title: Role of Occult and Post-acute Phase Replication in Protective Immunity Induced with a Novel Live Attenuated SIV Vaccine.
abstract: In order to evaluate the role of persisting virus replication during occult phase immunisation in the live attenuated SIV vaccine model, a novel SIVmac239Δnef variant (SIVrtTA) genetically engineered to replicate in the presence of doxycycline was evaluated for its ability to protect against wild-type SIVmac239. Indian rhesus macaques were vaccinated either with SIVrtTA or with SIVmac239Δnef. Doxycycline was withdrawn from 4 of 8 SIVrtTA vaccinates before challenge with wild-type virus. Unvaccinated challenge controls exhibited ~107 peak plasma viral RNA copies/ml persisting beyond the acute phase. Six vaccinates, four SIVmac239Δnef and two SIVrtTA vaccinates exhibited complete protection, defined by lack of wild-type viraemia post-challenge and virus-specific PCR analysis of tissues recovered post-mortem, whereas six SIVrtTA vaccinates were protected from high levels of viraemia. Critically, the complete protection in two SIVrtTA vaccinates was associated with enhanced SIVrtTA replication in the immediate post-acute vaccination period but was independent of doxycycline status at the time of challenge. Mutations were identified in the LTR promoter region and rtTA gene that do not affect doxycycline-control but were associated with enhanced post-acute phase replication in protected vaccinates. High frequencies of total circulating CD8+T effector memory cells and a higher total frequency of SIV-specific CD8+ mono and polyfunctional T cells on the day of wild-type challenge were associated with complete protection but these parameters were not predictive of outcome when assessed 130 days after challenge. Moreover, challenge virus-specific Nef CD8+ polyfunctional T cell responses and antigen were detected in tissues post mortem in completely-protected macaques indicating post-challenge control of infection. Within the parameters of the study design, on-going occult-phase replication may not be absolutely required for protective immunity.
authors.affiliation: Division of Virology, National Institute for Biological Standards and Control, South Mimms, United Kingdom.
authors.forename: Neil
authors.initials: N
authors.lastname: Berry
authors.affiliation: Institute for Infection & Immunity, St George's, University of London, London, United Kingdom.
authors.forename: Maria
authors.initials: M
authors.lastname: Manoussaka
authors.affiliation: Division of Virology, National Institute for Biological Standards and Control, South Mimms, United Kingdom.
authors.forename: Claire
authors.initials: C
authors.lastname: Ham
authors.affiliation: Division of Virology, National Institute for Biological Standards and Control, South Mimms, United Kingdom.
authors.forename: Deborah
authors.initials: D
authors.lastname: Ferguson
authors.affiliation: Division of Virology, National Institute for Biological Standards and Control, South Mimms, United Kingdom.
authors.forename: Hannah
authors.initials: H
authors.lastname: Tudor
authors.affiliation: Division of Virology, National Institute for Biological Standards and Control, South Mimms, United Kingdom.
authors.forename: Giada
authors.initials: G
authors.lastname: Mattiuzzo
authors.affiliation: Laboratory of Experimental Virology, Department of Medical Microbiology, Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Bep
authors.initials: B
authors.lastname: Klaver
authors.affiliation: Division of Virology, National Institute for Biological Standards and Control, South Mimms, United Kingdom.
authors.forename: Mark
authors.initials: M
authors.lastname: Page
authors.affiliation: Division of Biotherapeutics, National Institute for Biological Standards and Control, South Mimms, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Stebbings
authors.affiliation: Laboratory of Experimental Virology, Department of Medical Microbiology, Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Atze T
authors.initials: AT
authors.lastname: Das
authors.affiliation: Laboratory of Experimental Virology, Department of Medical Microbiology, Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Ben
authors.initials: B
authors.lastname: Berkhout
authors.affiliation: Division of Virology, National Institute for Biological Standards and Control, South Mimms, United Kingdom.
authors.forename: Neil
authors.initials: N
authors.lastname: Almond
authors.affiliation: Institute for Infection & Immunity, St George's, University of London, London, United Kingdom.
authors.forename: Martin P
authors.initials: MP
authors.lastname: Cranage
mesh_terms: D000818:Animals; D007150:Immunohistochemistry; D016130:Immunophenotyping; D008253:Macaca mulatta; D016133:Polymerase Chain Reaction; D018449:SAIDS Vaccines / Q000276:immunology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology*; D015302:Simian Immunodeficiency Virus / Q000276:immunology*; D014613:Vaccines, Attenuated; D014779:Virus Replication / Q000276:immunology*
chemical_list: D018449:SAIDS Vaccines; D014613:Vaccines, Attenuated