Abstract
Due to the durability and persistence of reservoirs of HIV-1-infected cells, combination antiretroviral therapy (ART) is insufficient in eradicating infection. Achieving HIV-1 cure or sustained remission without ART treatment will require the enhanced and persistent effective antiviral immune responses. Chimeric Antigen Receptor (CAR) T-cells have emerged as a powerful immunotherapy and show promise in treating HIV-1 infection. Persistence, trafficking, and maintenance of function remain to be a challenge in many of these approaches, which are based on peripheral T cell modification. To overcome many of these issues, we have previously demonstrated successful long-term engraftment and production of anti-HIV CAR T cells in modified hematopoietic stem cells (HSCs) in vivo. Here we report the development and in vivo testing of second generation CD4-based CARs (CD4CAR) against HIV-1 infection using a HSCs-based approach. We found that a modified, truncated CD4-based CAR (D1D2CAR) allows better CAR-T cell differentiation from gene modified HSCs, and maintains similar CTL activity as compared to the full length CD4-based CAR. In addition, D1D2CAR does not mediate HIV infection or stimulation mediated by IL-16, suggesting lower risk of off-target effects. Interestingly, stimulatory domains of 4-1BB but not CD28 allowed successful hematopoietic differentiation and improved anti-viral function of CAR T cells from CAR modified HSCs. Addition of 4-1BB to CD4 based CARs led to faster suppression of viremia during early untreated HIV-1 infection. D1D2CAR 4-1BB mice had faster viral suppression in combination with ART and better persistence of CAR T cells during ART. In summary, our data indicate that the D1D2CAR-41BB is a superior CAR, showing better HSC differentiation, viral suppression and persistence, and less deleterious functions compared to the original CD4CAR, and should continue to be pursued as a candidate for clinical study.
Highlights
Virus-specific T cell adaptive immunity is key to the elimination of HIV-1-infected cells and is crucial for any strategic approach to achieve cure of infection
We report a novel Chimeric Antigen Receptor (CAR)-based approach targeting HIV infection using the genetic modification of blood forming hematopoietic stem cells (HSCs)
This novel CAR approach uses a modified HIV receptor molecule as well as anti-HIV agents to modify HSCs to allow them to develop into cells that are protected from HIV infection and target HIV infected cells for the life of the individual
Summary
Virus-specific T cell adaptive immunity is key to the elimination of HIV-1-infected cells and is crucial for any strategic approach to achieve cure of infection. Allogeneic bone marrow transplantation is unlikely to be broadly translatable due to high mortality risk of this procedure, failures to repeat prior successes, and difficulties in finding matching donor bone marrow with homozygous CCR5Δ32 mutation [7, 8]. These studies highlight the fact that CCR5 elimination or other genetic strategies are essential for HIV-1 eradication, allogeneic HSC transplantation is not broadly applicable, underscoring the need to enhance host anti-viral responses in order to persistently suppress viral replication arising from residual, latently-infected cells
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