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Sofia NyströmImmunomodulatory effects exerted by HIV-1 on dendritic cells and the induction of regulatory suppressor T cells

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Molecular Virology, Department of Clinical and Experimental Medicine,
Linköping University Hospital

HIV remains a major global health issue. Approximately 34 million people are living with HIV world wide. For sexual transmission of HIV-1 to occur, the virus in genital and rectal secretions must cross the mucosal epithelial barrier and enconter HIV receptive immune cells. Dendritic cells (DCs) are one of the first cell types targeted by HIV-1. After exposure to HIV-1, mucosal DCs migrate to draining lymph nodes where DCs not only initiate HIV-specific immune responses by presenting HIV antigens to T cells. During this cellular interaction DCs also transmit virions to receptive T cells. HIV infected individuals have diminished levels and impaired function of both DCs and T cells.

The T cell dysfunction is due to elevated T cell expression of negative co-stimulatory molecules. New evidence indicates that HIV-1 has immune modulatory effects on DCs. In this study an in vitro model that aim to mimic in vivo situations of DC-T cell interaction in the presence of HIV-1 is used to study the effect HIV-1 exerts on DCs ability to prime T cells.

We have shown that high doses of HIV-1 impaired DC priming of allogeneic and autologous T cells. The impairment of T cell proliferation was cell-contact dependent, involving inhibitory molecules and transcriptional repressors. The new knowledge regarding HIV pathogenesis made from this project can be translated into new ways to block viral dissemination and immune impairment. The model for HIV-1 induced T cell impairment will be used to test strategies to enhance the capacity of the host response to control HIV infection.

In vitro model
Figure 1. In vitro model of DC-T cell interaction in the presence of HIV. DCs are generated by culture of human blood monocytes in the presence of IL4 and GM-CSF. Day 5 maturation is initiaited by addition of TLR3 agonist poly I:C. Day 6 mature DCs are pulsed with HIV-1, mock-pulsed DCs serve as control. At this stage it is possible to block viral access to DC cytosol with anti-gp120 neutralizing antibody. HIV-1 infected DCs are co-cultured with allogenic or autologous T cells. Day 7 co-culture is re-stimulated by addition of more DCs. Co-culture can be modified by blocking specific signaling pathways important for DC-T cell crosstalk. T cell proliferation, effector function and expression of negative stimulatory molecules are analysed as read out for DC-ability to prime T cells.

T cells

Figure 2. T cells primed by HIV-1 exposed DCs develop a regulatory phenotype. They proliferate less and have increased expression of inhibitory molecules (CTLA4, LAG-3, TIM-3, PD-1 and TRAIL) compared to T cells primed by mock-infected DCs. This is partly mediated by the STAT3/P38MAPK pathway. DC expression of indoleamine 2,3 dioxygenase (IDO) is known to induce regulatory T cells and may also contribute to the impaired T cell response mediated by HIV-1 exposed DC.



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