Abstract
Sustained viral suppression following antiretroviral treatment (ART) cessation is a major goal of HIV cure research1. Rare individuals mount immune responses able to control viral rebound without intervention2,3, however, the earliest moments in which these responses form remain poorly defined. We performed an intensively sampled, prospective analytical treatment interruption (ATI) to study the initial immune response to rebound and to understand its role in defining subsequent virus control. Profiling of peripheral blood mononuclear cells and plasma revealed consistent immune activation prior to systemic rebound, including upregulation of antiviral transcriptional pathways, expansion of CD16++ non-classical monocytes, and increases of inflammatory and antiviral soluble plasma proteins. Individuals with prior viral control (controllers) diverged from non-controllers with a slower slope of rebound, a longer period of immune activity prior to rebound, and engagement of a multifaceted immune program with less systemic inflammation. An intermediate immune signature emerged in a separate ATI cohort of individuals who experienced delayed rebound after receiving broadly neutralizing antibodies4, suggesting that immunotherapy can induce a potentially protective pre-rebound immune response. Together, these data resolve the earliest systemic host immune responses to HIV rebound and demonstrate broad immune differences associated with HIV control phenotypes.
Authors and Affiliations
Anna Farrell-Sherman¹˒²†, Walker Azam¹†, Natalia de la Force¹˒²†, Ellen L. White¹, Demi A. Sandel³, Antonio E. Rodriguez³, Tony Figueroa³, Thomas Dalhuisen³, Meghann C. Williams³, Viva Tai³, George W. Gruenhagen³, Alaa Abdellatif³, Gabriela K. Fragiadakis³, Peyman Samghabadi⁴, Carlo De la Sancha Verduzco⁴, Poonam Vohra⁴, Cynthia Gasper⁴, Steven Long⁴, Marina Caskey⁵, Bokai Zhu⁶˒⁷˒⁸˒⁹, Alex K. Shalek⁶˒⁷˒⁸˒⁹˒¹⁰, Rebecca Hoh³, Rachel L. Rutishauser³, Michael J. Peluso³, Steven G. Deeks³#, and Lillian B. Cohn¹˒¹¹#
¹ Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, United States
² Molecular and Cellular Biology Program, University of Washington, Seattle, WA, United States
³ Department of Medicine, University of California, San Francisco, San Francisco, CA, United States
⁴ Department of Pathology, University of California, San Francisco, San Francisco, CA, United States
⁵ Laboratory of Molecular Immunology, The Rockefeller University, New York, NY, United States
⁶ Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, United States
⁷ Broad Institute of MIT and Harvard, Cambridge, MA, United States
⁸ Institute of Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, United States
⁹ Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, United States
¹⁰ Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
¹¹ Department of Global Health, University of Washington, Seattle, WA, United States
† These authors contributed equally to the work.