CROI 2025 Abstract eBook

Abstract eBook

Poster Abstracts

531

Sustained HIV Remission Despite Transient Rebound Viremia After a CCR5∆32/∆32 Stem Cell Transplant Paul Rubinstein 1 , Liliana Pérez 2 , Damiano Rondelli 1 , Hannah Shepard 2 , Karen Sweiss 1 , Shrihari Kadkol 1 , Habiba Sultana 1 , Christine Fennessey 3 , Brandon Keele 3 , Robert Gorelick 3 , Peter Burbelo 4 , Rick Novack 1 , Frank Maldarelli 5 , Eli A. Boritz 2 1 University of Illinois at Chicago, Chicago, IL, USA, 2 National Institute of Allergy and Infectious Diseases, Baltimore, MD, USA, 3 Frederick National Laboratory for Cancer Research, Frederick, MD, USA, 4 National Institute of Dental and Craniofacial Research, Bethesda, MD, USA, 5 National Institutes of Health, Bethesda, MD, USA Background: Five persons have been reported to achieve long-term HIV remission through CCR5∆32/∆32 allogeneic stem cell transplantation (SCT). Dynamics of HIV elimination after SCT are uncertain, and there are no data regarding timing of analytic treatment interruption (ATI) post SCT. Here we report sustained HIV remission despite HIV reactivation following CCR5∆32/∆32 SCT. Methods: The HEME-17 protocol evaluates persons with HIV pre- and post allogeneic CCR5∆32/∆32 SCT, with analysis of coreceptor tropism (Trofile), frequent single copy determination of HIV RNA in plasma and HIV RNA and DNA in peripheral blood mononuclear cells (PBMCs). Chimerism is monitored by standard assays, and persistence of wild-type (wt) CCR5 DNA post-SCT is assessed by PCR. HIV env sequences in plasma are determined by single-genome sequencing, and env tropism predicted using Geno2pheno. Plasma antibodies to HIV gp120, p24, RT, and MA are quantified by luciferase immunoprecipitation assays. Antigen-reactive T cells in PBMC were quantified by staining for activation induced markers and intracellular cytokines. Results: A 67-year-old man with HIV and acute myeloid leukemia (AML) received reduced-intensity SCT from a 10/10 CCR5∆32/∆32 matched unrelated donor; SCT was successful, (100% engraftment by 1 month). Plasma HIV-1 RNA declined to <0.3 c/mL and HIV RNA/DNA in PBMC declined to <0.3 copy/ million cells (Fig.1). At 12 months, wt CCR5 DNA was undetectable in PBMC (Fig. 1). Anti-HIV antibodies declined to levels comparable to those of HIV uninfected controls, and HIV-reactive CD8 and CD4 T cells were undetectable. HIV rebounded (780, 300 copies/ml at weeks 8 and 9 following ATI) and ART was reintroduced . Despite rebound, no cell-associated HIV-1 RNA or DNA was identified in PBMCs (< 0.14 copies/million), which remained 100% donor (Fig. 1). HIV env sequences in rebound HIV were predicted to be R5-tropic. HIV RNA/DNA and HIV-reactive CD8 and CD4 T cells were undetectable in PBMC at rebound or thereafter. A second ATI was initiated 24 months after ART re initiation which resulted in 7-month and ongoing HIV remission. Conclusions: We report the first known case of sustained HIV remission after documented HIV-1 reactivation on ATI following CCR5∆32/∆32 SCT. Rebound does not rule out eradication or the possibility of HIV cure post SCT. Understanding dynamics of host, virus, and treatment factors after CCR5∆32/∆32 allogeneic SCT is essential to advance CCR5-gene-based approaches in HIV cure research. The figure, table, or graphic for this abstract has been removed. HIV Remission After Allogeneic Hematopoietic Stem Cell Transplant From CCR5Δ32/Δ32 Sibling Donor Marius Trøseid 1 , Anders E. Myhre 1 , Hanne H. Gullaksen 2 , Ole Søgaard 3 , Martin Tolstrup 3 , Maria Salgado 4 , Javier Martinez-Pìcado 4 , Anne-Marte B. Kran 5 , Dag Henrik Reikvam 1 , Pål Aukrust 1 , Tobias Gedde-Dahl 1 , Tuva B. Dahl 1 , Mari Kaarbo 1 , Malin H. Meyer-Myklestad 1 , for the Oslo HIV Cure Study Group 1 Oslo University Hospital, Oslo, Norway, 2 University of Oslo, Oslo, Norway, 3 Aarhus University, Aarhus, Denmark, 4 IrsiCaixa, Badalona, Spain, 5 Norwegian Institute of Public Health, Oslo, Norway Background: To date, a few cases of HIV remission after allogeneic hematopoietic stem cell transplantation (HSCT) have been reported. While most involved CCR5Δ32/Δ32 donors, there have been recent reports of remission without this mutation, suggesting that factors beyond CCR5 might be sufficient for remission. Further reports of HIV remission are crucial to understand the factors that influence the transition to donor dominance and the loss of viral reservoirs. Here, we present the Oslo patient, who is in remission 48 months after HSCT from a CCR5Δ32/Δ32 sibling donor. Methods: We examined HIV-specific T cell responses (proliferative and cytokine responses), serum avidity, western blot, donor chimerism, quantified the HIV reservoir (CD4+ cells from blood and CD45+ cells from ileum and colon) by intact proviral DNA assay (IPDA) and proviral HIV DNA by droplet digital PCR

