乌鸦传媒

A seventh patient has achieved sustained HIV remission after allogeneic hematopoietic stem cell transplantation, according to a new case report.

What is especially notable about this patient is that he received a transplant with a single, rather than double, mutation of the CCR5 gene (CCR5 wild type [WT]/Δ32), reported Christian Gaebler, MD, of the Charité - Universitätsmedizin Berlin, at the International AIDS Conference in Munich.

The patient, known as the "next Berlin patient," has had undetectable HIV plasma viral loads for more than 5 years and has not taken antiretroviral therapy (ART) since 2018. He joins six other patients who have experienced ART-free HIV remission.

Timothy Ray Brown, the first "Berlin patient" and first patient in the world to be considered cured of HIV, died from a leukemia recurrence in 2020.

"Our main question is really understanding and learning from these extremely rare but successful HIV cure cases," Gaebler told attendees. "What is remarkable about this patient is that he received stem cell transplantation with functional CCR5 receptors. And we believe this is important because it can show that potential HIV cure can be achieved after allogenic stem cell transplantation independent of the CCR5 status."

Until recently, durable HIV remission was only reported in five patients who received stem cell transplants in which the donors had a homozygous mutation in the CCR5 gene (CCR5 Δ32/Δ32). The CCR5 gene encodes for a receptor required for HIV to enter cells and having the rare homozygous mutation confers genetic resistance to HIV infection.

However, last year, another case report emerged of a person with HIV, known as the "Geneva patient," who received a stem cell transplant from a donor with wild-type CCR5 (CCR5 WT/WT) and achieved ART-free remission after the transplant for more than 20 months with no detectable HIV viral levels.

"I think it's important to highlight that roughly 85 million people have been or are living with HIV since the start of the epidemic," Gaebler noted. "This really highlights how rare these HIV cure cases are, and also what the critical needs for scalable solutions really are."

"The next Berlin patient's experience suggests that we can broaden the donor pool for these kinds of cases, although stem cell transplantation is only used in people who have another illness, such as leukemia," said Sharon Lewin, PhD, of the University of Melbourne and president of the International AIDS Society, at a press conference.

"This is also promising for future HIV cure strategies based on gene therapy, because it suggests that we don't have to eliminate every single piece of CCR5 to achieve remission," she added.

The next Berlin patient is a white male born in 1964 and diagnosed with HIV in 2009. Due to the treatment guidelines at the time, ART was not initiated until April 2015, Gaebler said, and the patient was then started on a raltegravir (Isentress)/abacavir/lamivudine regimen.

Around the same time, the patient received a diagnosis of acute myeloid leukemia. Although it became apparent that the patient needed a stem cell transplant, a donor with the CCR5 Δ32/Δ32 homozygous mutation could not be identified.

Instead, a human leukocyte antigen (HLA)-matched unrelated female donor who was heterozygous for CCR5 (CCR5 WT/Δ32) was selected. The patient received reduced-intensity conditioning and developed only mild graft-versus-host disease, which was confined to the skin and effectively managed with topical steroids.

Full donor chimerism -- meaning that 100% of bone marrow and blood cells are of donor origin -- occurred within 28 days of transplantation, and the patient achieved remission of leukemia. The researchers detected no known protective HLA alleles for HIV control in either the donor or recipient.

The patient stopped taking ART in September 2018. Repeated HIV DNA measurements have been negative in peripheral blood, as well as duodenal and ileal biopsies, Gaebler noted.

Also, no viral outgrowth was detected from stimulated CD4+ T cells, HIV-specific antibody levels have decreased, and there are no detectable HIV-specific T-cell responses after transplantation, Gaebler pointed out.

"Seeing that we are coming close to 6 years of HIV remission, I think we can quite confidently say that we can have HIV reservoir reduction, HIV remission, and potentially HIV cure independent of the CCR5 status," Gaebler said. "We really think that effective reservoir reductions, durable HIV remission, and potential cure can be achieved with functional viral co-receptors and we believe that allogenic immunity really fundamentally contributes to HIV eradication."

He added that "some of the questions we have in this case are, what is the role of underlying CCR5 heterozygosity ... and also, what are the contributions of innate immunity and NK [natural killer] cell contributions to reservoir depletion?"

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