Macrophage interactions with HIV-1-infected T cells

The human immunodeficiency virus (HIV) is mainly a sexually-transmitted infection. The tissues which protect the body from these infections are called mucosal surfaces. HIV-1 introduced onto a mucosal surface can not survive for long, and must infect certain cells types in which it can replicate. Some of the first cell types to become infected are called CD4 T cells and macrophages. Macrophages are professional scavenger-killer cells that track down infectious agents such as HIV and the cells they live in, and eliminate them. The balance between macrophages carrying out their virus killing activity and becoming infected themselves may be delicate, and we intend to study whether macrophages can be made more resistant to HIV infection. Macrophages resistant to HIV infection might then kill the virus before it can infect our cells. If we can achieve this in tissue culture in the laboratory, this may lead to the development of drugs that can achieve the same effect in people, reducing or preventing infection by HIV-1.

The macrophage plays a twin role in HIV-1 pathogenesis, the best known of which is as as a long-lived reservoir of viral infection: the intimate relationship between CD4+ T cells and macrophages is exploited by HIV-1 to disseminate itself. However, a less appreciated role of the macrophage is as a front line scavenger of HIV-1-infected T cells with potential virucidal activity. We have found that macrophages take up HIV-1-infected T cells and degrade viral DNA. During this process, however, virus is released into a non-degradative macrophage compartment from which the macrophage may become infected. We intend to fully characterise the process by which macrophages engulf and destroy virus infected T cells. In parallel we will analyse the non-degradative compartment into which HIV-1 is trafficked, and attempt to define conditions under which macrophages can be triggered to become refractory to viral infectivity. This will include type-1 interferon induction of cellular restriction factors, cytokine-driven macrophage polarisation and induction of autophagy. Additional studies will focus on the role of antibodies in macrophage-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) or antibody-dependent cell-mediated phagocytosis (ADCP) of HIV-1-infected T cells. It is hoped that results from these studies will inform design of future therapeutic or prophylactic interventions.