Anna-Lena Spetz group

The research group led by Anna-Lena Spetz is working towards the goal to discover new immunogens and immunization regimens that induces potent HIV-1 specific immune responses.

A longstanding goal for a HIV-1 vaccine is to induce both T-cell responses and broadly reactive antibodies that are able to neutralize the virus. The immune responses following stimulation with Toll Like Receptor (TLR) ligands and apoptotic cells are also investigated.

The aim with these projects is to enhance the understanding of early innate mechanisms during infections or tissue damage with the dendritic cell in focus. This knowledge will contribute to novel approaches of immune modeling during immune pathogenesis and the development of vaccine adjuvant, where the activation of dendritic cells has emerged as a key event in shaping the following adaptive immune responses.

Keywords: HIV, TLR, Dendritic cells, Neutralizing antibodies, Apoptosis

Members

Venkat Mohanram, Anna-Lena Spetz, Anette Sköld. Photo: Bosse Johansson.

Anna-Lena Spetz, Group Leader, MD PhD, Associate Professor

Anna-Lena Spetz has 18 years experience in the field of immunology and HIV. She has been working in research laboratories at Institut Pasteur, Paris, Stockholm University, Stockholm and Harvard Medical School, Boston and is currently heading a research group at CIM, Karolinska Institutet. She has previous experience from EU networks Auto/AlloCell, EUROPRISE, NGIN and CHAARM.

Phone: +46-8 58582272

anna-lena.spetz@ki.se

Annette Sköld, PhD student

Annette Sköld has an M.Sci degree from Uppsala University and is PhD student at Karolinska Institutet with main research interest in dendritic cells and immune modulation.

Phone: +46-8 58589688

annette.skold@ki.se

Venkat Mohanram, PhD student

Venkat Mohanram has an M.Sci degree from Madurai Kamaraj University, Nadu, India and is PhD student at Karolinska Institutet with main research interest in dendritic cells and HIV-1.

Phone: +46-8 58589688

venkatramanan.mohanram@ki.se

Projects

Discovery of HIV-1 immunogens

Recent studies have shown that 10-25% of HIV-1 infected individuals generate broadly cross-reactive neutralizing antibodies against HIV-1. Data from non-human primate studies show that the presence of broadly reactive neutralizing antibodies before virus exposure protects against infection, suggesting that such neutralizing antibodies might protect against infection in humans. These findings are hopeful for efforts to develop a HIV-1 vaccine. One of the major problems to develop a HIV-1 vaccine is the notion that the virus is constantly changing. This means that in principle every HIV-1 infected individual is carrying his/hers own variant of the virus, which can be compared with the influenza virus that changes more slowly but anyhow means that a new vaccine has to be tailored each year. But even HIV-1 has its Achilles´ heel with parts of the virus that can not be changed without deleterious consequences for the virus to replicate.

Anette Sköld. Photo: Bosse Johansson.We are focusing our efforts to find immunogens and immunization regimens that target constant regions of the virus. One of the goals is to discover immunogens to be included in a vaccine that can generate antibodies with capacity to neutralize the virus from many different HIV-1 variants. Research collaborations include EU-projects EUROPRISE, NGIN and collaborations in the US.

Development of HIV-1 microbicides

We are studying molecules able to restrict HIV-1 replication in dendritic cells and the signalling pathways engaged. We have discovered that HIV-1 replication is inhibited in dendritic cells upon contact with apoptotic activated CD4+ T-cells leading to induction of the restriction factor APOBEC3G in sufficient amounts to counteract the anti-APOBEC3G activity exerted by HIV-1 Vif. These findings have implications for the development of new strategies to restrict viral replication at the site of entry in the mucosa. Research collaborations include EU-project CHAARM.

