The Conference on Retroviruses and Opportunistic Infections (CROI) is taking place virtually again this year, running from February 12th to February 24th. In a session today on HIV cure research, Yvonne Bryson and colleagues from the IMPAACT research network presented important news about another potential example of an HIV cure achieved by stem cell transplantation.
The case involves a woman living with HIV who was diagnosed with acute myelogenous leukemia (AML), a life-threatening cancer, in 2017. The researchers sourced cord blood stem cells from a donor homozygous for the CCR5Δ32 mutation that prevents expression of the CCR5 co-receptor that most HIV strains use as an entryway into cells. The aim was to treat the cancer while also generating a new immune system made up of HIV-resistant cells, following the model that has produced three other known cases of likely HIV cures in men (Timothy Ray Brown, Adam Castillejo and the Düsseldorf patient).
A difference with prior cases is that stem cells from umbilical cord blood are less efficient at generating a new immune system after transplantation, so the woman also received stem cells from the peripheral blood of an adult relative who lacked the CCR5Δ32 mutation. Shortly after the transplant, most of the immune cells that could be detected were derived from the adult blood stem cells, but over time the proportion of cells derived from the cord blood transplant increased. From day 100 of follow-up, all T cells and myeloid cells (monocyte/macrophages) were progeny of the cord blood transplant and therefore possessed the CCR5Δ32 mutation. As reported at the Annual Meeting of the American Society for Hematology in 2018, remission of AML was achieved and the woman initially continued on antiretroviral therapy (ART) with HIV viral load remaining suppressed.
At CROI today, Yvonne Bryson reported that ART was interrupted three years after the transplant with no HIV viral load rebound. The woman, who’s described as middle aged and of mixed race, has now been off ART for more than 14 months with persistently undetectable HIV viral load (during this time they’ve received COVID-19 vaccination without any untoward effect).
Tests for HIV DNA, a surrogate measure of the HIV reservoir, have also been negative except one detection of trace amounts at an early timepoint after ART cessation. Antibody and T cell responses against HIV are no longer detectable. The absence of ART has been confirmed by measuring drug levels in blood. The researchers have tested the woman’s cells in the laboratory and found them to be resistant to HIV.
The case bolsters the evidence that an HIV cure is achievable and demonstrates that, for people with HIV and certain life-threatening cancers, stem cell transplantation from donors homozygous for the CCR5Δ32 mutation can work in women as well as men.
Bryson pointed out that cord blood stem cell banks can be tested for the presence of the CCR5Δ32 mutation, and the approach used in this case could increase the chances of identifying CCR5-negative donors for people with HIV who require stem cell transplants for cancers (cord blood stem cells have less stringent requirements for matching the genetics of recipients). Background on the use of cord blood stem cell transplants in HIV cure research and the possibilities of identifying matches for people of different races can be found in an overview article published in 2015 by Lawrence Petz and colleagues.
During the same CROI session on HIV cure research, Ole Søgaard provided additional encouragement with a presentation on results from the “eCLEAR” trial, which investigated the broadly neutralizing antibody 3BNC117 and a candidate latency-reversing agent, romidepsin.
The study enrolled 60 participants, approximately half with recent HIV infection (less than 6 months), and randomly assigned them to one of four groups:
- ART alone
- ART plus 3BNC117 at day 7 and 21 after ART initiation
- ART plus romidepsin at day 10, 17 and 24
- ART plus 3BNC117 and romidepsin (administered at the same times listed above)
The primary aim was to assess if administering these interventions around the time of ART initiation could accelerate clearance of the HIV reservoir and promote control of HIV viral load after an analytical treatment interruption (ATI). The rationale derived from a study demonstrating that the persistent HIV reservoir is formed close to the time of ART initiation in a substantial proportion of people with HIV.
Participants were followed for a year and then given the option of undergoing a 12-week analytical treatment interruption (ATI) at day 400 of follow up. The majority of participants were white men; a total of five women were enrolled but none were randomized to receive 3BNC117.
Receipt of 3BNC117 was associated with greater declines in levels of cells expressing HIV RNA and the HIV p24 protein, as well as increases in HIV-specific CD8 T cell responses. Furthermore, four out of the five participants whose pre-ART HIV samples were fully sensitive to 3BNC117 (i.e. no evidence of resistance to the anti-HIV effects of the antibody) maintained HIV viral load below 5,000 copies/ml throughout the 12-week ATI, compared to three of 15 participants who had pre-ART evidence of HIV resistance to 3BNC117 or did not receive the antibody. These effects appeared independent of receipt of romidepsin.
One participant from the 3BNC117 and romidepsin group remains off ART and has maintained undetectable HIV viral load for 3.7 years and counting. In the Q&A session after his talk, Søgaard noted that the HIV reservoir in this individual (as measured by an intact proviral DNA assay) is continuing to shrink in size over time.
Additional information on the association between 3BNC117 and improved CD8 T cell responses will be presented at CROI tomorrow by Míriam Rosás-Umbert (this presentation remains embargoed).
The results indicate that broadly neutralizing antibodies (bNAbs) like 3BNC117 may have the potential to enhance clearance of the HIV reservoir and promote containment of viral load after treatment interruption. Additional ongoing studies involving combinations of bNAbs and ATIs, such as the RIO trial, should shed further light on the efficacy of the approach. Combinations of bNAbs may be necessary to circumvent the problem of baseline HIV resistance to individual antibodies.
Links to the relevant CROI abstracts are below – presentation webcasts will become available on these pages in around 30 days (at the current time access is restricted to conference registrants).
HIV-1 Remission with CCR5Δ32Δ32 Haplo-Cord Transplant in a U.S. Woman: IMPAACT P1107 (abstract 65)
JingMei Hsu, Koen Van Besien, Marshall J. Glesby, Anne Coletti, Savita G. Pahwa, Meredith Warshaw, Amanda Golner, Frederic Bone, Nicole Tobin, Marcie Riches, John W. Mellors, Renee Browning, Deborah Persaud, Yvonne Bryson
The Impact of 3BNC117 and Romidepsin Treatment at ART Initiation on HIV-1 Persistence (abstract 62)
Jesper D. Gunst, Marie H. Pahus, Míriam Rosás-Umbert, Thomas Benfield, Henrik Nielsen, Isik S. Johansen, Rajesh Mohey, Lars Østergaard, Mariane H. Schleimann, Martin Tolstrup, Julie Fox, Michel Nussenzweig, Marina Caskey, Sarah Fidler, Ole Søgaard
Administration of 3BNC117 at ART Initiation Induces Long-Term HIV CD8 T-Cell Immunity (abstract 122)
Míriam Rosás-Umbert, Jesper D. Gunst, Rikke Olesen, Marina Caskey, Michel Nussenzweig, Martin Tolstrup, Ole Søgaard
Helpful media articles on the possible new HIV cure case:
A Woman Is Cured of H.I.V. Using a Novel Treatment - Apoorva Mandavilli, New York Times
Scientists have possibly cured HIV in a woman for the first time - Benjamin Ryan, NBC News
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