Effects of Acitretin on the activation of latent HIV


Principal Investigator: Peilin Li
Abstract: DESCRIPTION: More than 33 million people in the world live with HIV. Treatment with highly active antiretroviral therapy (HAART) has been successful, but therapy is not curative. HIV can establish a state of latency in individual T cells, and HIV is persistently produced in HIV patient, despite undetectable viral loads. The latent HIV reservoir is a major hurdle preventing the eradication and cure of HIV-1. Lifelong HAART is required, because the virus rebounds if HAART is stopped;however, prolonged HAART is costly and associated with various toxicities. Therefore, finding a way to eradicate latent HIV-1 has become an important goal. Acetylation of histone is involved in HIV latency through effects on chromatin structure, a process controlled by two families of enzymes: histone acetyl-transferases (HAT), and histone deacetylases (HDAC). It has been demonstrated that HDAC activation limits HIV-1 transcription, and HAT activation favors HIV-1 transcription. HDAC inhibitors (HDACi) are able to induce HIV-1 transcription in models of HIV latency. We have found that acitretin can induce HIV-1 transcription in HIV latent cell lines and CD4 T cells from HAART suppressed HIV patients. acitretin is a retinoic acid, which can activate HAT. Retinoic acid (RA) receptor RAR and RXR are nuclear retinoid receptors which act as transcription factors. In response to RA binding, RAR/RXR undergo conformational changes and co-activate HAT to recruit mediators into the RNA Pol II complex to initiate gene transcription. RA also upregulates interferon (IFN) regulator factor -1 (IRF-1) expression and IRF-1 is highly expressed in activated, but not in resting, CD4 T cells. IRF-1 is required for full NF-kb transcriptional activity at the HIV-1LTR, and is also required for efficient HIV replication. IRF-1 also can interact with HAT, such as p300/CBP (cAMP-responsive-element-binding factor (CREB)-binding protein) to evoke HIV transcription from the LTR in the absence of Tat. RA can also increase p300/CBP expression;p300/CBP acetylates HIV-Tat on a nucleosome (nuc) assembled HIV proviral DNA to increase transcription of HIV-1. In preliminary studies, we found that acitretin alone is a weak activator o HIV-1 transcription compare to suberoylanilide hydroxamic acid (SAHA) (HDACi), or the phorbol ester, prostratin, but acts synergistically with SAHA or prostratin to greatly induce HIV expression from latently infected cells. Acitretin treatment increases RXR, IRF-1 and p300 expression but does not induce polyclonal activation of CD4 T cells as measured by gene expression and cell surface immunophenotyping for markers of T cell activation. We propose this R21 project to define acitretin as a new drug for use in combination treatment to reduce the latent HIV reservoir. The aims of this project are to characterize mechanisms of acitretin activation of HIV-1 transcription in cell lines latently infected with HIV (Aim1) and to define thein vitro activity of acitretin alone and in combination with HDACi or phorbol esters for inducing vira transcription and clearance of CD4 T cells carrying HIV from HIV patients on suppressive HAART (Aim2) as the first steps in the development of a novel strategy for HIV eradication.
Funding Period: 2013-08-08 - 2015-07-31
more information: NIH RePORT

