CD43 - a molecular switch for efferocytosis and HIV-1 infection

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The immune system has evolved primarily to protect us from infection by microbes, and therefore needs to respond rapidly and robustly to infection. However excessively strong or sustained immune responses can be damaging to the host, resulting in disease from excess inflammation and ultimately persistent immune disorders such as autoimmunity. The immune system therefore needs to be carefully regulated to prevent such disease. A way that this may be achieved is by the use of proteins that prevent strong interactions from occurring inappropriately between immune cells. One such protein is CD43, found on immune cells such as T lymphocytes, that has an extended rod-like structure and projects well beyond the 'sugar-coat' of the cell membrane, the so-called glycocalyx. CD43 may thus inhibit interactions between cells simply by its size. However a second inhibitory activity of CD43 is its strong negative charge that will repel other similarly charged immune cells. Given that CD43 is a potent regulatory molecule, how might cells overcome this barrier to interact strongly when required? We have recently found that upon certain signals, including cell death and infection by the human immunodeficiency virus type-1 (HIV-1), CD43 is rapidly lost from the cell surface. The loss of CD43 results in these cells being recognised as damaged by another immune type of cell called a macrophage, that captures, engulfs and destroys these damaged cells. This process is an essential clean up of the local tissue environment and is required to prevent the build of of damaged and dying cells that may release their contents, triggering unwanted inflammation. However, some disease causing microbes, such as HIV-1, have evolved to use the contact between dying or infected cells and macrophages to jump into the macrophage and infect it. This type of viral spread allows faster viral spread and multiplication, increasing disease and persistence. We have found that infection of T helper lymphocytes by HIV-1 triggers loss of CD43 from the cell surface, in part by the virus inducing cell death. As described above, loss of CD43 attracts macrophages to engulf these infected T cells, and the infection is then passed in turn to the macrophages. This type of cell-to-cell spread is very efficient and allows macrophage infection by HIV-1 strains that would not usually infect them. An additional consideration is that CD43 on T helper cells acts as a barrier to HIV-1 infection, and so we will also investigate how the loss of CD43 makes these cells more susceptible to HIV-1 infection and how we might prevent this.We have identified a molecule called ADAM10 that causes the loss of CD43 on the surface of dying and infected T lymphocytes. ADAM10 is a cell-surface enzyme that when activated by infection or cell death cuts off CD43 at its base, releasing it from the cell. At present we do not know how cell death and HIV-1 infection trigger ADAM10 activation, and this is one of the main questions we will address in this application. Once we understand how ADAM10 is switched on by cell death and infection we can test drugs to inhibit or enhance this process. If successful, these drugs might then be used to either slow down HIV-1 infection of T cells and macrophages by preventing CD43 loss from infected T cells, or speed up the clearance of dying and dead cells that may be involved in inflammatory conditions such as cardiovascular (eg. atherosclerosis) and autoimmune (eg. systemic lupus erythematosus) diseases.