title: Conditionally-live attenuated SIV upregulates global T effector memory cell frequency under replication permissive conditions.
abstract: BACKGROUND
  Live attenuated SIV induces potent protection against superinfection with virulent virus; however the mechanism of this vaccine effect is poorly understood. Such knowledge is important for the development of clinically acceptable vaccine modalities against HIV.
  
  
  RESULTS
  Using a novel, doxycycline dependent, replication-competent live-attenuated SIVmac239Δnef (SIV-rtTAΔnef), we show that under replication-permissive conditions SIV-rtTAΔnef is fully viable. Twelve rhesus macaques were infected with a peak plasma vRNA on average two log10 lower than in 6 macaques infected with unconditionally replication-competent SIVΔnef. Consistent with the attenuated phenotype of the viruses the majority of animals displayed low or undetectable levels of viraemia by 42-84 days after infection. Next, comparison of circulating T cells before and after chronic infection with parental SIVΔnef revealed a profound global polarisation toward CD28-CCR7- T-effector memory 2 (TEM2) cells within CD95+CD4+ and CD95+CD8+ populations. Critically, a similar effect was seen in the CD95+ CD4+ population and to somewhat lesser extent in the CD95+ CD8+ population of SIV-rtTAΔnef chronically infected macaques that were maintained on doxycycline, but was not seen in animals from which doxycycline had been withdrawn. The proportions of gut-homing T-central memory (TCM) and TEM defined by the expression of α4β7 and CD95 and differential expression of CD28 were increased in CD4 and CD8 cells under replication competent conditions and gut-homing CD4 TCM were also significantly increased under non-permissive conditions. TEM2 polarisation was seen in the small intestines of animals under replication permissive conditions but the effect was less pronounced than in the circulation. Intracellular cytokine staining of circulating SIV-specific T cells for IL-2, IFN-γ, TNF-α and IL-17 showed that the extent of polyfunctionality in CD4 and CD8 T cells was associated with replication permissivity; however, signature patterns of cytokine combinations were not distinguishable between groups of macaques.
  
  
  CONCLUSIONS
  Taken together our results show that the global T memory cell compartment is profoundly skewed towards a mature effector phenotype by attenuated SIV. Results with the replication-conditional mutant suggest that maintenance of this effect, that may be important in vaccine design, might require persistence of replicating virus.
authors.forename: Maria S
authors.initials: MS
authors.lastname: Manoussaka
authors.forename: Neil
authors.initials: N
authors.lastname: Berry
authors.forename: Deborah
authors.initials: D
authors.lastname: Ferguson
authors.forename: Richard
authors.initials: R
authors.lastname: Stebbings
authors.forename: Mark
authors.initials: M
authors.lastname: Robinson
authors.forename: Claire
authors.initials: C
authors.lastname: Ham
authors.forename: Mark
authors.initials: M
authors.lastname: Page
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.forename: Atze T
authors.initials: AT
authors.lastname: Das
authors.forename: Ben
authors.initials: B
authors.lastname: Berkhout
authors.forename: Neil
authors.initials: N
authors.lastname: Almond
authors.forename: Martin P
authors.initials: MP
authors.lastname: Cranage
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology; D000914:Antibodies, Viral / Q000276:immunology*; D004318:Doxycycline / Q000494:pharmacology; D007156:Immunologic Memory / Q000502:physiology; D007421:Intestine, Small / Q000821:virology; D008253:Macaca mulatta; D010641:Phenotype; D012367:RNA, Viral / Q000235:genetics; D018449:SAIDS Vaccines / Q000276:immunology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000517:prevention & control / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000187:drug effects / Q000276:immunology* / Q000502:physiology; D015163:Superinfection / Q000517:prevention & control; D013601:T-Lymphocytes / Q000276:immunology*; D015854:Up-Regulation; D014613:Vaccines, Attenuated / Q000276:immunology; D014766:Viremia; D014779:Virus Replication
chemical_list: D000890:Anti-Infective Agents; D000914:Antibodies, Viral; D012367:RNA, Viral; D018449:SAIDS Vaccines; D014613:Vaccines, Attenuated; D004318:Doxycycline