Replication kinetics and persistence of a conditionally live attenuated SIV (SIVrtTA) in vivo...
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BioMed Central Page 1 of 2 (page number not for citation purposes) Retrovirology Open Access Poster presentation Replication kinetics and persistence of a conditionally live attenuated SIV (SIVrtTA) in vivo confers protection against SIVmac239 wild-type challenge in a rhesus macaque model Neil Berry* 1 , Atze Das 2 , Mark Page 1 , Hannah Tudor 1 , Mark Robinson 1 , Ruby Quartey-Papafio 1 , William Elsley 1 , Deborah Ferguson 1 , Bo Li 1 , Wendy Kleibeuker 2 , Bep Klaver 2 , Maria Manoussaka 3 , Richard Stebbings 1 , Martin Cranage 3 , Ben Berkhout 2 and Neil Almond 1 Address: 1 NIBSC, Division of Retrovirology, Health Protection Agency, South Mimms, Herts, EN6 3QG , UK, 2 Laboratory of Experimental Virology, Department of Medical Microbiology, Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center of the University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands and 3 Division of Cellular and Molecular Medicine, St. George's University of London, London, SW17 0RE, UK * Corresponding author Vaccination with live attenuated SIV confers potent pro- tection against wild-type SIV challenge in the SIV/ macaque model of HIV. Although safety concerns pre- clude the direct application of this vaccine approach in humans, a clearer understanding of its mechanism of pro- tection may lead to the development of novel AIDS vac- cines. A novel live attenuated SIVmac239 Δnef vaccine (SIVrtTA), dependent on doxycycline administration for replication, has been evaluated in vivo and its ability to protect against pathogenic SIV challenge determined. Two groups of six Indian rhesus macaques (Groups A and B) were vaccinated with SIVrtTA with an oral doxycycline dosing regime for 6 months. In Group A, doxycycline was stopped for 8 weeks before wtSIVmac239 challenge. A third group was vaccinated with a conventional SIVmac239Δnef vaccine. In the presence of doxycycline, all 12 macaques receiving SIVrtTA were infected exhibit- ing peak SIV RNA levels (log 10 3-5 SIV RNA copies/ml) which declined in all macaques but persisted at higher lev- els in three SIVrtTA vaccinates. Levels of virus replication measured by independent qRT-PCR and qDNA PCR assays were lower in SIVrtTA vaccinates compared with the SIVmac239Δnef vaccine which peaked in the log 10 4-6 SIV RNA copies/ml range. No escape from doxycycline dependence was identified. Upon challenge with wild- type SIVmac239 and compared with naive challenge con- trols (Group D), a significant vaccine effect was observed in all three vaccine groups, assessed by the comparative reduction of circulating viral RNA in plasma. Naive wtSIVmac239 challenge controls exhibited ~7 log 10 SIV RNA copies/ml at peak which persisted beyond the acute infection phase. This compared with all three vaccine groups where post wtSIVmac239 viral RNA levels were markedly reduced among SIVrtTA vaccinates with a more pronounced vaccine effect among Group A vaccinates. Viral RNA was un-detectable in one SIVrtTA vaccinate (Group A) and in the 2 log 10 range in another (Group B). The highest levels of protection in SIVrtTA vaccinates cor- related with an enhanced persistence of SIVrtTA as circu- lating viral RNA in the immediate post-acute infection vaccine period. Retrospective sequence analysis recovered from SIVrtTA vaccinates indicated a selection of sequence variants in the LTR promoter region and the Tat and rtTA genes that do not affect doxycycline control but which may have influenced replication in vivo. Vaccination with SIVrtTA induced a marked vaccine effect which will enable from Frontiers of Retrovirology: Complex retroviruses, retroelements and their hosts Montpellier, France. 21-23 September 2009 Published: 24 September 2009 Retrovirology 2009, 6(Suppl 2):P13 doi:10.1186/1742-4690-6-S2-P13 <supplement> <title> <p>Frontiers of Retrovirology: Complex retroviruses, retroelements and their hosts</p> </title> <note>Meeting abstracts - A single PDF containing all abstracts in this Supplement is available <a href="http://www.biomedcentral.com/content/files/pdf/1742-4690-6-S2-full.pdf">here</a>.</note> <url>http://www.biomedcentral.com/content/pdf/1742-4690-6-S2-info.pdf</url> </supplement> This abstract is available from: http://www.retrovirology.com/content/6/S2/P13 © 2009 Berry et al; licensee BioMed Central Ltd.
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Transcript of Replication kinetics and persistence of a conditionally live attenuated SIV (SIVrtTA) in vivo...
