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Andrea Savarino

Epigenetic drug Gar1041 in combination with antiretroviral therapy (ART) transiently reduces the proviral DNA reservoir in SIVmac251-infected macaques. Andrea Savarino. Objectives.

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Andrea Savarino

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  1. Epigenetic drug Gar1041 in combination with antiretroviral therapy (ART) transiently reduces the proviral DNA reservoir in SIVmac251-infected macaques Andrea Savarino

  2. Objectives • To develop an antiretroviral treatment regimen in SIV infected macaques that could be used to test eradication strategies • To increase the numbers and classes of effective antiviral drug for use in macaques that mirror treatments in human HIV cases • To initiate preliminary studies to determine if virus eradication or disease alteration is possible

  3. Virus Reservoirs Eradication • Prevent any virus spread by intensified ART • Target multiple sites of viral inhibition • Induce latently infected cells to replicate virus • Histone deacetylase inhibitors • Eliminate productive/infected cells • Virus replication/cytotoxicity • Immune response • Passive therapies

  4. Stimulation of HIV-1 LTR-controlled expression of GFP by MS-275 and buthionine sulfoximine (BSO) in a Jurkat cell clone (A1). Savarino, et al., Retrovirology 2009.

  5. NF-kB nuclear translocation Reactive oxygen species (ROS) induction Gar1041 72 h Gar1041 12 h Gar 1041 3 h TNF-a 72 h Pos. control (TNF-a 1.5 h) ACH2 ctrl 0.6 μM GAR1041 p24 induction Gar1041 Gar1041 Gar1041

  6. CD27 Downregulation TN TCM TTM TEM Mock 50nM Gar1041

  7. Response of SIVmac251-infected macaques to raltegravir RAL + PMPA + FTC RAL RAL + PMPA + FTC RAL RAL- 100mg BID, oral PMPA - 20mg/kg, SQ FTC – 50mg/kg, SQ Lewis M. Norelli S., et al., Retrovirology 2010.

  8. Treatment of monkeys with ART plus Gar1041 P < 0.05 *P < 0.05 **P < 0.01 ***P < 0.001 P < 0.05

  9. Darunavir (DRV) complexed with HIV-2 protease DRV complexed with SIVmac251 protease Kovalevsky et al., 2008 Barreca ML, Norelli S, and Savarino A, unpublished

  10. Addition of Ritonavir-boosted Darunavir to the ART/Gar1041 regimen *P < 0.05

  11. Proviral DNA in PBMC from SIV+ Macaques Following Addition of Ritonavir-boosted Darunavir ART/Gar1041 Regimen. iART/Gar1041 (average trend over time: P = 0.0207; t-test for regression). iART alone (average trend over time: P = 0.8878; t-test for regression).

  12. Stimulation of viral replication by histone deacetylase inhibitor, SAHA in SIVmac251-infected monkeys treated with intensified ART (iART) alone but not in monkeys SIVmac251-infected monkeys treated with iART and Gar1041 *P < 0.05 **P < 0.01 iART alone iART plus Gar1041

  13. Re-appearance of viral loads following treatment suspension Intensified ART alone Intensified ART plus Gar1041 * 3 SAHA cycles 2 SAHA cycles * *P < 0.05; Gehan-Breslow-Wilcoxon test for survival

  14. Drug free remission… eventually? iART plus Gar1041 iART alone *P < 0.05; paired Student’s t-test

  15. Drug free remission… eventually? iART alone iART plus Gar1041

  16. Conclusions Preliminary studies using oxidative stress inducing agents indicate the utility of the simian model to assess in-vivo the effectiveness of treatments that may stimulate the removal of latently infected cells Our findings suggest that Gar1041 impacts the proviral DNA reservoir in SIVmac251-infected macaques under treatment with ART, likely acting by an entirely novel mechanism (differentiation of long-lived or proliferation-competent memory T cells into short-lived effector-like phenotypes). They also highlight the need for ART intensification when adopting drugs capable of inducing HIV-1 replication.

  17. Acknowledgments Bioqual Matt Collins Jake Yalley-Ogunro University of Rome “Tor Vergata” Jack Greenhouse Enrico Garaci Wendy Wagner ICGEB Istituto Superiore di Sanità, RomeMarina Lusic Sandro Norelli Barbara Chirullo University of Rome, La Sapienza Marco Sgarbanti Rossella Sgarbanti Andrea Savarino Anna Teresa Palamara

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