HIV virus in disguise tricks immune system, Marie Larsson is Professor of Molecular Virology

Name: Marie LarssonTitle: Professor of Molecular Virology
Department: IKE

CONTACT

Phone: +46 (0)10-103 10 55
E-mail: marie.larsson@liu.se

Address:
Linköping University
Department of Clinical and Experimental Medicine
Virology
SE-581 85 Linköping
Sweden

Marie Larsson is Professor of Molecular Virology. Her research is in the area of immunovirology, specifically HIV research with focus on the immunomodulatory effect this virus has on dendritic cells and T cells. She has also ongoing projects exploring new adjuvants and vaccine constellations for cancer and virus. Furthermore, she is investigating the induction and sustainment of cancer associated inflammation and the deleterious effect this has on host immune defense.

Immunomodulatory effects of HIV-1’s interactions with DCs and T cells from

blood and mucosa
So far over 30 million people have died from HIV-1 infection (figure 1), the majority of them in the developing countries, and this epidemic is still cause for major concern. The existing antiretroviral therapy dampens the infection and the destruction of the immune system, i.e. AIDS, but does not cure the disease. Sadly, this therapy is not available to all HIV infected and is a very expensive lifelong commitment with severe side effects.

A vaccine blocking HIV infection is theDendritic cell sought-after solution but there is no hope that we will have such a vaccine in the near future. Instead we can hope for a therapy that induces a potent long lasting immune response consisting of CD4+ and CD8+ T cells, two types of control cells involved in the immune defense, that have proven to be important to control the infection. There exists a unique cell in all tissues in our bodies, the dendritic cell (DC) (Figure 2) with unique ability to activate T cells so they can perform their job in the body. DCs in the vaginal and rectal tissues are one of the first cells to encounter HIV during intercourse with an infected individual (Figure 3 and 4). Unfortunately, HIV hijacks the DCs, which makes this cell responsible for spreading the virus to interacting T cells in the body which provokes HIV-infection of T cells and cell death when it should be initiating immune responses to fight the infection.DC HIV

My research aspires to elucidate the mechanisms behind the immunomodulatory effects HIV exerts on DCs and on their ability to activate T cells. Focus will be on; Elucidation of the mechanisms involved in HIV’s binding to and uptake by DCs and the subsequent degradation that leads to DC antigen presentation of HIV peptides for activation of HIV specific T cells. Elucidation of the mechanisms responsible for the negative effects HIV exerts on DCs and if presence of HIV virions during DC T cell priming impairs the T cell function. Elucidate the effect opsonized HIV-1 exerts on immune cells such as DCs, NK cells and T cells. Identification of receptors and cells involved in the initial HIV infection of cervical mucosa and colorectal mucosa,  and potential microbiocides that can block the initial infection, and elucidation of why HIV affects the T cells in the gut to a higher extent than the T cells in blood.

HIV will continue to kill people and have a great impact on mankind until we have a drug that can stop this infection. My ambition is that the planed research will answer some basic questions regarding the role of DCs in HIV pathogenesis and induction of potent immune response against this virus. This knowledge will guide how a vaccine/therapy needs to be constructed in order to have high efficacy.

                                                             Mucosal transmission

                                                                Cervix

Cancer research

Elucidation the role of IL-1α and the microenvironment in development of pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is a common gastrointestinal malignancy with an exceptional poor prognosis and a mortality rate that nearly matches the rate of incidence. The cross-talk between PDAC and stroma cells, e.g. cancer associated fibroblasts (CAF), and immune cells, may create an environment with chronic inflammation augmenting tumor transformation and maintenance.

In PDAC, more than 70% of the total tumor mass can consist of fibrotic stroma, which makes CAFs the major component in this cancer. PDAC inflammatory environment consists of many mediators, e.g. IL-1, COX-2, IL-6, and CXCL8, and some of these factors correlate to tumor development and poor prognosis. Of note, elevated expression of IL-1 in tumors has been associated with more aggressive disease. Several studies, including ours have reported that dendritic cells (DCs), one of the immune cells found in the tumor microenvironment, show phenotypic and functional abnormalities when isolated from tumor bearing animals and individuals with PDAC. Recent findings provided some evidence that the COX-2 metabolite PGE2 is involved in the upregulation of immunomodulatory factors in DCs impairing their T cell stimulatory ability. The aims are to examine the receptor-ligands and signaling pathways involved in the cross talk between stroma cells, i.e. CAFs, and PDAC cells giving rise to the inflammatory environment and creating an environment sustaining the PDAC. To examine the role IL-1 cytokine family and effects these cytokines cell signaling have on creating the inflammatory environment and in tumor development and survival. To examine whether neutralization of IL1 signaling pathway enhances the survival and quality of life for individuals with pancreatic cancer.

The information gained from the proposed research will help us understand the mechanisms underlying the development of PDAC and the effect this solid tumor exert on the body and may help designing therapies for PDAC.

Source: Linköping University