BioMed CentralRetrovirology
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Open AccePoster presentationReplication kinetics and persistence of a conditionally live attenuated SIV (SIVrtTA) in vivo confers protection against SIVmac239 wild-type challenge in a rhesus macaque modelNeil Berry*1, Atze Das2, Mark Page1, Hannah Tudor1, Mark Robinson1, Ruby Quartey-Papafio1, William Elsley1, Deborah Ferguson1, Bo Li1, Wendy Kleibeuker2, Bep Klaver2, Maria Manoussaka3, Richard Stebbings1, Martin Cranage3, Ben Berkhout2 and Neil Almond1Address: 1NIBSC, Division of Retrovirology, Health Protection Agency, South Mimms, Herts, EN6 3QG , UK, 2Laboratory of Experimental Virology, Department of Medical Microbiology, Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center of the University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands and 3Division of Cellular and Molecular Medicine, St. George's University of London, London, SW17 0RE, UK
* Corresponding author
Vaccination with live attenuated SIV confers potent pro-tection against wild-type SIV challenge in the SIV/macaque model of HIV. Although safety concerns pre-clude the direct application of this vaccine approach inhumans, a clearer understanding of its mechanism of pro-tection may lead to the development of novel AIDS vac-cines. A novel live attenuated SIVmac239 Δnef vaccine(SIVrtTA), dependent on doxycycline administration forreplication, has been evaluated in vivo and its ability toprotect against pathogenic SIV challenge determined. Twogroups of six Indian rhesus macaques (Groups A and B)were vaccinated with SIVrtTA with an oral doxycyclinedosing regime for 6 months. In Group A, doxycycline wasstopped for 8 weeks before wtSIVmac239 challenge. Athird group was vaccinated with a conventionalSIVmac239Δnef vaccine. In the presence of doxycycline,all 12 macaques receiving SIVrtTA were infected exhibit-ing peak SIV RNA levels (log10 3-5 SIV RNA copies/ml)which declined in all macaques but persisted at higher lev-els in three SIVrtTA vaccinates. Levels of virus replicationmeasured by independent qRT-PCR and qDNA PCRassays were lower in SIVrtTA vaccinates compared withthe SIVmac239Δnef vaccine which peaked in the log10 4-6
SIV RNA copies/ml range. No escape from doxycyclinedependence was identified. Upon challenge with wild-type SIVmac239 and compared with naive challenge con-trols (Group D), a significant vaccine effect was observedin all three vaccine groups, assessed by the comparativereduction of circulating viral RNA in plasma. NaivewtSIVmac239 challenge controls exhibited ~7 log10 SIVRNA copies/ml at peak which persisted beyond the acuteinfection phase. This compared with all three vaccinegroups where post wtSIVmac239 viral RNA levels weremarkedly reduced among SIVrtTA vaccinates with a morepronounced vaccine effect among Group A vaccinates.Viral RNA was un-detectable in one SIVrtTA vaccinate(Group A) and in the 2 log10 range in another (Group B).The highest levels of protection in SIVrtTA vaccinates cor-related with an enhanced persistence of SIVrtTA as circu-lating viral RNA in the immediate post-acute infectionvaccine period. Retrospective sequence analysis recoveredfrom SIVrtTA vaccinates indicated a selection of sequencevariants in the LTR promoter region and the Tat and rtTAgenes that do not affect doxycycline control but whichmay have influenced replication in vivo. Vaccination withSIVrtTA induced a marked vaccine effect which will enable
from Frontiers of Retrovirology: Complex retroviruses, retroelements and their hostsMontpellier, France. 21-23 September 2009
Published: 24 September 2009
Retrovirology 2009, 6(Suppl 2):P13 doi:10.1186/1742-4690-6-S2-P13
<supplement> <title> <p>Frontiers of Retrovirology: Complex retroviruses, retroelements and their hosts</p> </title> <note>Meeting abstracts - A single PDF containing all abstracts in this Supplement is available <a href="http://www.biomedcentral.com/content/files/pdf/1742-4690-6-S2-full.pdf">here</a>.</note> <url>http://www.biomedcentral.com/content/pdf/1742-4690-6-S2-info.pdf</url> </supplement>
This abstract is available from: http://www.retrovirology.com/content/6/S2/P13
© 2009 Berry et al; licensee BioMed Central Ltd.
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Retrovirology 2009, 6(Suppl 2):P13 http://www.retrovirology.com/content/6/S2/P13
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the role of viral persistence to be evaluated in this vaccina-tion strategy. SIVrtTA represents a new tool to develop anddesign novel AIDS vaccines.
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