The Second Berlin Patient

Though a seventh individual has likely been cured of HIV via a stem cell transplant, a widely applicable cure remains elusive

In July, researchers presented evidence that another individual has likely been cured of HIV. The “second Berlin Patient,” an adult German male born in 1964, joins six others who have been cured by a stem cell transplant to jointly treat their blood cancer and HIV. The first person to be cured, Timothy Ray Brown, was an American living in Berlin, where he underwent the high-risk procedure in 2008. At the time, researchers referred to Brown as the Berlin Patient since he wished to remain anonymous.

Past HIV cure cases (Berlin, London, Düsseldorf, New York, and City of Hope) have involved stem cell transplants in which the donor cells were virtually impervious to HIV—the cells had a double “homozygous” gene mutation for a protein, CCR5, needed for HIV to enter a cell.

But the second Berlin Patient provides new evidence that this double mutation might not be the only path to a cure.

A single mutation

Prof. Christian Gaebler, of Charité–Universitäts-medizin Berlin and one of the study’s principal investigators, shared that the second Berlin patient has been in sustained HIV remission for five and a half years without antiretroviral therapy (ART) after a stem cell transplant of donor cells with only single “heterozygous” gene mutation for CCR5. (The team had been unable to find a donor with two copies of the HIV-resistant mutation.) In this case, the donor cells were fully susceptible to HIV infection, but the research team could find no residue of HIV after years of monitoring.

Similarly, another individual who has been cured, the Geneva Patient, underwent a transplant that used “wild-type” donor cells, with neither of the two genes for CCR5 mutated and, thus, like the second Berlin Patient, should be susceptible to HIV infection.

So how were the second Berlin Patient and the Geneva Patient cured?

Prof. Gaebler suggested that the speed at which the new immune system replaced the old one or the potential presence of special properties of his immune system, such as intensely active natural killer cells, might be explored as explanations.

Graft -versus-host response

Another explanation has been previously offered by amfAR grantee Dr. Jonah Sacha of Oregon Health & Science University. His study, published in the journal Immunity in July 2023, showed that of four monkeys infected with SIV (the simian version of HIV), treated with ART for several months, then transplanted with “wild-type” monkey cells, one was cured, just like the Geneva and second Berlin Patients. The research team linked this cure to “allogeneic immunity,” i.e., a post-transplant graft -versus-host response in which the donor’s T cells and monocytes react against all foreign cells, killing them (including those harboring SIV).

While stem cell transplant cures may provide valuable information about the mechanisms involved in curing HIV, they are too high-risk to make scalable. Widely applicable cure strategies will most likely depend on eradicating or controlling the HIV reservoir, where replication-competent virus lies dormant, through other means. This could involve gene editing to disarm the virus, relying on untapped properties of the body’s own immune system, or finding vulnerabilities in the reservoir and attacking the virus with broadly neutralizing antibodies, natural killer cells, CAR T cells, or immunotherapeutic agents.

amfAR Institute study

A complex trial conducted by the amfAR Institute for HIV Cure Research at the University of California, San Francisco, used an array of these curative strategies in one intervention to promising effect: an HIV DNA vaccine, the immune hormone IL-12, a vaccinia boost vaccine, broadly neutralizing antibodies, and a drug to activate the immune protein TLR9.

Researchers showed that individuals may be able to control HIV, at least in part, when they stop ART as part of this combination immunotherapy. While almost all participants showed signs that the virus persisted during the initial analytic treatment interruption, seven of the 10 did not rebound in the usual way, where a rapid burst of uncontrolled viral growth would be expected. Instead, they were able to control the virus in the absence of therapy. Five of the seven participants had some level of HIV control for at least 100 days off ART, and one of the seven had no detectable virus for 18 months.

While the news of the second Berlin Patient is encouraging, more questions than answers surround curing HIV for everyone, everywhere. And so the research, and amfAR’s pursuit of a cure, continues.

Click Here to read more from the December 2024 issue of amfAR INNOVATIONS.

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