title: CD8 T cell response maturation defined by anentropic specificity and repertoire depth correlates with SIVΔnef-induced protection.
abstract: The live attenuated simian immunodeficiency virus (LASIV) vaccine SIVΔnef is one of the most effective vaccines in inducing protection against wild-type lentiviral challenge, yet little is known about the mechanisms underlying its remarkable protective efficacy. Here, we exploit deep sequencing technology and comprehensive CD8 T cell epitope mapping to deconstruct the CD8 T cell response, to identify the regions of immune pressure and viral escape, and to delineate the effect of epitope escape on the evolution of the CD8 T cell response in SIVΔnef-vaccinated animals. We demonstrate that the initial CD8 T cell response in the acute phase of SIVΔnef infection is mounted predominantly against more variable epitopes, followed by widespread sequence evolution and viral escape. Furthermore, we show that epitope escape expands the CD8 T cell repertoire that targets highly conserved epitopes, defined as anentropic specificity, and generates de novo responses to the escaped epitope variants during the vaccination period. These results correlate SIVΔnef-induced protection with expanded anentropic specificity and increased response depth. Importantly, these findings render SIVΔnef, long the gold standard in HIV/SIV vaccine research, as a proof-of-concept vaccine that highlights the significance of the twin principles of anentropic specificity and repertoire depth in successful vaccine design.
authors: New England Primate Research Center, Harvard Medical School, Southborough Campus, Southborough, Massachusetts, United States of America.
authors: Sama
authors: S
authors: Adnan
authors: New England Primate Research Center, Harvard Medical School, Southborough Campus, Southborough, Massachusetts, United States of America.
authors: Arnaud D
authors: AD
authors: Colantonio
authors: New England Primate Research Center, Harvard Medical School, Southborough Campus, Southborough, Massachusetts, United States of America.
authors: Yi
authors: Y
authors: Yu
authors: New England Primate Research Center, Harvard Medical School, Southborough Campus, Southborough, Massachusetts, United States of America.
authors: Jacqueline
authors: J
authors: Gillis
authors: New England Primate Research Center, Harvard Medical School, Southborough Campus, Southborough, Massachusetts, United States of America.
authors: Fay E
authors: FE
authors: Wong
authors: Wisconsin National Primate Research Center, University of Wisconsin, Madison, Wisconsin, United States of America.
authors: Ericka A
authors: EA
authors: Becker
authors: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory, Frederick, Maryland, United States of America.
authors: Michael
authors: M
authors: Piatak
authors: New England Primate Research Center, Harvard Medical School, Southborough Campus, Southborough, Massachusetts, United States of America; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America.
authors: R Keith
authors: RK
authors: Reeves
authors: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory, Frederick, Maryland, United States of America.
authors: Jeffrey D
authors: JD
authors: Lifson
authors: Wisconsin National Primate Research Center, University of Wisconsin, Madison, Wisconsin, United States of America.
authors: Shelby L
authors: SL
authors: O'Connor
authors: New England Primate Research Center, Harvard Medical School, Southborough Campus, Southborough, Massachusetts, United States of America; Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, United States of America; Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, United States of America.
authors: R Paul
authors: RP
authors: Johnson
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005434:Flow Cytometry; D057131:Immune Evasion / Q000276:immunology*; D008253:Macaca mulatta; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018449:SAIDS Vaccines / Q000276:immunology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000628:therapy; D014613:Vaccines, Attenuated / Q000276:immunology; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000276:immunology
chemical_list: D018984:Epitopes, T-Lymphocyte; D018449:SAIDS Vaccines; D014613:Vaccines, Attenuated; D054311:nef Gene Products, Human Immunodeficiency Virus