robert Redfield, of the Centers for Disease Control and Prevention—who have both made sustained contributions to combatting aids—together with leaders of governmental health agencies, laid out a plan to end the spread of H.I.V. in the United States. The plan, which was published as an editorial in the Journal of American Medical Association, gives substance to the goal, which President Trump announced last month in his State of the Union address, to end the H.I.V. epidemic in the United States within ten years. The plan builds on decades of developing numerous effective antiviral drugs, which can reduce the level of H.I.V. in a patient to such a degree that it becomes “undetectable.” At that point, it also becomes “untransmittable”—the patient can no longer infect another person. –New Yorker
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