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Title: Multi-dose Romidepsin Reactivates Replication Competent SIV in Post-antiretroviral Rhesus Macaque Controllers

Journal Article · · PLoS Pathogens
 [1];  [2];  [2];  [3];  [2];  [3];  [4]; ORCiD logo [2];  [5];  [5];  [6];  [7];  [4];  [4];  [8];  [9];  [10];
  1. Univ. of Pittsburgh, PA (United States). Center for Vaccine Research; Univ. of Pittsburgh, PA (United States). Department of Infectious Diseases and Microbiology, Graduate School of Public Health
  2. Univ. of Pittsburgh, PA (United States). Center for Vaccine Research; Univ. of Pittsburgh, PA (United States). Department of Pathology, School of Medicine
  3. Univ. of Pittsburgh, PA (United States). Center for Vaccine Research; Univ. of Pittsburgh, PA (United States). Department of Microbiology and Molecular Genetics, School of Medicine
  4. Univ. of Pittsburgh, PA (United States). Department of Medicine, Perelman School of Medicine
  5. Univ. of Pittsburgh, PA (United States). Center for Vaccine Research
  6. Univ. of Pittsburgh, PA (United States). Division of Laboratory Animal Resources, School of Medicine
  7. Univ. of Pittsburgh, PA (United States). Department of Medicine, School of Medicine
  8. Los Alamos National Lab. (LANL), Los Alamos, NM (United States). Theoretical Biology and Biophysics Group
  9. Univ. of Pittsburgh, PA (United States). Center for Vaccine Research; Univ. of Pittsburgh, PA (United States). Department of Infectious Diseases and Microbiology, Graduate School of Public Health; Univ. of Pittsburgh, PA (United States). Department of Pathology, School of Medicine
  10. Univ. of Pittsburgh, PA (United States). Center for Vaccine Research; Univ. of Pittsburgh, PA (United States). Department of Infectious Diseases and Microbiology, Graduate School of Public Health; Univ. of Pittsburgh, PA (United States). Department of Microbiology and Molecular Genetics, School of Medicine
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Viruses that persist despite seemingly effective antiretroviral treatment (ART) and can reinitiate infection if treatment is stopped preclude definitive treatment of HIV-1 infected individuals, requiring lifelong ART. Among strategies proposed for targeting these viral reservoirs, the premise of the “shock and kill” strategy is to induce expression of latent proviruses [for example with histone deacetylase inhibitors (HDACis)] resulting in elimination of the affected cells through viral cytolysis or immune clearance mechanisms. Yet,ex vivo studies reported that HDACis have variable efficacy for reactivating latent proviruses, and hinder immune functions. We developed a nonhuman primate model of post-treatment control of SIV through early and prolonged administration of ART and performed in vivo reactivation experiments in controller RMs, evaluating the ability of the HDACi romidepsin (RMD) to reactivate SIV and the impact of RMD treatment on SIV-specific T cell responses. Ten RMs were IV-infected with a SIVsmmFTq transmitted-founder infectious molecular clone. Four RMs received conventional ART for >9 months, starting from 65 days post-infection. SIVsmmFTq plasma viremia was robustly controlled to <10 SIV RNA copies/mL with ART, without viral blips. At ART cessation, initial rebound viremia to ~106 copies/mL was followed by a decline to < 10 copies/mL, suggesting effective immune control. Three post-treatment controller RMs received three doses of RMD every 35–50 days, followed by in vivo experimental depletion of CD8+ cells using monoclonal antibody M-T807R1. RMD was well-tolerated and resulted in a rapid and massive surge in T cell activation, as well as significant virus rebounds (~104 copies/ml) peaking at 5–12 days post-treatment. CD8+ cell depletion resulted in a more robust viral rebound (107 copies/ml) that was controlled upon CD8+ T cell recovery. Our results show that RMD can reactivate SIV in vivo in the setting of post-ART viral control. Comparison of the patterns of virus rebound after RMD administration and CD8+ cell depletion suggested that RMD impact on T cells is only transient and does not irreversibly alter the ability of SIV-specific T cells to control the reactivated virus.

Research Organization:
Los Alamos National Lab, Los Alamos, NM (United States)
Sponsoring Organization:
USDOE National Nuclear Security Administration (NNSA); National Institutes of Health (NIH)/NIAID/NCRR/NHLBI
Grant/Contract Number:
AC52-06NA25396; R01 AI119346; P01 AI088564; R01 RR025781; R01 AI104373; R01 HL117715
OSTI ID:
1627913
Journal Information:
PLoS Pathogens, Vol. 12, Issue 9; ISSN 1553-7374
Publisher:
Public Library of ScienceCopyright Statement
Country of Publication:
United States
Language:
English

References (129)

HIV-1 persistence in CD4+ T cells with stem cell–like properties journal January 2014
HIV-1 infects multipotent progenitor cells causing cell death and establishing latent cellular reservoirs journal March 2010
T Memory Stem Cells and HIV: a Long-Term Relationship journal January 2015
Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy journal November 1997
Identification of a Reservoir for HIV-1 in Patients on Highly Active Antiretroviral Therapy journal November 1997
Recovery of Replication-Competent HIV Despite Prolonged Suppression of Plasma Viremia journal November 1997
Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy journal May 1999
Progressive contraction of the latent HIV reservoir around a core of less-differentiated CD4+ memory T Cells journal November 2014
Follicular helper T‐cell memory: establishing new frontiers during antibody response journal November 2013
Effect of Latent Human Immunodeficiency Virus Infection on Cell Surface Phenotype journal February 2002
Resting CD4+ T Cells from Human Immunodeficiency Virus Type 1 (HIV-1)-Infected Individuals Carry Integrated HIV-1 Genomes within Actively Transcribed Host Genes journal June 2004
Analysis of Human Immunodeficiency Virus Type 1 Gene Expression in Latently Infected Resting CD4+ T Lymphocytes In Vivo journal July 2003
Low-level viremia persists for at least 7 years in patients on suppressive antiretroviral therapy journal March 2008
Hide, shield and strike back: how HIV-infected cells avoid immune eradication journal February 2003
Induction of HIV-1 Replication in Latently Infected CD4 + T Cells Using a Combination of Cytokines journal July 1998
HIV-1 and T cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression journal December 1999
Persistence of HIV-1 Transcription in Peripheral-Blood Mononuclear Cells in Patients Receiving Potent Antiretroviral Therapy journal May 1999
Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection journal May 1997
Predicting the outcomes of treatment to eradicate the latent reservoir for HIV-1 journal August 2014
Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells journal May 2003
Antiretroviral-Free HIV-1 Remission and Viral Rebound After Allogeneic Stem Cell Transplantation: Report of 2 Cases journal September 2014
Long-Term Control of HIV by CCR5 Delta32/Delta32 Stem-Cell Transplantation journal February 2009
Viremic Relapse after HIV-1 Remission in a Perinatally Infected Child journal February 2015
Treatment intensification does not reduce residual HIV-1 viremia in patients on highly active antiretroviral therapy journal May 2009
No Evidence for Decay of the Latent Reservoir in HIV‐1–Infected Patients Receiving Intensive Enfuvirtide‐Containing Antiretroviral Therapy journal January 2010
The Effect of Raltegravir Intensification on Low-level Residual Viremia in HIV-Infected Patients on Antiretroviral Therapy: A Randomized Controlled Trial journal August 2010
A Randomized, Controlled Trial of Raltegravir Intensification in Antiretroviral-treated, HIV-infected Patients with a Suboptimal CD4+ T Cell Response journal April 2011
A Randomized, Placebo-Controlled Trial of Abacavir Intensification in HIV-1–Infected Adults With Virologic Suppression on a Protease Inhibitor–Containing Regimen journal December 2010
Expression of Latent HIV Induced by the Potent HDAC Inhibitor Suberoylanilide Hydroxamic Acid journal February 2009
BET bromodomain-targeting compounds reactivate HIV from latency via a Tat-independent mechanism journal February 2013
The BET bromodomain inhibitor JQ1 activates HIV latency through antagonizing Brd4 inhibition of Tat-transactivation journal October 2012
Recent developments in the search for a cure for HIV-1 infection: Targeting the latent reservoir for HIV-1 journal July 2014
Histone Deacetylase Inhibitor Romidepsin Induces HIV Expression in CD4 T Cells from Patients on Suppressive Antiretroviral Therapy at Concentrations Achieved by Clinical Dosing journal April 2014
Disulfiram Reactivates Latent HIV-1 in a Bcl-2-Transduced Primary CD4+ T Cell Model without Inducing Global T Cell Activation journal April 2011
Coaxing HIV-1 from resting CD4 T cells: histone deacetylase inhibition allows latent viral expression journal January 2004
Death of CD4+ T-Cell Lines Caused by Human Immunodeficiency Virus Type 1 Does Not Depend on Caspases or Apoptosis journal May 2002
Stimulation of HIV-1-Specific Cytolytic T Lymphocytes Facilitates Elimination of Latent Viral Reservoir after Virus Reactivation journal March 2012
Comparison of HDAC inhibitors in clinical development: Effect on HIV production in latently infected cells and T-cell activation journal May 2013
New ex vivo approaches distinguish effective and ineffective single agents for reversing HIV-1 latency in vivo journal March 2014
Depletion of latent HIV-1 infection in vivo: a proof-of-concept study journal August 2005
Reactivation of latent HIV by histone deacetylase inhibitors journal June 2013
HDAC inhibitors in HIV journal November 2011
The Depsipeptide Romidepsin Reverses HIV-1 Latency In Vivo journal September 2015
Elevated Plasma Viral Loads in Romidepsin-Treated Simian Immunodeficiency Virus-Infected Rhesus Macaques on Suppressive Combination Antiretroviral Therapy journal December 2015
Histone Deacetylase Inhibitors Impair the Elimination of HIV-Infected Cells by Cytotoxic T-Lymphocytes journal August 2014
The Challenge of Finding a Cure for HIV Infection journal March 2009
Quantification of HIV-1 latency reversal in resting CD4+ T cells from patients on suppressive antiretroviral therapy journal March 2014
Defective Human Immunodeficiency Virus-Specific CD8+ T-Cell Polyfunctionality, Proliferation, and Cytotoxicity Are Not Restored by Antiretroviral Therapy journal September 2009
Primary CD8+ T cells from elite suppressors effectively eliminate non-productively HIV-1 infected resting and activated CD4+T cells journal July 2013
Effect of Histone Deacetylase Inhibitors on HIV Production in Latently Infected, Resting CD4+ T Cells From Infected Individuals Receiving Effective Antiretroviral Therapy journal June 2012
Treatment of chronically FIV-infected cats with suberoylanilide hydroxamic acid journal August 2014
Broad CTL response is required to clear latent HIV-1 due to dominance of escape mutations journal January 2015
Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys journal October 2013
HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation journal June 2009
Novel Cell and Gene Therapies for HIV journal October 2012
Nonhuman Primate Models for HIV Cure Research journal August 2012
Animal Models for HIV Cure Research journal January 2016
Loss of Function of Intestinal IL-17 and IL-22 Producing Cells Contributes to Inflammation and Viral Persistence in SIV-Infected Rhesus Macaques journal February 2016
A Highly Intensified ART Regimen Induces Long-Term Viral Suppression and Restriction of the Viral Reservoir in a Simian AIDS Model journal June 2012
Short Communication: Comparative Evaluation of Coformulated Injectable Combination Antiretroviral Therapy Regimens in Simian Immunodeficiency Virus-Infected Rhesus Macaques journal February 2016
Rapid seeding of the viral reservoir prior to SIV viraemia in rhesus monkeys journal July 2014
HIV-1 infection, response to treatment and establishment of viral latency in a novel humanized T cell-only mouse (TOM) model journal January 2013
From reactivation of latent HIV-1 to elimination of the latent reservoir: The presence of multiple barriers to viral eradication: Review essays journal April 2013
Post-Treatment HIV-1 Controllers with a Long-Term Virological Remission after the Interruption of Early Initiated Antiretroviral Therapy ANRS VISCONTI Study journal March 2013
Genetic Identity and Biological Phenotype of a Transmitted/Founder Virus Representative of Nonpathogenic Simian Immunodeficiency Virus Infection in African Green Monkeys journal September 2010
Serum Immune Activation Markers Are Persistently Increased in Patients with HIV Infection after 6 Years of Antiretroviral Therapy despite Suppression of Viral Replication and Reconstitution of CD4 + T Cells journal October 2009