Detail Information

Research Grants30

  1. The Shelf Live Evaluation of Investigational Dosage Forms
    Jonathan White; Fiscal Year: 2013
    ..This contract is essential for continued assurance of the quality of drugs undergoing clinical investigation for different types of cancer by Cancer Therapeutics Evaluation Program. ..
  2. Role of Chromatin and Gene Poising in T Cell Differentiation and Activation
    Artem Barski; Fiscal Year: 2013
    ..Taken together, results of these studies will contribute to our understanding of acquired immune response. ..
  3. Role of Factor Acetylation in the Regulation of HIV Transcription
    MELANIE MARIA OTT; Fiscal Year: 2013
    ..We anticipate that these studies will increase our molecular understanding of the biology of HIV transcription and provide novel insight into the therapeutic potential of HDAC inhibitors in HIV infection. ..
  4. HIV Tropism, Persistence, Inflammation and Neurocognition in Therapy Initiation
    RONALD I SWANSTROM; Fiscal Year: 2013
    ..Collectively, these studies will bring a detailed understanding of viral replication and viral evolution, with the attendant issues of inflammation and neuronal damage, ..
  5. Targeted Modification of Host and Proviral DNA to Treat Latent HIV Infection
    Hans Peter Kiem; Fiscal Year: 2013
    ..Given our leading roles in Transplantation and HIV research, we believe we are uniquely positioned to move these concepts from a highly relevant nonhuman primate HIV/SHIV model toward a cure for HIV-infected patients. ..
  6. B-cell Biology of Mucosal Immune Protection from SIV Challenge
    Eric Hunter; Fiscal Year: 2013
  7. Targeting Pten - An Upstream, Downstream and Offstream Approach
    ZE apos EV A RONAI; Fiscal Year: 2013
    ..abstract_text> ..
  8. Optical Technologies and Molecular Imaging for Cervical Neoplasia
    Michele Follen; Fiscal Year: 2013
    ..abstract_text> ..
    Thomas J Kipps; Fiscal Year: 2013
    ..abstract_text> ..
    Katherine A Jones; Fiscal Year: 2013
    ..Together, these experiments will better define the Tat transactivation mechanism and its role in p21Cip1 downregulation and T cell apoptosis. ..
  11. HIV Latency, Epigenetics, and Therapeutics
    David M Margolis; Fiscal Year: 2013
    ..Therefore a more detailed understanding is needed of the epigenetic mechanisms behind persistent infection. ..
  12. Epigenetic regulation of HIV latency
    ERIC M VERDIN; Fiscal Year: 2013
    ..Here we propose to study the role of epigenetic modifications in HIV latency and the possible role of drugs that modify epigenetic silencing as a novel therapeutic approach to induce the reactivation of latent HIV. ..
  13. CCR5 Regulation and Promoter Variants in HIV-1
    Srinivas Mummidi; Fiscal Year: 2013
    ..These studies may result in advancing our knowledge about factors that influence HIV-AIDS susceptibility. ..
  14. Molecular mechanisms in the regulation of p53 functions by PAD4
    Yanming Wang; Fiscal Year: 2013
    ..Consistent with this idea, inhibition of PAD4 by its inhibitor or depletion of PAD4 by its siRNAs increased the expression of the p53 target gene p21, suggesting that PAD4 is a hopeful novel target for cancer treatment. ..
    John C Crabbe; Fiscal Year: 2013
    ..An Education and Outreach component trains pre- and post-doctoral students in alcohol research, disseminates research findings to the public, and engages in a range of activities with elementary-to-high school students. ..
  16. Northeast Biodefense Center
    W Ian Lipkin; Fiscal Year: 2013
    ..As a Center based in a School of Public Health and a State Department of Health, the NBC has a firm commitment to and practical understanding of Emergency Preparedness. ..
  17. Genome maintenance functions of CREB/ATF transcription factors
    RANDAL SCOT TIBBETTS; Fiscal Year: 2013
  18. Expression of anti-HIV siRNA in Blood Cells
    JOHN JOSEPH ROSSI; Fiscal Year: 2013
    ..The long term goal of these studies is the establishment of a method for activation of latent virus followed by selective purging of these cells from infected individuals, ultimately leading to a cure from HIV-1 infection. ..
  19. Tat Transactivation
    BORIS MATIJA PETERLIN; Fiscal Year: 2013
    ..This proposal will investigate how Tat uses these complexes for optimal HIV replication and how these Cdks could be manipulated pharmacologically in the future. ..
  20. Latent Viral Reservoirs in HIV 1 Infection
    Robert F Siliciano; Fiscal Year: 2013
    ..Curing HIV infection will require new ways to eliminate this latent reservoir. The studies proposed here are designed to find new drugs that can eliminate this latent reservoir. ..
  21. Center for Study of Opioid Receptors and Drugs of Abuse (CSORDA)
    Christopher J Evans; Fiscal Year: 2013
    ..Balleine, Bonci, Koob, Levitt, Nestler and Whybrow ex-officio, will provide programmatic oversight and coordinate training, outreach and a Pilot Program for the center. ..
    Dora L Costa; Fiscal Year: 2013
    ..Project 4 deals with the differences across urban and rural areas in the process of aging. ..
  23. Tat cofactors and control of HIV-1 latency
    Qiang Zhou; Fiscal Year: 2013
    ..The proposed studies may enable the development of novel adjunctive therapeutic strategies to specifically and efficiently eradicate latent HIV reservoirs in infected patients. ..
  24. Novel Epigenetic Roles of the Proteasome in Long-term Synaptic Plasticity
    SVITLANA BACH; Fiscal Year: 2013
  25. A Phase II/II Investigation of the Effect of Vorinostat (VOR) in HIV Infection
    David M Margolis; Fiscal Year: 2013
    ..Histone deacetylase (HDAC) inhibitors disrupt latent proviral infection ex vivo. We will directly assess the effect of HDAC inhibitors on HIV latency in vivo. ..
  26. The contribution of Tcell tolerance to latent HIV infection
    Joseph K Wong; Fiscal Year: 2013