title: Early biodistribution and persistence of a protective live attenuated SIV vaccine elicits localised innate responses in multiple lymphoid tissues.
abstract: Vaccination of Mauritian cynomolgus macaques with the attenuated nef-truncated C8 variant of SIVmac251/32H (SIVmacC8) induces early, potent protection against pathogenic, heterologous challenge before the maturation of cognate immunity. To identify processes that contribute to early protection in this model the pathogenesis, anatomical distribution and viral vaccine kinetics were determined in relation to localised innate responses triggered by vaccination. The early biodistribution of SIVmacC8 was defined by rapid, widespread dissemination amongst multiple lymphoid tissues, detectable after 3 days. Cell-associated viral RNA dynamics identified mesenteric lymph nodes (MLN) and spleen, as well as the gut mucosae, as early major contributors of systemic virus burden. Rapid, localised infection was populated by discrete foci of persisting virus-infected cells. Localised productive infection triggered a broad innate response, with type-1 interferon sensitive IRF-7, STAT-1, TRIM5α and ApoBEC3G genes all upregulated during the acute phase but induction did not prevent viral persistence. Profound changes in vaccine-induced cell-surface markers of immune activation were detected on macrophages, B-cells and dendritic cells (DC-SIGN, S-100, CD40, CD11c, CD123 and CD86). Notably, high DC-SIGN and S100 staining for follicular and interdigitating DCs respectively, in MLN and spleen were detected by 3 days, persisting 20 weeks post-vaccination. Although not formally evaluated, the early biodistribution of SIVmacC8 simultaneously targets multiple lymphoid tissues to induce strong innate immune responses coincident at the same sites critical for early protection from wild-type viruses. HIV vaccines which stimulate appropriate innate, as well as adaptive responses, akin to those generated by live attenuated SIV vaccines, may prove the most efficacious.
authors.affiliation: Division of Virology, NIBSC, South Mimms, Hertfordshire, United Kingdom.
authors.forename: Deborah
authors.initials: D
authors.lastname: Ferguson
authors.affiliation: Division of Virology, NIBSC, South Mimms, Hertfordshire, United Kingdom.
authors.forename: Giada
authors.initials: G
authors.lastname: Mattiuzzo
authors.affiliation: Division of Virology, NIBSC, South Mimms, Hertfordshire, United Kingdom.
authors.forename: Claire
authors.initials: C
authors.lastname: Ham
authors.affiliation: Division of Biotherapeutics, NIBSC, South Mimms, Hertfordshire, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Stebbings
authors.affiliation: Division of Biotherapeutics, NIBSC, South Mimms, Hertfordshire, United Kingdom.
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.affiliation: Division of Virology, NIBSC, South Mimms, Hertfordshire, United Kingdom.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Rose
authors.affiliation: Division of Virology, NIBSC, South Mimms, Hertfordshire, United Kingdom.
authors.forename: Edward T
authors.initials: ET
authors.lastname: Mee
authors.affiliation: Division of Virology, NIBSC, South Mimms, Hertfordshire, United Kingdom.
authors.forename: Deborah
authors.initials: D
authors.lastname: Smith
authors.affiliation: Division of Virology, NIBSC, South Mimms, Hertfordshire, United Kingdom.
authors.forename: Mark
authors.initials: M
authors.lastname: Page
authors.affiliation: Institute of Infection and Immunity, St. George's, University of London, London, United Kingdom.
authors.forename: Martin P
authors.initials: MP
authors.lastname: Cranage
authors.affiliation: Division of Virology, NIBSC, South Mimms, Hertfordshire, United Kingdom.
authors.forename: Neil
authors.initials: N
authors.lastname: Almond
authors.affiliation: MRC Centre of Medical Molecular Biology, Division of Infection and Immunity, UCL, London, United Kingdom.
authors.forename: Greg J
authors.initials: GJ
authors.lastname: Towers
authors.affiliation: Division of Virology, NIBSC, South Mimms, Hertfordshire, United Kingdom.
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Berry
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000821:virology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000821:virology; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D007113:Immunity, Innate / Q000187:drug effects*; D050839:Interferon Regulatory Factor-7 / Q000235:genetics / Q000276:immunology; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology / Q000821:virology; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology / Q000821:virology; D008252:Macaca fascicularis; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000821:virology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology; D009418:S100 Proteins / Q000235:genetics / Q000276:immunology; D018449:SAIDS Vaccines / Q000008:administration & dosage / Q000096:biosynthesis / Q000276:immunology* / Q000493:pharmacokinetics*; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000276:immunology; D016097:Simian Acquired Immunodeficiency Syndrome / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D015302:Simian Immunodeficiency Virus / Q000187:drug effects* / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000821:virology; D014613:Vaccines, Attenuated; D019562:Viral Load / Q000187:drug effects; D016335:Zinc Fingers / Q000235:genetics / Q000276:immunology; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D015703:Antigens, CD; D015815:Cell Adhesion Molecules; D050839:Interferon Regulatory Factor-7; D037181:Lectins, C-Type; D011956:Receptors, Cell Surface; D009418:S100 Proteins; D018449:SAIDS Vaccines; D050794:STAT1 Transcription Factor; D014613:Vaccines, Attenuated; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin