Epigenetic drug Gar1041 in combination with antiretroviral therapy (ART) transiently reduces the pro...
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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

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

Andrea Savarino


Objectives

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


Virus reservoirs eradication

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


Andrea savarino

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.


Andrea savarino

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


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CD27 Downregulation

TN

TCM

TTM

TEM

Mock

50nM Gar1041


Andrea savarino

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.


Andrea savarino

Treatment of monkeys with ART plus Gar1041

P < 0.05

*P < 0.05

**P < 0.01

***P < 0.001

P < 0.05


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Darunavir (DRV) complexed with HIV-2 protease

DRV complexed with SIVmac251 protease

Kovalevsky et al.,

2008

Barreca ML, Norelli S, and Savarino A,

unpublished


Andrea savarino

Addition of Ritonavir-boosted Darunavir to the ART/Gar1041 regimen

*P < 0.05


Andrea savarino

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).


Andrea savarino

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


Andrea savarino

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


Andrea savarino

Drug free remission… eventually?

iART plus Gar1041

iART alone

*P < 0.05; paired Student’s t-test


Andrea savarino

Drug free remission… eventually?

iART alone

iART plus Gar1041


Conclusions

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.


Acknowledgments

Acknowledgments

Bioqual

Matt Collins

Jake Yalley-OgunroUniversity of Rome “Tor Vergata”

Jack Greenhouse Enrico Garaci

Wendy Wagner

ICGEB

Istituto Superiore di Sanità, RomeMarina Lusic

Sandro Norelli

Barbara ChirulloUniversity of Rome, La Sapienza

Marco SgarbantiRossella Sgarbanti

Andrea SavarinoAnna Teresa Palamara


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