puc-header

BCL-2 Antagonism Sensitizes CTL-Resistant HIV Reservoirs to Elimination Ex Vivo

62 Pages Posted: 9 May 2019 Sneak Peek Status: Review Complete

See all articles by Yanqin Ren

Yanqin Ren

Weill Cornell Medical College - Infectious Diseases Division

Szu Han Huang

Weill Cornell Medical College - Infectious Diseases Division

Shabnum Patel

George Washington University - Children's National Medical Center

Dean Magat

Weill Cornell Medical College - Infectious Diseases Division

Amanda B. Macedo

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

Ryan Durga

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

Elizabeth Zale

Weill Cornell Medicine, Infectious Diseases Division

Talia Mota

Weill Cornell Medical College - Infectious Diseases Division

Ronald Truong

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

Thomas Rohwetter

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

Chase D. McCann

Weill Cornell Medical College - Infectious Diseases Division

Colin C. Kovacs

Maple Leaf Medical Clinic

Erika Benko

Maple Leaf Medical Clinic

Avery Wimpelberg

Whitman Walker Health

Christopher Cannon

Whitman Walker Health

W. David Hardy

Whitman Walker Health; Johns Hopkins University, School of Medicine, Division of Infectious Diseases

Alberto Bosque

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

Catherine M. Bollard

Children's National Medical Center; George Washington University - Department of Microbiology, Immunology and Tropical Medicine

R. Brad Jones

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

More...

Abstract

Curing HIV infection will require the elimination of a reservoir of infected CD4+ T-cells that persists despite HIV-specific CTL responses. While viral latency is a critical factor in this persistence, recent evidence also suggests a role for intrinsic resistance of reservoir-harboring cells to CTL killing. We explored the hypothesis that this resistance is mediated by BCL-2 family proteins, which can antagonize CTL-induced apoptosis. We show that the reactivatable HIV reservoir is disproportionately present in BCL-2hi CD4+ T-cells, which are relatively resistant to CTL. BCL-2/BCL-XL antagonists were sufficient for inducing the elimination of HIV-infected cells from a primary-cell model of latency, but did not drive reductions in ex vivo viral reservoirs when tested either alone or with a latency reversing agent (LRA). The triple combination of LRAs, HIV-specific T-cells, and a BCL-2 antagonist uniquely enabled depletions in ex vivo viral reservoirs, providing rationale for novel therapeutic approaches targeting HIV cure.

Keywords: HIV reservoir, HIV eradication, BCL-2, BCL-2 antagonist, BCL-XL antagonist, HIV-Specific T cells, resistance to CTL killing

Suggested Citation

Ren, Yanqin and Huang, Szu Han and Patel, Shabnum and Magat, Dean and Macedo, Amanda B. and Durga, Ryan and Zale, Elizabeth and Mota, Talia and Truong, Ronald and Rohwetter, Thomas and McCann, Chase D. and Kovacs, Colin C. and Benko, Erika and Wimpelberg, Avery and Cannon, Christopher and Hardy, W. David and Bosque, Alberto and Bollard, Catherine M. and Jones, R. Brad, BCL-2 Antagonism Sensitizes CTL-Resistant HIV Reservoirs to Elimination Ex Vivo (May 9, 2019). IMMUNITY-D-19-00472. Available at SSRN: https://ssrn.com/abstract=3385137 or http://dx.doi.org/10.2139/ssrn.3385137
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Yanqin Ren

Weill Cornell Medical College - Infectious Diseases Division ( email )

New York, NY
United States

Szu Han Huang

Weill Cornell Medical College - Infectious Diseases Division

New York, NY
United States

Shabnum Patel

George Washington University - Children's National Medical Center

DC
United States

Dean Magat

Weill Cornell Medical College - Infectious Diseases Division

New York, NY
United States

Amanda B. Macedo

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

Washington, DC
United States

Ryan Durga

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

Washington, DC
United States

Elizabeth Zale

Weill Cornell Medicine, Infectious Diseases Division ( email )

New York, NY
United States

Talia Mota

Weill Cornell Medical College - Infectious Diseases Division

New York, NY
United States

Ronald Truong

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

Washington, DC
United States

Thomas Rohwetter

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

Washington, DC
United States

Chase D. McCann

Weill Cornell Medical College - Infectious Diseases Division

New York, NY
United States

Colin C. Kovacs

Maple Leaf Medical Clinic

Toronto, Ontario
Canada

Erika Benko

Maple Leaf Medical Clinic

Toronto, Ontario
Canada

Avery Wimpelberg

Whitman Walker Health

Washington, DC
United States

Christopher Cannon

Whitman Walker Health ( email )

Washington, DC
United States

W. David Hardy

Whitman Walker Health

Washington, DC
United States

Johns Hopkins University, School of Medicine, Division of Infectious Diseases

Baltimore, MD
United States

Alberto Bosque

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

Washington, DC
United States

Catherine M. Bollard

Children's National Medical Center

DC
United States

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

Washington, DC
United States

R. Brad Jones (Contact Author)

Weill Cornell Medical College - Infectious Diseases Division ( email )

New York, NY
United States

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

Washington, DC
United States

Click here to go to Cell.com

Paper statistics

Abstract Views
433
Downloads
20