NAME: Soriano-Sarabia, Natalia. era COMMONS USER NAME: natalia_soriano

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1 NAME: Soriano-Sarabia, Natalia OMB No /0002 (Rev. 08/12 Approved Through 8/31/2015) BIOGRAPHICAL SKETCH Provide the following information for the Senior/key personnel and other significant contributors. Follow this format for each person. DO NOT EXCEED FIVE PAGES. era COMMONS USER NAME: natalia_soriano POSITION TITLE: Research Instructor of Medicine (New early-stage investigator, ESI) EDUCATION/TRAINING INSTITUTION AND LOCATION DEGREE Completion Date FIELD OF STUDY University of Alcala de Henares, Madrid, Spain BS 09/2001 Cellular and Molecular Biology University of Seville, Spain MS 07/2004 Biomedicine University of Seville and Virgen del Rocio Hospital, PhD 07/2007 HIV-HCV coinfection Seville. Spain Innate immunity in HIV Virgen del Rocio Hospital, Seville, Spain Postdoctoral infection Immune functions of γδ Justus Liebig University, Giessen, Germany Postdoctoral T cells HIV reservoirs and University of North Carolina at Chapel Hill Postdoctoral latency 1. Personal Statement The goal of the proposed research is to investigate the role of γδ T lymphocytes in HIV latency. I have a broad background in HIV pathogenesis and long interest in γδ T cells, leaving me with the expertise necessary to carry out the proposed work. My doctoral studies encompassed research in the pathogenesis of HIV and hepatitis C virus coinfection, using both cellular and molecular techniques. As an early postdoctoral fellow I conducted research as PI funded by the Spanish Sanitary Research Foundationfocusing on the innate immunity in HIV-infected patients, mentoring in the PhD program and directing the teaching of graduate degree students. Later, I focused in the study of γδt cells as a postdoctoral fellow in Germany, where I earned a postdoctoral fellowship award from the Max Planck Institute and studied the specific requirements for γδ T cell function. Given the wide range of effector functions these cells can exert, I hypothesized that γδ T cells could be targets for HIV infection, and might play a role in HIV persistence. My grant application to analyze the role of γδ T cells in HIV latency was funded by the Carlos III Institutes of Health, Spain (CD10/00438) and I came to Dr. David Margolis laboratory at the University of North Carolina at Chapel Hill to execute this project. Working with his group, my preliminary studies published in PLoS Pathogens show for the first time that γδ T lymphocytes harbor replication-competent HIV and constitute a previously unrecognized reservoir for HIV-1 infection. A funding application with Dr. Margolis was funded via the R56 bridge mechanism, and I have used this to obtain further data and establish independence. In August 2015, I was promoted to Research Instructor of Medicine and I am optimally positioned to continue this research independently as I have the necessary institutional support to conduct and manage this project independently. I will establish the specific role of γδ T cells in HIV latency, and determine whether specific therapeutics are needed to purge this reservoir of persistent infection. 1. Soriano-Sarabia N, Vallejo A, Molina-Pinelo S, Genebat M, Rodríguez M.M, Sánchez-Quijano A, Martínez-Moya M, Vivancos J, Leal M. HIV-HCV coinfection is associated with decreased plasmatic interleukin-7 levels. AIDS 2007; 21: Pulido I, Leal M, Genebat M, Pacheco YM, Sáez ME, Soriano-Sarabia N. The TLR4 Asp299Gly is a risk factor for active tuberculosis in Caucasian HIV-infected patients. Curr HIV Res 2010; 8:

2 3. Soriano-Sarabia N, Sandvold H, Jomaa H, Bein G, Hackstein H. Primary MHC-Class II+ cells are necessary to promote resting Vδ2 cell expansion in response to (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate and isopentenyl pyrophosphate. J Immunol 2012; 189: Soriano-Sarabia N, Archin NM, Bateson E, Dahl NP, Crooks AM, Kuruk JD, Garrido C, Margolis DM. Peripheral Vγ9Vδ2 T cells are a novel reservoir of latent HIV infection PLoS Pathog 2015; 11(10):e This work was presented at the Conference on retroviruses and Opportunistic Infections (CROI). Oral presentation, B. Positions and Honors Positions and Employment Research Instructor in Medicine, Division of Infectious Diseases, University of North Carolina at Chapel Hill Honors and awards 2004 Fellowship award, HIV-DART 2004, Montego Bay, Jamaica. Oral presentation 2007 PhD Magna cum laude 2007 Best oral presentation discussion award, European AIDS Society 2007, Madrid, Spain 2010 Research fellowship award Excellence Cluster, Max Planck Institute, Justus-Liebig University of Giessen and Frankfurt University, Germany 2011 Competitive contract for postdoctoral training Sara Borrell, Carlos III Institutes of Health, Ministry of Innovation and Science, Spain 2013 Young investigator award, CROI 2013, Atlanta, GA. Oral presentation Professional Membership Member of the HIV Spanish Network (Red de Investigación en SIDA, R.I.S) Member of the Foundation for the Prevention and Investigation of AIDS in Spain (FIPSE) C. Contribution to Science HIV reservoirs and latency HIV infection remains incurable due to the persistence of a viral reservoir integrated within host cellular DNA. This latent infection, unaffected by antiretroviral therapy and hidden from the immune system, constitutes the major barrier to an HIV cure. Efforts to eradicate HIV infection require the description of all cellular reservoirs that might harbor replication-competent virus. My research is focused in defining new potential reservoirs as we explore new approaches to eradicate HIV infection. 1. Barton KM, Burch BD, Soriano-Sarabia N, Margolis DM. Prospects for treatment of latent HIV. Clin Pharmacol Ther 2013; 93: Soriano-Sarabia N, Bateson RE, Dahl NP, Crooks AM, Kuruc JD, Margolis DM, Archin NM. The quantitation of replication-competent HIV-1 in populations of resting CD4 + T cells. J Virol 2014; 88: Archin NM, Sung JA, Garrido C, Soriano-Sarabia N, Margolis DM. Eradicating HIV infection: Seeking to clear a persistent pathogen. Nature Rev Microbiol 2014; 50: Soriano-Sarabia N, Archin NM, Bateson E, Dahl NP, Crooks AM, Kuruk JD, Garrido C, Margolis DM. Peripheral Vγ9Vδ2 T cells are a novel reservoir of latent HIV infection (under review). This work was presented at the Conference on retroviruses and Opportunistic Infections (CROI). Oral presentation, Innate Immunity As a recent postdoctoral fellow I was interested in different aspects of innate immune responses to HIV infection. TLR regulate the function of both innate and adaptive immune responses. We analyzed the specific role of several SNPs on TLR demonstrating that TLR9 1635/AA was associated with disease progression. In addition, I was the PI in a second study focused on analyzing the impact of SNP on HIV-infected patients comorbidities. We showed that the Asp299Gly SNP is a risk factor for active tuberculosis in HIV-infected patients. These studies have implications as novel therapeutic approaches targeting TLRs are being developed. I also focused my interest for the innate arm of the immune system on γδ T cells, that constitute the bridge between the innate and the adaptive immunity and their function is crucial to establish potent adaptive immune responses. These cells have the capacity to greatly expand and respond very rapidly to a given challenge and

3 this unique property is being exploited in the cancer field. We developed a highly sensitive sorting method to study specific requirements of γδ T cells to be activated and expand. We demonstrated that the antigens recognized by these cells must be presented by accompanying cells, preferentially dendritic cells, over monocytes/macrophages or αβ T cells. We also defined the expression of protease activated receptors in γδ T cells as well as in other cell types including CD8 cells, monocytes /macrophages and NK cells. 