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A Participant-Derived Xenograft Model of HIV Enables Long-Term Evaluation of Autologous Immunotherapies

63 Pages Posted: 22 May 2020 Publication Status: Review Complete

See all articles by Chase McCann

Chase McCann

Cornell University - Weill Cornell Medicine

Christiaan van Dorp

Government of the United States of America - Los Alamos National Laboratory

Adam R. Ward

George Washington University, School of Medicine and Health Sciences

Ali Danesh

Infectious Diseases Division, Department of Medicine, Weill Cornell Medical College

Thomas Dilling

Cornell University - Weill Cornell Medicine

Talia Mota

Cornell University - Infectious Diseases Division

Elizabeth Zale

Weill Cornell Medicine, Infectious Diseases Division

Shabnum Patel

George Washington University - Children's National Medical Center

Chanson Brumme

University of British Columbia (UBC) - British Columbia Centre for Excellence in HIV/AIDS

Winnie Dong

University of British Columbia (UBC) - British Columbia Centre for Excellence in HIV/AIDS

Douglas S. Jones

Repertoire Immune Medicines

Thomas L. Andresen

Repertoire Immune Medicines

Bruce D. Walker

Ragon Institute of MGH, MIT and Harvard; Howard Hughes Medical Institute (HHMI) - Chevy Chase; Massachusetts Institute of Technology (MIT) - Institute for Medical Engineering and Science

Zabrina Brumme

University of British Columbia (UBC) - British Columbia Centre for Excellence in HIV/AIDS

Catherine Bollard

Children's National Health System; Children's National Hospital - Center for Cancer and Immunology Research

Alan Perelson

Government of the United States of America - Theoretical Biology and Biophysics; Government of the United States of America - Los Alamos National Laboratory

Darrell Irvine

Massachusetts Institute of Technology - Koch Institute for Integrative Cancer Research; Harvard University - Howard Hughes Medical Institute

R. Brad Jones

Cornell University - Infectious Diseases Division; George Washington University - Department of Microbiology, Immunology and Tropical Medicine

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Abstract

HIV-specific CD8 + T-cells partially control viral replication and delay disease progression, but rarely provide lasting protection – largely due to immune escape. 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, which were augmented by engineering with IL-15 superagonist-containing nanogels. Ultimately, in vivo activity was limited by the selection of diverse 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.

Keywords: HIV, CD8+ T-cells, immunotherapy, T-cell therapy, immunoengineering, escape mutations, patient derived xenografts

Suggested Citation

McCann, Chase and van Dorp, Christiaan and Ward, Adam R. and Danesh, Ali and Dilling, Thomas and Mota, Talia and Zale, Elizabeth and Patel, Shabnum and Brumme, Chanson and Dong, Winnie and Jones, Douglas S. and Andresen, Thomas L. and Walker, Bruce D. and Brumme, Zabrina and Bollard, Catherine and Perelson, Alan and Irvine, Darrell and Jones, R. Brad, A Participant-Derived Xenograft Model of HIV Enables Long-Term Evaluation of Autologous Immunotherapies. Available at SSRN: https://ssrn.com/abstract=3596601 or http://dx.doi.org/10.2139/ssrn.3596601
This version of the paper has not been formally peer reviewed.

Chase McCann

Cornell University - Weill Cornell Medicine

Christiaan Van Dorp

Government of the United States of America - Los Alamos National Laboratory

Los Alamos, NM 87545
United States

Adam R. Ward

George Washington University, School of Medicine and Health Sciences

3200m St NW
Washington, DC 20037
United States

Ali Danesh

Infectious Diseases Division, Department of Medicine, Weill Cornell Medical College

1300 York Avenue
New York, NY 10065
United States

Thomas Dilling

Cornell University - Weill Cornell Medicine

1300 York Avenue
New York, NY 10065
United States

Talia Mota

Cornell University - Infectious Diseases Division

New York, NY
United States

Elizabeth Zale

Weill Cornell Medicine, Infectious Diseases Division ( email )

New York, NY
United States

Shabnum Patel

George Washington University - Children's National Medical Center

DC
United States

Chanson Brumme

University of British Columbia (UBC) - British Columbia Centre for Excellence in HIV/AIDS

608-1081 Burrard Street
Vancouver, V6Z 1Y6
Canada

Winnie Dong

University of British Columbia (UBC) - British Columbia Centre for Excellence in HIV/AIDS

608-1081 Burrard Street
Vancouver, V6Z 1Y6
Canada

Douglas S. Jones

Repertoire Immune Medicines

Cambridge, MA
United States

Thomas L. Andresen

Repertoire Immune Medicines

Cambridge, MA
United States

Bruce D. Walker

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Howard Hughes Medical Institute (HHMI) - Chevy Chase ( email )

4000 Jones Bridge Road
Chevy Chase, MD 20815-6789
United States

Massachusetts Institute of Technology (MIT) - Institute for Medical Engineering and Science ( email )

Cambridge, MA
United States

Zabrina Brumme

University of British Columbia (UBC) - British Columbia Centre for Excellence in HIV/AIDS

608-1081 Burrard Street
Vancouver, V6Z 1Y6
Canada

Catherine Bollard

Children's National Health System

111 Michigan Ave NW
Washington, DC 20010
United States

Children's National Hospital - Center for Cancer and Immunology Research ( email )

United States

Alan Perelson

Government of the United States of America - Theoretical Biology and Biophysics

Government of the United States of America - Los Alamos National Laboratory

Los Alamos, NM 87545
United States

Darrell Irvine

Massachusetts Institute of Technology - Koch Institute for Integrative Cancer Research ( email )

77 Massachusetts Avenue
50 Memorial Drive
Cambridge, MA 02139-4307
United States

Harvard University - Howard Hughes Medical Institute ( email )

220 Longwood Avenue
Boston, MA 02115
United States

R. Brad Jones (Contact Author)

Cornell University - Infectious Diseases Division ( email )

New York, NY
United States

George Washington University - Department of Microbiology, Immunology and Tropical Medicine ( email )

Washington, DC
United States

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