Biomarkers of immune dysfunction following combination antiretroviral therapy for HIV infection journal April 2011
Plasma HIV Viral Rebound following Protocol-Indicated Cessation of ART Commenced in Primary and Chronic HIV Infection journal August 2012
New Tools for Quantifying HIV-1 Reservoirs: Plasma RNA Single Copy Assays and Beyond journal January 2012
Simian Immunodeficiency Virus SIVsab Infection of Rhesus Macaques as a Model of Complete Immunological Suppression with Persistent Reservoirs of Replication-Competent Virus: Implications for Cure Research journal April 2015
Measurement of Cell Death in Mammalian Cells journal March 2012
Constitutive expression of CD69 in interspecies T-cell hybrids and locus assignment to human chromosome 12 journal June 1992
The end of AIDS: HIV infection as a chronic disease journal November 2013
Decay characteristics of HIV-1-infected compartments during combination therapy journal May 1997
Combination of romidepsin with cyclophosphamide, doxorubicin, vincristine, and prednisone in previously untreated patients with peripheral T-cell lymphoma: a non-randomised, phase 1b/2 study journal April 2015
Electrocardiographic effects of class 1 selective histone deacetylase inhibitor romidepsin journal April 2015
Short-Course Antiretroviral Therapy in Primary HIV Infection journal January 2013
Duration of HIV-1 Viral Suppression on Cessation of Antiretroviral Therapy in Primary Infection Correlates with Time on Therapy journal October 2013
Immunological biomarkers predict HIV-1 viral rebound after treatment interruption journal October 2015
Immunovirologic Control 24 Months After Interruption of Antiretroviral Therapy Initiated Close to HIV Seroconversion journal September 2012
Activation of HIV Transcription with Short-Course Vorinostat in HIV-Infected Patients on Suppressive Antiretroviral Therapy journal November 2014
Quantitation of Replication-Competent HIV-1 in Populations of Resting CD4+ T Cells journal September 2014
Replication-Competent Noninduced Proviruses in the Latent Reservoir Increase Barrier to HIV-1 Cure journal October 2013
How to Define the Latent Reservoir: Tools of the Trade journal February 2016
Progress Toward HIV Eradication: Case Reports, Current Efforts, and the Challenges Associated with Cure journal January 2016
In vitro characterization of primary SIVsmm isolates belonging to different lineages. In vitro growth on rhesus macaque cells is not predictive for in vivo replication in rhesus macaques journal June 2007
TRIM5 Suppresses Cross-Species Transmission of a Primate Immunodeficiency Virus and Selects for Emergence of Resistant Variants in the New Species journal August 2010
Simian Immunodeficiency Virus SIVagm.sab Infection of Caribbean African Green Monkeys: a New Model for the Study of SIV Pathogenesis in Natural Hosts journal April 2006
Rapid production and clearance of HIV-1 and hepatitis C virus assessed by large volume plasma apheresis journal November 1999
Current Estimates for HIV-1 Production Imply Rapid Viral Clearance in Lymphoid Tissues journal September 2010
Deep Gene Sequence Cluster Analyses of Multi-Virus-Infected Mucosal Tissue Reveal Enhanced Transmission of Acute HIV-1 journal January 2021
A Randomized, Placebo-Controlled Trial of Abacavir Intensification in HIV-1–Infected Adults With Virologic Suppression on a Protease Inhibitor–Containing Regimen journal January 2010
Expression of Latent HIV Induced by the Potent HDAC Inhibitor Suberoylanilide Hydroxamic Acid text January 2009
HIV-1 infection, response to treatment and establishment of viral latency in a novel humanized T cell-only mouse (TOM) model text January 2013
No Evidence for Decay of the Latent Reservoir in HIV‐1–Infected Patients Receiving Intensive Enfuvirtide‐Containing Antiretroviral Therapy text January 2010
Short-Course Antiretroviral Therapy in Primary HIV Infection journal May 2013
The Effect of Raltegravir Intensification on Low-level Residual Viremia in HIV-Infected Patients on Antiretroviral Therapy: A Randomized Controlled Trial text January 2010
Serum immune activation markers are persistently increased in patients with HIV infection after 6 years of antiretroviral therapy despite suppression of viral replication and reconstitution of CD4+ T cells. journal October 2009