5. López ML, Soriano-Sarabia N, Bruges G, Marquez ME, Klaus T, Preissner KT, Schmitz ML, Hackstein H. Expression pattern of protease activated receptors in lymphoid cells. Cell Immunol 2014; 288: Soriano-Sarabia N, Vallejo A, Ramírez-Lorca R, Rodríguez MM, Salinas A, Pulido I, Sáez ME, Leal M. Influence of the Toll-like receptor A/G polymorphism on CD4 count, HIV viral load and clinical progression. J Acquir Immune Defic Syndr 2008; 49: This work was presented at the European AIDS Conference (EACS). Oral presentation, Luque J, Lozano JM, García-Jurado G, Soriano-Sarabia N, González R, Vallejo A, Leal M, Peña J. NK-associated regulatory receptors in a structured HAART interruption of HIV-1+ individuals. AIDS Res Hum Retrovir 2008; 24: Antiretroviral therapy interruption strategies During my graduate studies, it was thought that structured treatment interruptions (STI) held potential for the treatment of HIV. Although clinically unsuccessful, voluntary and supervised STI were extremely helpful in understanding virologic and immunologic processes such as viral rebound, and CD4 cell depletion. We confirmed cellular and viral dynamics to be similar to the set point prior to ART introduction, defining also specific groups of patients who were more likely to need ART at a sooner time than others. These studies were extremely helpful to detect elite controllers that were taken off their medications. We also showed functional and mechanistic aspects of the HIV pathogenesis as well as the role of Hepatitis C virus coinfection. 8. González-Serna A, Abad-Fernández M, Soriano-Sarabia N, Leal M, Vallejo A. Alterations of CD8 T cell receptor Vβ chain repertoire are related with immunologic markers in HIV-1-infected patients during treatment interruption and are restored by antiretroviral therapy. J Clin Virol 2013; 58: Soriano-Sarabia N, Vallejo A, Fernández G, Genebat M, Gutiérrez S, Muñoz-Fernández MA, Leal M. Control of HIV-1 RNA load alter HAART interruption: relationship with CCR5 co-receptor density and proviral DNA load. J Clin Virol 2007; 40: This work was presented at the HIV-Frontiers in drug development for antiretroviral therapy Conference (DART). Oral presentation, Molina-Pinelo S, Vivancos J, De Felipe B, Soriano-Sarabia N, Valladares A, de la Rosa R, Vallejo A, Leal M. Thymic volume predicts CD4 T-cell decline in HIV-infected adults under prolonged treatment interruption. J Acquir Immune Defic Syndr 2006; 42: Soriano-Sarabia N, Abad MA, Vallejo A, Gutiérrez S, Leal M. HCV and HGV coinfection influence over viral and cellular dynamic in HIV-infected patients on HAART interruption. Clin Microb Infect 2006; 12: Effect of hepatitis C virus coinfection on HIV pathogenesis My thesis work was focused in understanding how HCV had an effect on HIV infection in patients on antiretroviral therapy. I studied several different aspects of the coinfection from phenotype of the immune cells to functional defects such as decreased capacity of coinfected patients to produce IL-7. This was important as repopulation of CD4 cells was impaired in coinfected patients. We also demonstrated that B cell immunity and antigen production capacity was also impaired. 12. De Felipe B, Leal M, Soriano-Sarabia N, Gutiérrez A, López-Cortés L, Molina-Pinelo S, Vallejo A. HCV RNA in peripheral blood subsets in HCV-HIV coinfected patients at the end of PegIFN/RBV treatment is associated with virologic relapse. J Viral Hepatitis 2009; 16: Soriano-Sarabia N, Vallejo A, Molina-Pinelo S, Genebat M, Rodríguez M.M, Sánchez-Quijano A, Martínez-Moya M, Vivancos J, Leal M. HIV-HCV coinfection is associated with decreased plasmatic interleukin-7 levels. AIDS 2007; 21: Soriano-Sarabia N, Abad MA, Vallejo A, Gutiérrez S, Leal M. HCV and HGV coinfection influence over viral and cellular dynamic in HIV-infected patients on HAART interruption. Clin Microb Infect 2006; 12: Soriano-Sarabia N, Leal M, Delgado C, Molina-Pinelo S, de Felipe B, Ruiz-Mateos E, Sánchez- Quijano A, Lissen E, Vallejo A. Effect of hepatitis c virus coinfection on humoral immune alterations in naïve HIV-infected adults on HAART: a three year follow-up study. J Clin Immunol 2005; 25:

