Redirection of Cord Blood T Cells and Natural Killer Cells for Elimination of Autologous HIV-1-Infected Target Cells Using Bispecific DART® Molecules.

Pollara, Justin

Edwards, R Whitney

Jha, Shalini

Lam, Chia-Ying Kao

Liu, Liqin

Diedrich, Gundo

Nordstrom, Jeffrey L

Huffman, Tori

Pickeral, Joy A

Denny, Thomas N

Permar, Sallie R

Ferrari, Guido

2021-01-04T21:00:50Z

2021-01-04T21:00:50Z

2020-01

2021-01-04T21:00:47Z

Mother-to-child transmission of HIV-1 remains a major global health challenge. Currently, HIV-1-infected infants require strict lifelong adherence to antiretroviral therapy to prevent replication of virus from reservoirs of infected cells, and to halt progression of disease. There is a critical need for immune interventions that can be deployed shortly after infection to eliminate HIV-1-infected cells in order to promote long-term remission of viremia, or to potentially cure pediatric HIV-1-infection. Bispecific HIV × CD3 DART® molecules able to co-engage the HIV-1 envelope protein on the surface of infected cells and CD3 on cytolytic T cells have been previously shown to eliminate HIV-1 infected cells in vitro and are candidates for passive immunotherapy to reduce the virus reservoir. However, their potential utility as therapy for infant HIV-1 infection is unclear as the ability of these novel antibody-based molecules to work in concert with cells of the infant immune system had not been assessed. Here, we use human umbilical cord blood as a model of the naïve neonatal immune system to evaluate the ability of HIV x CD3 DART molecules to recruit and redirect neonatal effector cells for elimination of autologous CD4+ T cells infected with HIV-1 encoding an envelope gene sequenced from a mother-to-child transmission event. We found that HIV × CD3 DART molecules can redirect T cells present in cord blood for elimination of HIV-infected CD4+ T cells. However, we observed reduced killing by T cells isolated from cord blood when compared to cells isolated from adult peripheral blood-likely due to the absence of the memory and effector CD8+ T cells that are most cytolytic when redirected by bispecific DART molecules. We also found that newly developed HIV × CD16 DART molecules were able to recruit CD16-expressing natural killer cells from cord blood to eliminate HIV-infected cells, and the activity of cord blood natural killer cells could be substantially increased by priming with IL-15. Our results support continued development of HIV-specific DART molecules using relevant preclinical animal models to optimize strategies for effective use of this immune therapy to reduce HIV-1 infection in pediatric populations.

1664-3224

1664-3224

https://hdl.handle.net/10161/21996

eng

Frontiers Media SA

Frontiers in immunology

10.3389/fimmu.2020.00713

bispecific DART molecules

cytotoxic T cells

natural killer cells

pediatric HIV-1

redirected cytotoxicity

umbilical cord blood

Redirection of Cord Blood T Cells and Natural Killer Cells for Elimination of Autologous HIV-1-Infected Target Cells Using Bispecific DART® Molecules.

Journal article

Ferrari, Guido|0000-0001-7747-3349

713

School of Medicine

Duke Human Vaccine Institute

Duke Global Health Institute

Medicine, Duke Human Vaccine Institute

Duke

Institutes and Centers

University Institutes and Centers

Institutes and Provost's Academic Units

Medicine

Clinical Science Departments

Molecular Genetics and Microbiology

Surgery, Surgical Sciences

Basic Science Departments

Surgery

Immunology

Duke Science & Society

Duke Innovation & Entrepreneurship

Pathology

Pediatrics, Infectious Diseases

Initiatives

Pediatrics

Published

11