Public policy,federalism, and AIDS

Abstract

The AIDS epidemic poses important challenges to the American political system. In the context of AIDS, relationships between the public and private sectors as well as those among federal, state, and local governments have had a significant impact in shaping the nations response to the epidemic. The character of health policy in the United States has in large part been determined by uncertainty regarding the appropriate role of the public sector and by persistent beliefs that the best solutions are private sector ones. Similarly, relationships across levels of government are clouded by concerns about the presumed excesses of centralized (federal) government and the widespread conviction that the most appropriate solutions are state and local ones. AIDS emerged as a public health issue at a point in the early 1980s when a new federal administration was calling for a reduction in public sector and federal responsibility for addressing health and social needs. Since that time, stronger public and federal leadership appears to be developing, and both are essential to forging the policy partnerships between the public and private sectors and across levels of government that are essential to the development of a comprehensive policy response to the AIDS epidemic.     

Extracellular truncations of h beta c, the common signaling subunit for interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-5, lead to ligand-independent activation

The hypothesis that extracellular truncation of the common receptor subunit for interleukin-3 (IL-3), granulocyte-macrophage colony- stimulating factor, and IL-5 (h beta c) can lead to ligand-independent activation was tested by infecting factor-dependent hematopoietic cell lines with retroviruses encoding truncated forms of h beta c. A truncation, resembling that in v-Mpl, and retaining 45 h beta c-derived extracellular residues, led to constitutive activation in the murine myeloid cell line, FDC-P1. However, infection of cells with retrovirus encoding a more severely truncated receptor, retaining only 7 h beta c- derived extracellular residues, did not confer factor independence on these cells. These experiments show that truncation activates the receptor and define a 37-amino acid segment of h beta c (H395-A431) which contains two motifs conserved throughout the cytokine receptor superfamily (consensus Y/H XX R/Q VR and WSXWS), as essential for factor-independent signaling. The mechanism of activation was also investigated in less severe truncations. A receptor that retains the entire membrane-proximal domain (domain 4) also conferred factor independent growth on FDC-P1 cells; however, a retrovirus encoding a truncated form of h beta c having two intact membrane proximal domains did not have this ability, suggesting that domain 3 may have an inhibitory role in h beta c. The ability of these receptors to confer factor independence was cell specific as demonstrated by their inability to confer factor-independent growth when introduced into the murine IL-3-dependent pro-B cell line BaF-B03. These results are consistent with a model in which activation requires unmasking of an interactive receptor surface in domain 4 and association with a myeloid- specific receptor or accessory component. We suggest that in the absence of ligand intramolecular interactions prevent inappropriate signaling.