Final Report Summary - HIV INNATE IMMUNITY (HIV and dendritic cells: the immunologycal and virological roles of SamHD1)
Dendritic cells (DC) are antigen-presenting cells linking innate and adaptive immune responses against many pathogens. Their main function is to capture the pathogen and present it to other immune cells in order to trigger an initial immune response (mainly interpheron-based) that will ultimately lead to a more specific antibody-based response.
The human immunodeficiency virus (HIV-1) is a retroviruses that causes acquired immunodeficiency syndrome (AIDS) a condition of progressive failure of the immune system until subsequent oportunistic infection will end with the patient´s life. The actual anti-retroviral treatment against HIV-1 has increased significantly the life expectancy of the infected patients, however, a complete erradication of the virus is still a matter of study.
Recent findings point out that DC are poorly sensitive to HIV-1 suggesting that the virus may remain hidden and undetected by our innate immune system. Two years ago, two different groups discovered a factor present in DC that was essential for the infection of these cells with HIV-1, named SAMHD1. It functions as a deoxynucleotide triphosphate hydrolase and also has enzymatic activity to degrade the excess of DNA inside the cells. The presence of SAMHD1 stops the replication life cycle of HIV-1 within the cell. Instead, HIV-1 use DC as trojan horses to travel throughout the body without being detected and finally reach their target, the lymphocyte CD4 T cells.
HIV-1 shares many similarities with HIV-2 and the simian immunodeficiency virus SIV, two different viruses with a less pathogenic outcome. However, SIV and HIV-2, both contain a protein in its genome, Vpx, that degrades the factor SAMHD1, whereas HIV-1 does not. A possible relationship between the presence of Vpx and the pathogeneicity of the infection has been a hypothesis of this study.
Besides, HIV-1 is known to be transmitted between cells, through cellular contacts or virologycal synapses. This is a more rapid and efficient mechanism for HIV-1 to spread. Previous studies that showed the role of SAMHD1 in the retsriction to HIV-1 infection in DC were performed in vitro using cell-fre viral preparations. We have developed a system of cell-to-cell HIV-1 transmission and evaluated the effect of SAMHD1 during this highly efficient mode of spread. Our results probed that SAMHD1 is active during cell-to-cell transmission and no IFN-immune response is triggered in the presence of SAMHD1. Removing SAMHD1 by adding the Vpx protein or using gene-silecning tools showed an increase in the infection and detection of HIV by DC.
Comparative studies between HIV-1 and HIV-2 on infection and immune detection by DC were performed in collaboration with the PhD student Lise Chauveau. There is still some ongoing work on this project.
Understanding how HIV-1 evades the innate immune response is clue to completely erradicate the virus. HIV-1 remains hidden in the cells of the immune system, which in turn become reservoirs for the virus. New therapetic strategis are needed to target these reservoirs of infected cells. This will utlimately have an impact on the cure for this pandemic disease.
The human immunodeficiency virus (HIV-1) is a retroviruses that causes acquired immunodeficiency syndrome (AIDS) a condition of progressive failure of the immune system until subsequent oportunistic infection will end with the patient´s life. The actual anti-retroviral treatment against HIV-1 has increased significantly the life expectancy of the infected patients, however, a complete erradication of the virus is still a matter of study.
Recent findings point out that DC are poorly sensitive to HIV-1 suggesting that the virus may remain hidden and undetected by our innate immune system. Two years ago, two different groups discovered a factor present in DC that was essential for the infection of these cells with HIV-1, named SAMHD1. It functions as a deoxynucleotide triphosphate hydrolase and also has enzymatic activity to degrade the excess of DNA inside the cells. The presence of SAMHD1 stops the replication life cycle of HIV-1 within the cell. Instead, HIV-1 use DC as trojan horses to travel throughout the body without being detected and finally reach their target, the lymphocyte CD4 T cells.
HIV-1 shares many similarities with HIV-2 and the simian immunodeficiency virus SIV, two different viruses with a less pathogenic outcome. However, SIV and HIV-2, both contain a protein in its genome, Vpx, that degrades the factor SAMHD1, whereas HIV-1 does not. A possible relationship between the presence of Vpx and the pathogeneicity of the infection has been a hypothesis of this study.
Besides, HIV-1 is known to be transmitted between cells, through cellular contacts or virologycal synapses. This is a more rapid and efficient mechanism for HIV-1 to spread. Previous studies that showed the role of SAMHD1 in the retsriction to HIV-1 infection in DC were performed in vitro using cell-fre viral preparations. We have developed a system of cell-to-cell HIV-1 transmission and evaluated the effect of SAMHD1 during this highly efficient mode of spread. Our results probed that SAMHD1 is active during cell-to-cell transmission and no IFN-immune response is triggered in the presence of SAMHD1. Removing SAMHD1 by adding the Vpx protein or using gene-silecning tools showed an increase in the infection and detection of HIV by DC.
Comparative studies between HIV-1 and HIV-2 on infection and immune detection by DC were performed in collaboration with the PhD student Lise Chauveau. There is still some ongoing work on this project.
Understanding how HIV-1 evades the innate immune response is clue to completely erradicate the virus. HIV-1 remains hidden in the cells of the immune system, which in turn become reservoirs for the virus. New therapetic strategis are needed to target these reservoirs of infected cells. This will utlimately have an impact on the cure for this pandemic disease.