Histone deacetylase inhibitor romidepsin induces HIV expression in CD4 T cells from patients on suppressive antiretroviral therapy at concentrations achieved by clinical dosing. journal April 2014
Measurement of Cell Death in Mammalian Cells journal June 2004
Disulfiram Reactivates Latent HIV-1 in a Bcl-2-Transduced Primary CD4+ T Cell Model without Inducing Global T Cell Activation text January 2011
Predicting the outcomes of treatment to eradicate the latent reservoir for HIV-1 text January 2014
HIV “cure”: A shot in the arm? journal April 2019
Valproic acid: a potential role in treating latent HIV infection journal August 2005
Barriers to a cure for HIV: new ways to target and eradicate HIV-1 reservoirs journal June 2013
HIV infection: epidemiology, pathogenesis, treatment, and prevention journal July 2014
Meeting an unmet need for peripheral T-cell lymphoma journal April 2015
Second hideout for HIV-1 journal May 2010
Absence of Detectable HIV-1 Viremia after Treatment Cessation in an Infant journal November 2013
Histone Deacetylase Inhibitors (HDACis) That Release the Positive Transcription Elongation Factor b (P-TEFb) from Its Inhibitory Complex Also Activate HIV Transcription journal March 2013
Considerations in the development of nonhuman primate models of combination antiretroviral therapy for studies of aids virus suppression, residual virus, and curative strategies journal May 2013
Relationship of HIV reservoir characteristics with immune status and viral rebound kinetics in an HIV therapeutic vaccine study journal January 2014
The size of the expressed HIV reservoir predicts timing of viral rebound after treatment interruption journal November 2015
Treatment interruption in chronically HIV-infected patients with an ultralow HIV reservoir journal January 2016
Plasma Viremia and Cellular HIV-1 DNA Persist Despite Autologous Hematopoietic Stem Cell Transplantation for HIV-Related Lymphoma journal January 2013
Effect of Suberoylanilide Hydroxamic Acid (SAHA) Administration on the Residual Virus Pool in a Model of Combination Antiretroviral Therapy-Mediated Suppression in SIVmac239-Infected Indian Rhesus Macaques journal September 2014
New Real-Time Reverse Transcriptase-Initiated PCR Assay with Single-Copy Sensitivity for Human Immunodeficiency Virus Type 1 RNA in Plasma journal October 2003
Virus Subtype-Specific Features of Natural Simian Immunodeficiency Virus SIVsmm Infection in Sooty Mangabeys journal May 2007
Rapid Viral Decay in Simian Immunodeficiency Virus-Infected Macaques Receiving Quadruple Antiretroviral Therapy journal September 2006
Selected Drugs with Reported Secondary Cell-Differentiating Capacity Prime Latent HIV-1 Infection for Reactivation journal June 2012
Simian Immunodeficiency Virus Infects Follicular Helper CD4 T Cells in Lymphoid Tissues during Pathogenic Infection of Pigtail Macaques journal January 2013
HIV Latency in the Humanized BLT Mouse journal November 2011
Effects of Prostratin on T-Cell Activation and Human Immunodeficiency Virus Latency journal August 2002
Repeated Low-Dose Mucosal Simian Immunodeficiency Virus SIVmac239 Challenge Results in the Same Viral and Immunological Kinetics as High-Dose Challenge: a Model for the Evaluation of Vaccine Efficacy in Nonhuman Primates journal March 2004
Molecular Epidemiology of Simian Immunodeficiency Virus SIVsm in U.S. Primate Centers Unravels the Origin of SIVmac and SIVstm journal July 2005
CD4 T follicular helper cell dynamics during SIV infection journal September 2012
Interleukin-21 combined with ART reduces inflammation and viral reservoir in SIV-infected macaques journal October 2015
Finding a Cure for HIV: Much Work to Do journal September 2014
HIV-1 DNA predicts disease progression and post-treatment virological control journal September 2014

Cited By (5)

Mucosal antibody responses to vaccines targeting SIV protease cleavage sites or full-length Gag and Env proteins in Mauritian cynomolgus macaques journal August 2018
Monkey Models and HIV Vaccine Research book January 2018
The B-Cell Follicle in HIV Infection: Barrier to a Cure journal January 2018
African green monkeys avoid SIV disease progression by preventing intestinal dysfunction and maintaining mucosal barrier integrity journal March 2020
Modeling Kick-Kill Strategies toward HIV Cure journal August 2017

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