The involvement of the chemokines IL-8 and GRO-alpha in the pathogenesis of AIDS -associated Kaposi's sarcoma.

Chemokines are a family of cytokines that play a role in leukocyte trafficking and inflammation. Chemokines also prevent infection by HIV, as this virus can utilize one of several chemokine receptors (e.g., CCR5, CXCR4) as a co-receptor, along with CD4, to enter cells. While much is known about the actions of the ligands for CCR5 (MIP-1alpha, MIP-1beta, and RANTES) and CXCR4 (SDF-1alpha) in the context of HIV infection, the role of other chemokines has remained unclear. This dissertation examines the effects of the C-X-C chemokines interleukin-8 (IL-8) and growth-regulated oncogene-alpha (GRO-alpha) on HIV-1 replication in primary human monocyte-derived macrophages and CD4+ T lymphocytes. We have determined that HIV-1 gp120 ligation of CXCR4 on macrophages stimulates the production of GRO-alpha and GRO-alpha, in turn, stimulates HIV-1 replication in both macrophages and T lymphocytes (see Chapter 1I). In addition, we have demonstrated that exposure of macrophages to HIV-1 virions or the viral proteins Tat or gp120 leads to a substantial increase in IL-8 levels, thus initiating an autocrine/paracrine loop in which IL-8 also enhances the replication of HIV-1 (see Chapter III). Both GRO-alpha and IL-8 serve to increase viral entry, by decreasing the production of MIP-1alpha, MIP-1beta, and RANTES, and increasing surface expression of CCR5 and CXCR4 on activated T cells (see Chapter IV). We have also shown that TNF-alpha has the opposite effect on macrophages, causing an increase in RANTES, MIP-1alpha, and MIP-1beta production and a decrease in CCR5, which protects macrophages from infection (see Chapter V). Thus, regulation of the CCR5 receptor and its ligands appears to be a major effector of the immune response to HIV. Inhibitors of IL-8 and/or GRO-alpha function disrupt the autocrine/paracrine loop in which these chemokines participate and markedly reduce viral replication in lymphocytes and macrophages (see Chapters II, III, IV). Finally, endothelial cells produce IL-8 in response to HIV-1 and Kaposi's sarcoma-associated herpesvirus, and IL-8 is central to the development of the angiogenic lesions seen when KSHV-infected endothelial cells are implanted into nude mice (see Chapter III). Therapeutic compounds currently under development for chemokine-mediated inflammatory disease thus have the potential to be exploited for the therapy of HIV/AIDS and AIDS-associated Kaposi's sarcoma.PhDBiological SciencesHealth and Environmental SciencesImmunologyMicrobiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/129845/2/3042105.pd