A participant-derived xenograft model of HIV enables long-term evaluation of autologous immunotherapies

Author:

McCann Chase D.12ORCID,van Dorp Christiaan H.3ORCID,Danesh Ali1ORCID,Ward Adam R.45ORCID,Dilling Thomas R.1ORCID,Mota Talia M.1ORCID,Zale Elizabeth2ORCID,Stevenson Eva M.1ORCID,Patel Shabnum67ORCID,Brumme Chanson J.8ORCID,Dong Winnie8ORCID,Jones Douglas S.9ORCID,Andresen Thomas L.9ORCID,Walker Bruce D.101112ORCID,Brumme Zabrina L.813ORCID,Bollard Catherine M.67ORCID,Perelson Alan S.3ORCID,Irvine Darrell J.12141516ORCID,Jones R. Brad12ORCID

Affiliation:

1. Infectious Diseases Division, Department of Medicine, Weill Cornell Medical College, New York, NY

2. Immunology & Microbial Pathogenesis Graduate Program, Weill Cornell Graduate School of Medical Sciences, New York, NY

3. Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM

4. Department of Microbiology, Immunology & Tropical Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC

5. PhD Program in Epidemiology, Milken Institute School of Public Health, The George Washington University, Washington, DC

6. Center for Cancer and Immunology Research, Children’s National Health System, Washington, DC

7. George Washington University Cancer Center, George Washington University, Washington, DC

8. British Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada

9. Repertoire Immune Medicines, Cambridge, MA

10. Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Boston, MA

11. Institute for Medical and Engineering Sciences, Massachusetts Institute of Technology, Cambridge, MA

12. Howard Hughes Medical Institute, Chevy Chase, MD

13. Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada

14. Department of Material Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA

15. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA

16. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA

Abstract

HIV-specific CD8+ T cells partially control viral replication and delay disease progression, but they rarely provide lasting protection, largely due to immune escape. Here, we show that engrafting mice with memory CD4+ T cells from HIV+ donors uniquely allows for the in vivo evaluation of autologous T cell responses while avoiding graft-versus-host disease and the need for human fetal tissues that limit other models. Treating HIV-infected mice with clinically relevant HIV-specific T cell products resulted in substantial reductions in viremia. In vivo activity was significantly enhanced when T cells were engineered with surface-conjugated nanogels carrying an IL-15 superagonist, but it was ultimately limited by the pervasive selection of a diverse array of escape mutations, recapitulating patterns seen in humans. By applying mathematical modeling, we show that the kinetics of the CD8+ T cell response have a profound impact on the emergence and persistence of escape mutations. This “participant-derived xenograft” model of HIV provides a powerful tool for studying HIV-specific immunological responses and facilitating the development of effective cell-based therapies.

Funder

National Institute of Allergy and Infectious Diseases

National Institutes of Health

National Institute on Drug Abuse

National Institute of Mental Health

National Institute of Neurological Disorders and Stroke

National Institutes of Health Office of the Director

National Center for Advancing Translational Sciences

District of Columbia Developmental Center for AIDS Research

National Cancer Institute

Eunice Kennedy Shriver National Institute of Child Health and Human Development

National Heart, Lung, and Blood Institute

National Institute on Aging

Fogarty International Center

National Institute of General Medical Sciences

National Institute of Diabetes and Digestive and Kidney Diseases

Office of AIDS Research

Canadian Institutes of Health Research

Michael Smith Foundation for Health Research

U.S. Department of Energy

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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