title: Persistent Low-Level Replication of SIVΔnef Drives Maturation of Antibody and CD8 T Cell Responses to Induce Protective Immunity against Vaginal SIV Infection.
abstract: Defining the correlates of immune protection conferred by SIVΔnef, the most effective vaccine against SIV challenge, could enable the design of a protective vaccine against HIV infection. Here we provide a comprehensive assessment of immune responses that protect against SIV infection through detailed analyses of cellular and humoral immune responses in the blood and tissues of rhesus macaques vaccinated with SIVΔnef and then vaginally challenged with wild-type SIV. Despite the presence of robust cellular immune responses, animals at 5 weeks after vaccination displayed only transient viral suppression of challenge virus, whereas all macaques challenged at weeks 20 and 40 post-SIVΔnef vaccination were protected, as defined by either apparent sterile protection or significant suppression of viremia in infected animals. Multiple parameters of CD8 T cell function temporally correlated with maturation of protection, including polyfunctionality, phenotypic differentiation, and redistribution to gut and lymphoid tissues. Importantly, we also demonstrate the induction of a tissue-resident memory population of SIV-specific CD8 T cells in the vaginal mucosa, which was dependent on ongoing low-level antigenic stimulation. Moreover, we show that vaginal and serum antibody titers inversely correlated with post-challenge peak viral load, and we correlate the accumulation and affinity maturation of the antibody response to the duration of the vaccination period as well as to the SIVΔnef antigenic load. In conclusion, maturation of SIVΔnef-induced CD8 T cell and antibody responses, both propelled by viral persistence in the gut mucosa and secondary lymphoid tissues, results in protective immune responses that are able to interrupt viral transmission at mucosal portals of entry as well as potential sites of viral dissemination.
authors.affiliation: Yerkes National Primate Research Center, Emory University, Atlanta GA, United States of America.|New England Primate Research Center, Harvard Medical School, Southborough Campus, Pine Hill Drive, Southborough, MA, United States of America.
authors.forename: Sama
authors.initials: S
authors.lastname: Adnan
authors.affiliation: New England Primate Research Center, Harvard Medical School, Southborough Campus, Pine Hill Drive, Southborough, MA, United States of America.|Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA, United States of America.
authors.forename: R Keith
authors.initials: RK
authors.lastname: Reeves
authors.affiliation: New England Primate Research Center, Harvard Medical School, Southborough Campus, Pine Hill Drive, Southborough, MA, United States of America.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Gillis
authors.affiliation: New England Primate Research Center, Harvard Medical School, Southborough Campus, Pine Hill Drive, Southborough, MA, United States of America.
authors.forename: Fay E
authors.initials: FE
authors.lastname: Wong
authors.affiliation: New England Primate Research Center, Harvard Medical School, Southborough Campus, Pine Hill Drive, Southborough, MA, United States of America.
authors.forename: Yi
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States of America.
authors.forename: Jeremy V
authors.initials: JV
authors.lastname: Camp
authors.affiliation: Nebraska Center for Virology and School of Biological Sciences, University of Nebraska-Lincoln, Lincoln, Nebraska, United States of America.
authors.forename: Qingsheng
authors.initials: Q
authors.lastname: Li
authors.affiliation: New England Primate Research Center, Harvard Medical School, Southborough Campus, Pine Hill Drive, Southborough, MA, United States of America.
authors.forename: Michelle
authors.initials: M
authors.lastname: Connole
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Piatak
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Lifson
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, MA, United States of America.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Li
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America.
authors.forename: Brandon F
authors.initials: BF
authors.lastname: Keele
authors.affiliation: Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States of America.
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Kozlowski
authors.affiliation: Department of Pathology, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Desrosiers
authors.affiliation: Department of Microbiology, Medical School, University of Minnesota, MMC 196, 420 Delaware Street S.E., Minneapolis, Minnesota, United States of America.
authors.forename: Ashley T
authors.initials: AT
authors.lastname: Haase
authors.affiliation: Yerkes National Primate Research Center, Emory University, Atlanta GA, United States of America.|New England Primate Research Center, Harvard Medical School, Southborough Campus, Pine Hill Drive, Southborough, MA, United States of America.|Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, United States of America.
authors.forename: R Paul
authors.identifier: http://orcid.org/0000-0002-2600-120X
authors.initials: RP
authors.lastname: Johnson
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D000914:Antibodies, Viral / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D007111:Immunity, Cellular / Q000276:immunology; D056724:Immunity, Humoral / Q000276:immunology; D008253:Macaca mulatta; D060888:Real-Time Polymerase Chain Reaction; D018449:SAIDS Vaccines / Q000276:immunology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology*; D015302:Simian Immunodeficiency Virus / Q000276:immunology*; D014621:Vagina / Q000276:immunology / Q000821:virology; D019562:Viral Load
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D018449:SAIDS Vaccines