Animal model of elite controlled infection SIVagm.sab Infection of Rhesus Macaques

1. Animal model of elite controlled infection SIVagm.sab Infection of Rhesus Macaques CristianApetrei Center for Vaccine Research, University of Pittsburgh Tulane National Primate Research Center, Covington, LA

2. Background Elite controlled (EC) HIV infection • infection for more than 7 years • stable CD4+ T cell counts (greater than 600 cells/l) • low/undetectable levels of HIV in the peripheral blood; • no symptoms of HIV-induced disease In some of these patients • presence of a vigorous, multifunctional, persistent immune response against HIV • Association with particular MHC alleles (HLA-B57 and HLA-B27)

3. Background Elite controlled (EC) HIV infection • infection for more than 7 years • stable CD4+ T cell counts (greater than 600 cells/l) • low/undetectable levels of HIV in the peripheral blood; • no symptoms of HIV-induced disease In some of these patients • presence of a vigorous, multifunctional, persistent immune response against HIV • Association with particular MHC alleles (HLA-B57 and HLA-B27) • all these features occur in the absence of any antiretroviral therapy.

4. Background Elite controlled (EC) HIV infection • infection for more than 7 years • stable CD4+ T cell counts (greater than 600 cells/l) • low/undetectable levels of HIV in the peripheral blood; • no symptoms of HIV-induced disease In some of these patients • presence of a vigorous, multifunctional, persistent immune response against HIV • Association with particular MHC alleles (HLA-B57 and HLA-B27) • all these features occur in the absence of any antiretroviral therapy. Study of EC infection in humans may generate essential information for designing new strategies to control HIV infection

5. Background Limitations • Most of the EC infections are identified when they meet the criteria, i.e., AFTER infection is controlled • It is likely that EC infection occurs as a consequence of the interaction between host and possibly viral factors early during infection and driving it to the EC status. THESE FACTORS ARE PROBABLY ACTING AT THE TIME OF THE ACTIVE INFECTION (during the acute infection? – likely) Need for an animal model of EC infection!

6. RM Infection with SIVagm High levels of viral replication during acute infection Massive mucosal CD4+ T cell depletion during acute infection

7. RM Infection with SIVagm High levels of viral replication during acute infection, followed by complete control during the chronic stage (6 years p.i.) Massive mucosal CD4+ T cell depletion during acute infection

8. RM Infection with SIVagm High levels of viral replication during acute infection, followed by complete control during the chronic stage (6 years p.i.) Massive mucosal CD4+ T cell depletion during acute infection, followed by COMPLETE mucosal CD4+ T cell restoration

9. Complete Control of SIVagm Replication in Rhesus Macaques Seroreversion (with the control of viral replication) Control of virus replication at mucosal and lymphoid sites INT LNs PBMCs

10. Is the Control of SIVagm Infection Due to Host Restriction Factors? RMs AGMs In vitro SIVagm replication on RM PBMCs Similar rates of hypermutation in AGMs and RMs

11. Is the EC SIVagm Infection in RMs Resulting from a Restricted Viral Replication in Tissues During Acute Infection? SIVagm.sab RNA copies/ml Day postinfection

12. SIVagm Replication in RM Tissues is not Restricted to Particular Anatomical Sites SIVagm.sab RNA copies/166 cells Animal and time point of necropsy

13. RM Infection with SIVagm CD8 cell depletion with cM-T807 mAb High levels of viral replication during acute infection, followed by complete control during the chronic stage (6 years p.i.) Massive mucosal CD4+ T cell depletion during acute infection, followed by COMPLETE mucosal CD4+ T cell restoration

14. In vivo CD8+ Cell Depletion in RMs after 4 Years of Elite Controlled SIVagm Infection Percent of peripheral CD8+ T cells Absolute counts of peripheral CD8+ T cells

15. Elite Control of SIVagm Replication is Reverted by In Vivo CD8+ Cell Depletion in RMs

16. Elite Control of SIVagm Replication is Reverted by In Vivo CD8+ Cell Depletion in RMs

17. Rebound of SIVagm Replication Resulted in a Second CD4+ T Cell Depletion Peripheral blood Intestine

18. In vivo CD8+ Cell Depletion Results in Inceases in CD4+ T Cell Immune Activation Peripheral blood Intestine

19. Conclusions • SIVagm infection is completely controlled in RMs • Control is not due to restricted viral replication during acute infection • Although control through host restriction factors cannot be ruled out, APOBEC restriction seems unlikely • CD8 depletion in vivo experiments suggested control through cellular immune effectors

20. Applications • This animal model of EC infection permit the study of early events of infection, before the virus is controlled. It can be used to: • clearly establish if immune responses or innate responses can control viral replication in EC-essential for the design of effective preventive and therapeutic vaccine approaches • assess the role of immune activation in driving viral replication, to design effective immunotherapies aimed at preventing disease progression; • assess the timing of virus spread and control in different tissues, which is of importance for both vaccine strategies and HIV therapy aimed at preferentially targeting the main sites of viral replication and persistence; • determine what T cell subsets are spared/restored in EC infection in order to develop vaccines or therapies aimed in preservation of these cell populations.

21. Acknowledgements • TNPRC • Ronald Veazey • Preston Marx • Andrew Lackner • Jason Dufour • Marion Ratterree • NIH, NIAID • Vanessa Hirsch Apetrei /Pandrea labs (TNPRC) ThaidraGaufin, PhD Rajeev Gautam, DVM, PhD Daniel Mandell Jeanne MacFarland Melissa Pattison Apetrei /Pandrea labs (Pitt) David Kuhrt, PhD ViskamWijewardana, DVM, PhD Dongzhou Ma, PhD Julia Nyaoundy, DVM Laura Catchpole Rebecca Nusbaum Rebecca Garlena Brandy Cox Funded by NIH/NCRR/NIAID R01 RR025781 (IP, CA); RO1 AI065325 (CA) RO1 AI064066 (IP); AMFAR (CA)