Regardless of the extraordinary progress performed in the control of HIV-1 replication by highly active antiretroviral therapy (HAART), a cure is not yet achievable, and HIV-1 persistence in reservoirs represents the major obstacle for its eradication. Understanding the molecular mechanisms involved in the establishment and persistence of HIV-1 reservoirs can provide clues and suggests new strategies for the eradication, or at least the control, of long-term reservoirs.
This issue has been the main avenue of research of the group from the very beginning, when we analyzed the regulation of NF-kB which is the major transcription factor involved in HIV reactivation (Nabel G, et al. Nature. 1987 Apr 16-22;326(6114):711-3.). In last period we are trying to address the mechanisms governing HIV latency, a challenging issue because of the technical difficulties to characterize a “negative” phenomenon in appropriate cellular models.
The “Latency team” is led by Mayte Coiras (Senior researcher), being part of the group María Rosa López-Huertas (Tenure Post-doc), Sara Rodríguez-Mora (Junior Post-doc), María Sánchez del Cojo (PhD student) and Elena Mateos (Technician).
Our main contributions to this field have been:
- The demonstration of the dependence of NF-kB in driving HIV-1 transcription in the cellular context of natural CD4 lymphocytes (Alcamí J, et al. EMBO J. 1995 Apr 3;14(7):1552-60.).
- The characterization of the nuclear shuttling of IKBα in resting and activated CD4 lymphocytes from peripheral blood (Laín de Lera T, et al. Oncogene. 1999 Feb 25;18(8):1581-8. and Coiras M, et al. 2007 Aug 8;4:56.).
- The identification of a new molecular form of RelA/p65 (Coiras M, et al. 2008 Dec 1;5:109.).
- In collaboration with Mariano Esteban from Centro Nacional de Biotecnología (Madrid) we characterized the regulation of NF-kB by PKR, a mechanism bridging innate immunity and cell survival (Gil J, et al. Mol Cell Biol. 1999 Jul;19(7):4653-63., Gil J, et al. Oncogene. 2000 Mar 9;19(11):1369-78. and Gil J, et al. Oncogene. 2001 Jan 18;20(3):385-94.).
In 2006, using proteomic and gene arrays, we started a new project to analyze the impact of the HIV-1 Tat protein in the regulation of cellular gene expression. Besides, using Jurkatt cells with stable expression of different versions of Tat, we assessed the potential role of the second exon of Tat -that is dispensable for elongation of viral mRNA- in modifying the phenotype of Tat-expressing cells. This research line was led by Mayte Coiras and has contributed to a better understanding of Tat function beyond its role as an elongation factor of the HIV genome.
The publications related to this line of research are:
- A global description of the modifications in the human T cell proteome induced by intracellular HIV-1 Tat protein expression (Coiras M, et al. Proteomics. 2006 Apr;6 Suppl 1:S63-73.).
- Changes in host cell cytoskeleton structure and function mediated by expression of full length Tat protein (López-Huertas MR, et al. Nucleic Acids Res. 2010 Jun;38(10):3287-307.).
- The anti-apoptotic effect of HIV-1 Tat protein in CD4+ T lymphocytes (López-Huertas MR, et al. J Biol Chem. 2013 Mar 15;288(11):7626-44.).
- The regulation of specific miRNA by Tat (Sánchez del Cojo M, et al. submitted).
- Disregulation of mitochondria functions by Tat in T lymphocytes (Rodríguez-Mora S, et al. submitted).
Finally, we have written different reviews on this issue, some of them being reference in the field:
- Application of proteomics technology for analyzing the interactions between host cells and intracellular infectious agents (Coiras M, et al. Proteomics. 2008 Feb;8(4):852-73.).
- Understanding HIV-1 latency provides clues for the eradication of long-term reservoirs (Coiras M, et al. Nat Rev Microbiol. 2009 Nov;7(11):798-812.).
- Dual role of host cell factors in HIV-1 replication: restriction and enhancement of the viral cycle (Coiras M, et al. AIDS Rev. 2010 Apr-Jun;12(2):103-12.).
- HIV-1 latency and eradication of long-term viral reservoirs (Coiras M, et al. Discov Med. 2010 Mar;9(46):185-91.).
- Mechanisms of RNA interference in the HIV-1-host cell interplay (Sánchez-Del Cojo M, et al. AIDS Rev. 2011 Jul-Sep;13(3):149-60.).