Dendritic cells and immunomodulation

We are investigating the cellular responses following stimulation with TLR ligands or apoptotic cells. The aim with this project is to enhance the understanding of early innate mechanisms during infections or tissue damage with the dendritic cell in focus. This knowledge will contribute to novel approaches of immune modeling during immune pathogenesis and the development of vaccine adjuvants, where the activation of dendritic cells has emerged as a key event in shaping the following adaptive immune responses.

Selected publications

Sköld AE, Hasan M, Vargas L, Saidi H, Bosquet N, Le Grand R, Smith CI, Spetz AL. Single-stranded DNA oligonucleotides inhibit TLR3-mediated responses in human monocyte-derived dendritic cells and in vivo in cynomolgus macaques. Blood. 2012 Jul 26;120(4):768-77. Epub 2012 Jun 13. PMID: 22700721.

 

Spetz AL, Chiodi F. Reduction of HIV-1 load in semen during follow-up study of the RV144 vaccine trial boosts the interest for novel correlates of immune protection in genital mucosa. J Infect Dis. 2012 Jul 24. [Epub ahead of print] PMID: 22829649.

 

Pathak SK, Sköld AE, Mohanram V, Persson C, Johansson U, Spetz AL. Activated apoptotic cells induce dendritic cell maturation via engagement of Toll-like receptor 4 (TLR4), dendritic cell-specific intercellular adhesion molecule 3 (ICAM-3)-grabbing nonintegrin (DC-SIGN), and ²2 integrins. J Biol Chem. 2012 Apr 20;287(17):13731-42. Epub 2012 Mar 6. PMID: 22396536.

 

Koopman G, Beenhakker N, Hofman S, Walther-Jallow L, Mäkitalo B, Mooij P, Anderson J, Verschoor E, Bogers WM, Heeney JL, Spetz AL. Immunization with apoptotic pseudovirus transduced cells induces both cellular and humoral responses: a proof of concept study in macaques. Vaccine. 2012 Mar 28;30(15):2523-34. Epub 2012 Feb 5. PMID: 22314133.

 

Mohanram, V, Johansson, U., Sköld,A.E., Fink,J.,Kumar Pathak, S., Mäkitalo,B., Walther-Jallow, L. and Spetz, AL. Exposure to Apoptotic Activated CD4+ T cells Induces Maturation and APOBEC3G Mediated Inhibition of HIV-1 Infection in Dendritic Cells. PLoS One. 2011;6(6):e21171.

 

Uchtenhagen, H., Friemann, R.,Raszewski, G., Spetz., AL.,Nilsson, L. and Achour, A. Crystal Structure of the HIV-2 Neutralizing Fab Fragment 7C8 with High Specificity to the V3 Region of gp125. PloS One, 2011 Apr 26;6(4):e18767.

 

Gómez Román,V.R., Vinner, L., Grevstad, B.; Hansen, J.J.; Wegmann, F.; Spetz, AL. and Fomsgaard, A. Development of standard operating procedures to obtain longitudinal vaginal specimens from nulliparous rabbits as part of HIV vaccine mucosal immunogenicity studies. J Immunol Methods, 2010 Dec 15;363(1):29-41.

 

Özkaya Sahin,G, Bowles,E.J.,Parker,P, Uchtenhagen,H, Sheik-Khalil, E., Taylor, S., Pybus,O., Mäkitalo, B.,Walther Jallow,L., Spångberg,M., Thorstensson,R., Achour,A., Fenyö,E.-M., Stewart-Jones,G., and Spetz AL. Generation of Neutralizing Antibodies and Divergence of SIVmac239 in Cynomolgus Macaques Following Short-term Early Antiretroviral Therapy. PLoS Pathogens, 2010 Sep 2;6(9):e1001084.

 

Johansson U, Walther-Jallow L, Hofmann A, Spetz AL. Dendritic cells are able to produce IL-12p70 after uptake of apoptotic cells. Immunobiology, 2011 Jan-Feb;216(1-2):251-5. Epub 2010 Apr 10.

