HIV-1 transmission from DCs to T cells: A role for membrane nanotubes?
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Infection with HIV-1 routinely leads to the acquired immune deficiency syndrome (AIDS) in the absence of antiviral treatment. An estimated 30 million people have already died of AIDS since the discovery of the virus in 1981, 33 million people worldwide are currently living with HIV-1 and approximately 6800 people per day are newly infected with this retrovirus. These numbers are truly alarming and new approaches to block the transmission and spread of HIV-1 are urgently needed particularly in the developing world. The danger HIV-1 poses for the infected person strongly depends on the ability of this virus to spread within the body. HIV-1 primarily infects certain types of immune cells, called T cells, dendritic cells (DCs) and macrophages. Normally, the function of these cells is to defend the body from infections, but HIV-1 exploits these cells for its own infectious advantage. HIV-1 preferentially spreads from an infected to an uninfected cell when these two cells are in close contact. Recently, a new mode of cell-to-cell contact has been discovered. Immune cells that were located a long distance from each other were found to be connected via thin tethers, which were named membrane nanotubes. Using light microscopy, these membrane nanotubes were shown to bridge T cells over distances ranging up to 8 T-cell diameters. When one population of T cells was infected with fluorescent HIV-1 and mixed with an uninfected population of T cells, fluorescent HIV-1 was shown to traffic along nanotubes from infected to uninfected T cells. Thus, HIV-1 can exploit membrane nanotubes between T cells for rapidly moving from one cell to the next. Membrane nanotubes also connect multiple dendritic cells creating a complex network between those cells. Dendritic cells play an important amplifying role during HIV-1 infection, as they are believed to carry HIV-1 from its entry sites in the body to the sites where T cells are located. At these sites, called lymph nodes, DCs transfer HIV-1 to the T cells, which are the main source of HIV-1 production. Despite knowing that both cell types are able to form membrane nanotubes between themselves, it is not known whether membrane nanotubes form between DCs and T cells and whether HIV-1 can also exploit these connections for effective spread. We now propose to investigate this intriguing possibility and in the process to perhaps identify a novel route for cell-cell transmission of HIV between DCs and T cells that markedly amplifies overall infection. We will apply live cell imaging to visualize nanotubes between DCs and T cells and follow the movement of fluorescent HIV-1 virions that were exposed to DCs and then co-cultured with uninfected T cells. We will further elucidate how virion transfer is mediated, whether any specific viral or cellular proteins are necessary for transfer along membrane nanotubes and compare the efficiency of this mode of spread to viral transmission when an HIV-1-bearing DC is in close contact to a T cell. Understanding the routes HIV-1 takes to spread between cells could certainly aid the design of effective drugs against HIV-1 infection.