4 This work was presented at the 13 th Diseases. Oral presentation, International Symposium on HIV and Emerging Infectious Immune reconstitution in HIV-infected patients naïve for antiretroviral therapy I collaborated in a series of works from our group focused on understanding the mechanisms and implications of the thymus in the immune reconstitution. At that time, it had been just discovered that the thymus was a functional organ. Our group demonstrated the importance of a functional thymus in HIV infection and how its measurement was an accurate tool to predict the immune reconstitution in HIV-infected patients who were naïve for antiretroviral therapy. 16. Molina-Pinelo S, Vallejo A, Díaz L, Soriano-Sarabia N, Ferrando-Martínez S, Resino S, Muñoz- Fernández MA, Leal M. Premature immunosenescence in HIV-infected patients on HAART with lowlevel CD4 T cell repopulation. J Antimicrob Chemoth 2009; 64: Molina-Pinelo S, Leal M, Soriano-Sarabia N, Gutiérrez S, Fernández G, Muñoz-Fernández MA, Lissen E, Vallejo A. Prevalence and factors involved in discordant responses to highly active antiretroviral treatment in a closely followed cohort of treatment-naïve HIV-infected patients. J Clin Virol 2005; 33: Ruiz-Mateos E, de la Rosa E, Soriano N, Martínez-Moya M, Rubio A, Sánchez-Quijano A, Leal M, Lissen E. Comparison of thymic function related markers to predict early CD4+ T-cell repopulation in adult HIV-infected patients on HAART. Antiviral Therapy, 2003; 8: Ruiz-Mateos E, de la Rosa R, Martínez-Moya M, Soriano N, Sánchez-Quijano A, Leal M, Lissen E. Endogenous IL-7 triggers thymic rebound in adult HIV infected patients on HAART. AIDS 2003; 17: Complete List of Published Work in My Bibliography (23 publications and 1 manuscript in review): D. Research Support Ongoing Research Support R56 AI A1 Margolis (PI) 03/13/15-02/26/16 The Role of Gamma Delta T Cells as Persistent Reservoirs of HIV Infection The goal of this study is to get preliminary data on the role of γδ T cells in HIV latency Role: Senior Postdoctoral Fellow U19 AI Margolis (PI) 07/008/11-06/30/16 Martin Delaney Collaboratory to Eradicate HIV-1 Infection. This project funds 17 principal investigators and 4 cores. The Margolis laboratory receives funding for a research project within this collaborative, to study the effect of reagents to perturb latent infection in CD4+ T cells, to study latent infection in CD4+ cell populations, and a supplement to perform a study of the durability of immune response to AGS-004. Completed Research Support CD10/00438, Carlos III Institutes of Health, Spain Soriano-Sarabia (PI) 09/01/11-11/13/13 γδ T cells in HIV latency This was a competitive Postdoctoral Contract (Sara Borrell) to analyze the role of γδ T cells in HIV latency. Role: PI Collaborative ECCPS project, Germany Hackstein (PI) 01/10/10-05/31/11 Dissecting novel immune-regulatory functions of γδ T cells Institute for Clinical Immunology and Transfusion Medicine and Max-Plank Institute. We analyse specific requirements of Vδ2 cells to expand in vitro. Role: Co-investigator 0241/2005, Spanish Sanitary Research Foundation Leal (PI) 01/31/07-01/30/09 Role of Toll-like receptors in the morbi-mortality associated to HIV infection

5 The objective of this project was to analyse the influence of common SNP in TLR in HIV disease progression and opportunistic infections. Role: Postdoctoral fellow PI040272, Spanish Sanitary Research Foundation Leal (PI) Role of the thymus in viral and cellular kinetics in HIV-infected adults alter HAART interruption The goal of this project was to identify the role of the thymus in the immune repopulation and in the HIV rebound. Role: GR G03/173 Spanish AIDS Research Network (RIS) Leal (PI) 2006 Collaboration Projects in Epidemiology, Basic and Clinic Investigation for the year This was a collaboratory of Spanish scientists to analyse several aspects of the HIV infection on and off therapy. 02/24 Health Service of Andalusia Leal (PI) 2004 Influence of the Hepatitis C virus coinfection on the immune reconstitution HIV-infected patients on HAART. Analysis of the potential role of thymic dysfunction on the lower reconstitution induced by HCV infection. 03/119 Health Service of Andalusia Vallejo (PI) Effect of Highly Active Antirretroviral Therapy on humoral immune alterations induced by HIV in adult patients. Influence of the Hepatitis C virus coinfection.