HIV-1 and Macrophages
Macrophages
Macrophages are large cells found within many types of tissue. They derive from monocytes (a type of white blood cell) that have entered tissues. Macrophages phagocytise (engulf and then digest) invading microorganisms and also scavenge dead and damaged cells and cellular debris.
When a macrophage ingests a pathogen (see left figure below), the pathogen becomes trapped in a vacuole, which then fuses with a lysosome. Within the lysosome, enzymes and toxic peroxides digest the microorganism. After digestion, the macrophage will load antigen onto MHC II and present it to a responding CD4+ T cell. In some cases, recognition by a T cell is the final trigger to completely destroy the engulfed pathogen.
In addition, infected macrophages produce cytokines that attract other immune cells, and cause dilation of local blood vessels, thereby allowing these immune cells to migrate from the blood into the tissue.
Macrophages are large cells found within many types of tissue. They derive from monocytes (a type of white blood cell) that have entered tissues. Macrophages phagocytise (engulf and then digest) invading microorganisms and also scavenge dead and damaged cells and cellular debris.
When a macrophage ingests a pathogen (see left figure below), the pathogen becomes trapped in a vacuole, which then fuses with a lysosome. Within the lysosome, enzymes and toxic peroxides digest the microorganism. After digestion, the macrophage will load antigen onto MHC II and present it to a responding CD4+ T cell. In some cases, recognition by a T cell is the final trigger to completely destroy the engulfed pathogen.
In addition, infected macrophages produce cytokines that attract other immune cells, and cause dilation of local blood vessels, thereby allowing these immune cells to migrate from the blood into the tissue.
Role in HIV pathogenesis
Macrophages play a crucial role in HIV-1 infection. They are among the first cells infected by HIV-1, and have been proposed to form a reservoir of HIV-1 in infected persons (see right figure above). They also serve as a means of spreading virus to other tissues such as the brain. Two recent studies have shown that HIV-1 in macrophages assembles in a newly-identified intracellular compartment that is a large and complex invaginated plasma membrane domain (Welsch et al, PLoS Path 2007 / Deneka et al, JCB 2007). Presumably, HIV can be stored here, whilst being protected from neutralizing antibodies.
Macrophages play a crucial role in HIV-1 infection. They are among the first cells infected by HIV-1, and have been proposed to form a reservoir of HIV-1 in infected persons (see right figure above). They also serve as a means of spreading virus to other tissues such as the brain. Two recent studies have shown that HIV-1 in macrophages assembles in a newly-identified intracellular compartment that is a large and complex invaginated plasma membrane domain (Welsch et al, PLoS Path 2007 / Deneka et al, JCB 2007). Presumably, HIV can be stored here, whilst being protected from neutralizing antibodies.
HIV-1 spread across a virological synapse
In direct T cell-T cell spread of HIV-1, we and others have demonstrated that HIV-1 forms a 'virological synapse' (VS) (Jolly et al, J Exp Med 2004). The VS is a multi-molecular complex that forms at the interface between HIV-1-infected and uninfected, receptor-expressing cells. Its assembly is driven by Env-(co)receptor interactions and depends upon stable cell-cell junctions maintained by adhesion molecules. Direct T cell-T cell spread is the dominant mode of viral spread between these cells in culture, and probably in vivo.
We investigated the transfer of HIV-1 from macrophages to autologous CD4+ T cells, and found that transfer of virus is rapid, and takes place across transient VS between T cells and macrophages (see picture below: CD4 on the T cell colocalizes with HIV Gag and Env in the macrophage). We propose that an infected macrophage can infect at least one T cell every six hours. Since HIV-1-infected macrophages can survive for many weeks, these resullts highlight the central role played by macrophages in HIV-1 infection and pathogenesis. [Groot, Welsch and Sattentau, Blood 2008, PDF].
In direct T cell-T cell spread of HIV-1, we and others have demonstrated that HIV-1 forms a 'virological synapse' (VS) (Jolly et al, J Exp Med 2004). The VS is a multi-molecular complex that forms at the interface between HIV-1-infected and uninfected, receptor-expressing cells. Its assembly is driven by Env-(co)receptor interactions and depends upon stable cell-cell junctions maintained by adhesion molecules. Direct T cell-T cell spread is the dominant mode of viral spread between these cells in culture, and probably in vivo.
We investigated the transfer of HIV-1 from macrophages to autologous CD4+ T cells, and found that transfer of virus is rapid, and takes place across transient VS between T cells and macrophages (see picture below: CD4 on the T cell colocalizes with HIV Gag and Env in the macrophage). We propose that an infected macrophage can infect at least one T cell every six hours. Since HIV-1-infected macrophages can survive for many weeks, these resullts highlight the central role played by macrophages in HIV-1 infection and pathogenesis. [Groot, Welsch and Sattentau, Blood 2008, PDF].
Virological synapses between HIV-infected macrophages and autologous CD4+ T cells. Macrophage in right upper panel is outlined in white; M: macrophage; T: T cell. T cells were pre-stained for CD4 (green), co-cultured with macrophages for 6 hours, followed by fixation, permeabilization, staining for HIV Gag (blue) and Env (red), and samples were subseqently analysed by laser scanning confocal microscopy. This figure was originally published in Blood, Journal of the American Society of Hematology.