 

Jespers V, Harandi AM, Hinkula J, Medaglini D, Le Grand R, Stahl-Hennig C, Bogers W, El Habib R, Wegmann F, Fraser C, Cranage M, Shattock RJ, Spetz AL. Assessment of mucosal immunity to HIV-1. Expert Rev Vaccines, 2010 Apr;9(4):381-94

 

Kumawat K, Pathak SK, Spetz AL, Kundu M, Basu J. Exogenous Nef is an inhibitor of Mycobacterium tuberculosis-induced tumor necrosis factor-alpha production and macrophage apoptosis. J Biol Chem. 2010 Apr 23;285(17):12629-37

 

Brave A, Johansson U, Hallengärd D, Heidari S, Gullberg H, Wahren B, Hinkula J, Spetz AL. Induction of HIV-1-specific cellular and humoral immune responses following immunization with HIV-DNA adjuvanted with activated apoptotic lymphocytes. Vaccine, 2010 Feb 25;28(9):2080-7

 

Koopman G, Beenhakker N, Hofman S, Walther-Jallow L, Mäkitalo B, Mooij P, Anderson J, Verschoor E, Bogers WM, Heeney JL, Spetz AL. Immunization with apoptotic pseudovirus transduced cells induces both cellular and humoral responses: a proof of concept study in macaques. Vaccine. 2012 Mar 28;30(15):2523-34. Epub 2012 Feb 5. PMID: 22314133.

 

Uchtenhagen H, Sourial S, Friemann R, Ehnlund M, Spetz AL, Harris RA, Madhurantakam C, Achour A. Production, purification, crystallization and preliminary X-ray diffraction analysis of the HIV-2-neutralizing V3 loop-specific Fab fragment 7C8. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2009 Jul 1;65(Pt 7):705-8

 

Hinkula J, Walther-Jallow L, Laurén A, Mäkitalo B, Oberg M, Wahren B, Fenyö EM, Spetz AL. Neutralizing activity and cellular immune responses induced in mice after immunization with apoptotic HIV-1/murine leukemia virus infected cells. Vaccine, 2009 Oct 30;27(46):6424-31.

 

Yu L*, Mohanram V*, Simonson OE, Smith CI, Spetz AL*, Mohamed AJ*. Proteasome inhibitors block HIV-1 replication by affecting both cellular and viral targets. Biochem Biophys Res Commun. 2009 Jul 17;385(1):100-5.*equal contribution.

 

Smed-Sörensen, A., Moll, M., Cheng, T-Y., Loré, K., Norlin, A-C., Perbeck, L., Moody, B., Spetz, AL., Sandberg, J. IgG regulates the CD1 expression profile and lipid antigen presenting function in human dendritic cells via Fc RIIa. Blood, 2008 May 15;111(10):5037-46

 

Bergsmedh, A, Ehnfors,J., Spetz, AL and Holmgren, L. A Cre-LoxP based system for studying horizontal gene transfer. FEBS Lett. 2007 581:2943-6.

 

Behbahani, H., Walther-Jallow, L., Klareskog, E., French, A., Patterson, B.K., Garcia, P., Spetz, AL., Andersson, J. and Landay, A. Pro-Inflammatory and Type 1 Cytokine Expression in Cervical Mucosa During HIV-1 and HPV Infection. J. of AIDS, 2007 45:9-19.

 

Johansson, U., Walther-Jallow, L., Smed-Sörensen, A. and Spetz, AL. Triggering of Dendritic Cell Responses after Exposure to Activated, but not Resting, Apoptotic PBMCs. J. Immunol. 2007 179:1711-20

Open positions

We always want to get in touch with talented potential co-workers. If you are interested in doing research within our group, as a degree project or as a researcher, please contact the group leader Anna-Lena Spetz.

Links

Next Generation HIV-1 Immunogens inducing broadly reactive Neutralising antibodies

Combined Highly Active Anti-Retroviral Microbicides

Europrise

Infectious Disease Medicine