Background:
Antiretroviral therapy (ART) fails to fully restore immune function and is not curative, therefore more effective therapies are required for people with HIV (PWH). A cure for HIV has previously been observed in several individuals in which bone marrow transfer of CCR5-modified stem cells for leukemia treatment was also found to eliminate HIV. While these results are encouraging, a less invasive and more broadly applicable curative strategy is warranted. Transfer of autologous CCR5-modified CD4 T cells has been found to be safe and well-tolerated in PWH. However, whether this treatment re-programs the immune response to provide long-term viral control is unknown.
Methods:
We performed two clinical studies, SB-728-902 (n = 9) and SB-728-1101 (n = 9), in which participants were provided a single infusion of autologous CCR5-modified T cells and ART was either maintained or interrupted (ATI), respectively. At 3-6 timepoints over 6 years, we collected blood samples and comprehensively profiled the immune response using multi-parameter flow cytometry and single-cell RNA sequencing.
Results:
A single infusion of autologous CCR5-modified CD4 T cells led to a significant increase in absolute CD4 T cell count (+162 cells/μL, P = 0.02), reduced integrated HIV DNA (P = 0.004) in patients on ART (SB-728-902) and control of plasma viremia (for 1 to 6 years) upon ATI in 5 participants (SB-728-1101). These outcomes were associated with high frequencies of CCR5-modified CD45RAintCD45ROint CD4 T cells that had a quiescent metabolic profile (high oxidative phosphorylation) and were enriched in pathways/markers that regulate stemness (i.e., TCF1 protein, WNT/b-catenin signaling and TGF-b cascades). Single-cell trajectory analyses showed that this population gave rise to an effector CD4 T cell population which expressed high interferon inducible anti-viral genes. Higher frequencies of this subset were associated with both heightened effector CD8 T cell responses and reduced viral load.
Conclusions:
Our results indicate that a single infusion of autologous CCR5-modified CD4 T products that are enriched in the novel CD45RAintCD45ROint stem-like phenotype are protected against HIV “re-infection” because they express mutated CCR5, which favors this anti-viral signature. This protection from infection promotes long-lasting effector CD4/8 T cell responses that can control viremia and facilitate a functional cure against HIV.