(ddPCR), and viral outgrowth assay (qVOA) up to 24 months post analytical treatment interruption (ATI). The patient was included in IciStem 2.0 (IciS2-56). Results: A 58-year-old male with a 14-year history of HIV-1 clade B, CCR5 tropism, and suppressed viremia underwent HSCT for myelodysplastic syndrome. The graft came from his HLA-identical brother with CCR5Δ32/Δ32, whereas the patient carried CCR5Δ32/wt. He developed severe acute graft versus host disease (GvHD) of the gut and skin and was treated with the Janus kinase inhibitor (JAKi) ruxolitinib. T-cell reconstitution was achieved within a year. Complete donor chimerism in peripheral blood was documented by day 90 and later in gut-associated lymphoid tissues (GALT). Post HSCT, plasma HIV RNA remained undetectable, and at 24 months, ATI was initiated. Twenty-four months into ATI, HIV-specific CD4+ and CD8+ T cell responses were absent, serum HIV avidity showed weak functional affinity, and western blot showed waning HIV-1-specific antibody responses. Traces of HIV DNA were found in GALT, but no intact HIV DNA was detected in blood or GALT. Importantly, no replication competent virus was detected in 65 million CD4+ T cells by qVOA. Conclusions: We report a novel case of HIV remission after HSCT from a sibling donor, confirmed by extensive translational work-up. The donor’s CCR5Δ32/Δ32 variant likely prevented reseeding of HIV to the allograft and prolonged GvHD possibly facilitated complete donor chimerism of GALT. Like the Geneva patient, he was treated with JAKi, which may reduce viral reservoirs. The Oslo patient adds valuable evidence to understanding HIV remission after HCST. Tazemetostat Enhances CTL Killing of HIV-Infected Cells and Reduces Reservoirs In Vivo Andrea Gramatica 1 , Itzayana G. Miller 1 , Adam R. Ward 1 , Farzana Khan 1 , Tyler J. Kemmer 1 , Jared Weiler 1 , Tan Thinh Huynh 1 , Paul Zumbo 1 , Andrew P. Kurland 2 , Louise Leyre 1 , Colin M. Kovacs 3 , Doron Betel 1 , Jeffrey Johnson 2 , Ali Danesh 1 , R. Brad Jones 1 1 Weill Cornell Medicine, New York, NY, USA, 2 Mount Sinai School of Medicine, New York, NY, USA, 3 University of Toronto, Toronto, Canada Background: HIV reservoirs in CD4 + T cells may be selected for the ability to evade immune clearance, hindering HIV cure efforts. Overexpression of enhancer of zeste homolog 2 (EZH2) in HIV-infected CD4 + T cells that survive cytotoxic T lymphocyte (CTL) exposure suggests a putative mechanism of immune resistance. This study investigated whether inhibition of EZH2 with the FDA-approved drug tazemetostat (taz) can enhance immune-mediated elimination of HIV reservoirs. Methods: We performed RNA sequencing on in vitro HIV-infected CD4 + T cells that survived CTL exposure to assess EZH2 expression. The impact of taz on MHC-I expression and CTL-mediated killing was also evaluated in vitro using primary CD4 + T cells from people with HIV (PWH) (n=6). Viral inhibition assays with or without taz treatment measured suppression of HIV replication over seven days. In a participant-derived xenograft (PDX) mouse model, we examined the effects of taz on MHC-I expression, reservoir seeding, and CD8 + T-cell phenotypes, including exhaustion markers. Results: EZH2 was significantly overexpressed in HIV-infected CD4 + T cells that survived CTL exposure (p.adj. <0.05). In vitro taz treatment reduced H3K27me3 levels and increased surface MHC-I expression by 1.4-fold on CD4 + T cells, counteracting HIV Nef–mediated MHC-I downregulation. This enhancement improved CTL-mediated elimination of HIV-infected cells by up to 90% and significantly suppressed viral replication. In the PDX mouse model, taz increased expression of MHC-I and the pro-apoptotic protein BIM in CD4 + T cells, facilitating CD8 + T-cell–mediated reduction of HIV reservoir seeding. Mice treated with both taz and autologous CD8 + T cells showed a significant decrease in intact HIV proviruses compared to controls (p.adj <0.05). Additionally, taz promoted sustained skewing of CD8 + T cells toward less differentiated (increased TCF-1) and less exhausted (lower PD-1) phenotypes, persisting for at least 79 days post-treatment. Conclusions: Our findings identify EZH2 overexpression as a novel mechanism of CTL-resistance in HIV-infected CD4 + T cells. Inhibition of EZH2 with tazemetostat enhances immune recognition and elimination of these cells by increasing MHC-I expression and modulating apoptotic pathways. The reduction in HIV reservoir formation and improvement in CD8 + T-cell phenotypes support tazemetostat as a therapeutic strategy to enhance clearance of HIV reservoirs. These results warrant clinical evaluation of tazemetostat in PWH towards a cure for HIV.

533

Poster Abstracts

532

The figure, table, or graphic for this abstract has been removed.

CROI 2025 138