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Molecular mechanisms of HIV latency and reactivation from latency

POLONEZ 1

Fellowship registration number: 2015/19/P/NZ6/02188

Description

Major reason that a cure for HIV continues to elude us is that the virus hides away in cells, forming a persistent reservoir in which the virus is dormant (i.e. latent), and in such cells the virus is not visible to the immune system and to antiretroviral therapy. Consequently, latency persists, cannot be eliminated and represent a major hurdle to finding a cure.  Latency is a very complex phenomenon and results from multiple molecular mechanisms that block HIV gene expression. Most of the characterized molecular mechanisms of HIV latency suppress the HIV transcription (transcriptional latency), however virus can also be inhibited at the steps following HIV transcription (posttranscriptional latency). Our research is focusing on understanding the molecular mechanisms that leads to HIV latency with the special emphasis on less-characterised posttranscriptional HIV latency. Recent findings clearly show that current strategies (i.e. „shock-and-kill”) are not efficient to eliminate the latent reservoir. Consequently, targeting both transcriptional and posttranscriptional blocks may positively impact the development of more efficient “shock-and-kill” strategies. 

 

Research Interests

  • Virus-host interactions.
  • HIV transcription and posttranscriptional processes.
  • Molecular mechnisms leading to HIV latency/reactivation from latency.
  • Implications for therapeutic approaches.

Education & Experience

  • 2009: PhD dissertation, International Centre for Genetic Engineering and Biotechnology (Italy) affiliated with Open University (United Kindgom).
  • 2017-untill now: POLONEZ fellowship from the National Science Centre co-funded from the EU H2020 Marie Skłodowska-Curie Actions, Malopolska Centre of Biotechnology (MCB), Jagiellonian University, Krakow, Poland.
  • 2013-2016: Post-doctoral fellow at the Universitè Libre de Bruxelles (ULB), the Institute of Molecular Biology and Medicine (IBMM), Gosselies, Belgium.
  • 2009-2012: Post-doctoral fellow at the International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy. 
  • 2005-2009: PhD studies at the International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy.
  • 2000-2005: MSc studies at the Faculty of Biology, University of Gdansk, Gdansk, Poland.
  • 2004: Internship at the Biosearch Technologies Chemistry for Genomics, Novato, California, USA.

Grants

  • 2017-2019: POLONEZ-1 program from the National Science Centre co-funded from the EU H2020 Marie Skłodowska-Curie Actions (PI: Anna Kula-Pacurar).
  • 2014-2016: Les Amis des Instituts Pasteur à Bruxelles.
  • 2009-2011: Central European Initiative Research Fellowship Programme (CERES). SP3 People Marie Składowska-Curie Actions

Publications

Kula A, Delacourt N, Bouchat S, Darcis G, Avettand-Fenoel V, Verdikt R, Corazza F, Necsoi C, Vanhulle C, Bendoumou M, Burny A, De Wit S, Rouzioux C, Rohr O and Van Lint O. Heterogeneous HIV-1 reactivation patterns of disulfiram and combined disulfiram+romidepsin treatments. J Acquir Immune Defic Syndr. 2019 Apr 15;80(5):605-613

Sarracino A, Gharu L, Kula A, Pasternak A, Avettand-Fenoel V, Rouzioux C, Bardina M, De Witt S, Benkirane M, Berkhout B, Van Lint C and Marcello A. Post-transcriptional regulation 1of HIV-1 gene expression during replication and reactivation from latency by nuclear matrix protein MATR3. MBio. 2018 Nov 13;9(6)

Fauguenoy S, Robette G*, Kula A*, Vanhulle C, Bouchat S, Delacourt  N, Rodari A, Marban C, Schwartz  C, Burny A, Rohr O, Van Driessche B and Van Lint C. Repression of Human T-lymphotropic virus type 1 Long Terminal Repeat sense transcription by Sp1 recruitment to novel Sp1 binding sites. Scientific Reports, 2017 Mar 3;7:43221

Gama L, Abreu CM, Shirk EN, Price SL, Li M, Laird GM, Pate KA, Wietgrefe SW, O'connor SL, Pianowski L, Haase AT, Van Lint C, Siliciano RF, Clements JE, Authors D; LRA-SIV Study Group. The LRA-SIV Study Group: Queen S, Bullock BT, Croteau J, Pianowski LF , Gellerup D, Beck SE, Mangus LM, Adams RJ, Perkey K, Rouzioux C, De Wit S, Kula A, Darcis G, Zink C, Mankowski JL. Reactivation of SIV reservoirs in the brain of virally suppressed macaques. AIDS, 2017 Jan 2;31(1):5-14

Darcis G, Bouchat*, Kula A*, Van Driessche B, Delacourt  N, Vanhulle C, Avettand-Fenoel A,  De Wit S, Rohr O, Rouzioux C, and Van Lint C. Reactivation capacity by latency-reversing agents ex vivo correlates with the size of the HIV-1 reservoir. AIDS, 2017 Jan 14;31(2):181-189

Bouchat S, Delacourt  N, Kula A, Darcis G, Corazza F, Gatot J-G, Melard A, Vanhulle C, Van Driessche B, Kabeya K, Pardons, Avettand-Fenoel A, Clumeck N, De Wit S, Rohr O, Rouzioux C, and Van Lint C. Sequential treatment with 5-aza-2’deoxycitidin and Deacetylase Inhibitors Reactivates HIV-1 from Latency. EMBO Mol Med. 2016 Feb 1;8(2):117-38

Darcis G*, Kula A*, Bouchat S, Fujinaga K, Corazza F, Ait-Ammar A, Delacourt N, Melard A, Kabeya K, Vanhulle C, Van Driessche B, Gatot J-G, Cherrier T, Pianowski LF, Gama L, Schwartz  C, Vila J, Burny A, Clumeck N, Moutschen M, De Wit S, Peterlin M, Rouzioux C, Rohr O and Van Lint C. An In-Depth Comparison of Latency Reversing Drug Combinations in Various in vitro and ex vivo HIV-1 Latency Models Identified Bryostatin-1+JQ1 and Ingenol B+JQ1 to Potently Reactivate HIV-1. PLoS Pathog. 2015 Jul 30;11(7):e1005063

Kula A., Gharu L., Marcello A. HIV-1 pre-mRNA commitment to Rev mediated export through PSF and Matrin 3. Virology. 2013 Jan 20;435(2):329-40.

Roesch F, Meziane O, Kula A, Nisole S, Porrot F, Mammano F, Fassati A, Marcello A, Benkirane M, Schwartz O. Hyperthermia stimulates HIV-1 replication. PLoS Pathog. 2012;8(7):e1002792

Kula A., Marcello A. Dynamic post-transcriptional regulation of HIV-1 gene expression. Biology (Basel). 2012 Jul 3;1(2):116-33

Maiuri P, Knezevich A, De Marco A, Mazza D, Kula A, McNally J, Marcello A. Fast transcription rates of RNA polymerase II in human cells. EMBO Rep. 2011 Dec 1;12(12):1280-5

Kula A, Guerra J, Knezevich A, Kleva D, Myers MP, Marcello A. Characterization of the HIV-1 RNA associated proteome identifies Matrin3 as a nuclear cofactor of Rev function. Retrovirology. 2011 Jul 20;8:60

Dieudonné M, Maiuri P, Biancotto C, Knezevich A, Kula A, Lusic M, Marcello A. Transcriptional competence of the integrated HIV-1 provirus at the nuclear periphery.  EMBO J. 2009 Aug 5;28(15):2231-43. 

 
*- equal contribution
This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 665778