Projects and funding
Spanish Ministry of Research:
- Molecular analysis of the functional role of NF-kB and the HIV-1 Tat protein in the initiation of HIV transcription (SAF 96/0186). Principal Investigator: P Alcamí. 1996-1999.
- Mechanisms of proviral latency in HIV-infected lymphocytes (SAF 00/0028). Principal Investigator: P Alcamí. 2000-2003.
- Post-translational modifications induced by the intracellular expression of HIV-1 Tat protein in T lymphocytes and its impact on RNA metabolism (SAF 2010-18388). Principal Investigator: M Coiras. 2011-2013.
Spanish Ministry of Health. Instituto de Salud Carlos III:
- Methabolic pathways involved in LTR-driven transcription (FIS 1904-E). Principal Investigator: P Alcamí. 1994-1995.
- Molecular mechanisms of HIV-1 latency and reactivation in CD4 lymphocytes from peripheral blood (FIS 94/200). Principal Investigator: P Alcamí. 1995-1997.
- Molecular interaction at nuclear and cytosolic level of NF-kB and IkB (FIS 96/1804E). Principal investigator: P Alcamí. 1996-1997.
- Cellular changes induced by the expression of Tat protein and search for potential pharmacological targets (FIS PI040614). Principal Investigator: P Alcamí. 2005-2007.
Foundation for Research and Prevention of AIDS in Spain (FIPSE):
- Changes in the cellular proteome induced by expression of the Tat protein (FIPSE 36584/06). Principal investigator: P Alcamí. 2006-2009.
- Regulation of the degradation of p65/RelA in human T lymphocytes (FIPSE 36633/07). Principal investigator: M Coiras. 2008-2010.
- Methabolic pathways involved in LTR-driven transcription (BIOMED 1, FP5). Principal Investigators: JL Virelizier (Institut Pasteur, Paris), RT Hay (University of St Andrews, Scotland), P Alcamí (Hospital Universitario 12 de Octubre, Madrid) and J Moscat (Centro de Biología Molecular Severo Ochoa, Madrid). 1994-1995.
- Regulation of NF-kB activity in immune competent cells: from basic research to therapeutic intervention (BIOMED 2, FP5). Principal investigators: JL Virelizier (Institut Pasteur, Paris), RT Hay (University of St Andrews, Scotland), P Alcamí (Hospital 12 de Octubre, Madrid), C Dargemont (Institut Curie, Paris) and A Boousseau (Rhône-Poulenc, France). 1996-1997.
In the 90s several projects were carried out in close collaboration with the Viral Immunology Unit of Institut Pasteur, led by Jean-Louis Virelizier. This collaboration, aiming at the characterization of NF-kB activating pathways, gave us the opportunity to participate in European Networks (BIOMED 1 and 2 programs) together with Ron Hay from University of St Andrews, Catherine Dargemont from Institut Curie and Jorge Moscat from Centro de Biología Molecular Severo Ochoa.
In the field of HIV-1 regulation through NF-kB-driven LTR transcription, we developed productive collaborations with Mariano Esteban at Centro Nacional de Biotecnología (Gil J, et al. Mol Cell Biol. 1999 Jul;19(7):4653-63., Gil J, et al. Oncogene. 2000 Mar 9;19(11):1369-78. and Gil J, et al. Oncogene. 2001 Jan 18;20(3):385-94.), Esteban Domingo at Centro de Biología Molecular Severo Ochoa (Quiñones-Mateu ME, et al. Virus Res. 1998 Sep;57(1):11-20.), Manuel López-Cabrera from Hospital Universitario de La Princesa (Gómez-Gonzalo M, et al. J Biol Chem. 2001 Sep 21;276(38):35435-43.) and África Holguín from Hospital Carlos III (Ramírez de Arellano E, et al. Virus Genes. 2007 Apr;34(2):111-6. and de Arellano ER, et al. Antiviral Res. 2010 Nov;88(2):152-9.), all in Madrid.
In last years we have closely collaborated with Carles Suñé from Instituto de Parasitología y Biomedicna “López-Neyra” in Granada, Spain, to characterize the role of TCERG/p300 in HIV-1 transcription and RNA elongation (Coiras M, et al. Retrovirology. 2013 Oct 28;10:124).