Granulocyte-macrophage colony-stimulating factor : Potential therapeutic, immunological and antiretroviral effects in HIV infection

The potential consequences of progressive HIV-1 infection include the development of potentially lethal opportunistic infections and malignancies, as well as progressive neurological disease, wasting and hematopoietic abnormalities, including anemia and neutropenia. Although the administration of highly active antiretroviral therapy often results, at least temporarily, in the apparent sustained suppression of viral replication, failure of therapy remains all too common. Furthermore, such therapy has not achieved virological cure, even in those patients in whom HIV RNA remains undetectable in the plasma for prolonged periods of time. This failure of eradication is the consequence of the persistence of replication-competent virus within cellular reservoirs, which include memory T cells and macrophages. Profound dysregulation of the cytokine network is at the epicenter of HIV pathogenesis. For example, the production of IL-2 is impaired early in infection, whereas TNF- alpha levels in the serum become increased later in the course of the illness. One cytokine whose role in HIV disease has been less well defined is granulocyte-macrophage colony-stimulating factor (GM-CSF), a hematopoietic growth factor whose effects extend well beyond that of its colony-stimulating activity. This 127 amino acid monomeric glycoprotein plays an important role in the development and maintenance of cellular immune responses, and may also reduce the infectivity of macrophages by HIV-1. The administration of recombinant human GM-CSF is effective in the management of neutropenia in patients with AIDS. The ability of GM-CSF to augment host defenses against opportunistic pathogens and against HIV itself, as well as its ability to interfere with HIV infection of macrophages, suggests the potential for additional therapeutic roles for this recombinant molecule.