HIV-1 Env-chemokine receptor interactions in primary human macrophages: entry and beyond

While HIV has subverted the chemokine receptors CCR5 and CXCR4 for its own use as an entry co-receptor, their normal functions are to transduce signals in response to extracellular ligands. Our lab is interested in understanding how HIV-1 glycoprotein 120 (gp120) may activate intracellular signals through these receptors in primary human macrophages, and how these responses may contribute to pathogenesis. Our studies demonstrate HIV-1 gp120 elicits several different types of signals in macrophages through CXCR4 and CCR5, including calcium elevations, ionic channel activation, non-receptor protein tyrosine kinase activation, and activation of MAP kinases. Receptor activation is triggered by both monomeric gp120 and whole HIV virus. Furthermore, gp120 elicits a number of functional responses in macrophages, such as secretion of chemokines and other soluble products, and we demonstrate that specific pathways linked to the chemokine receptors are responsible. These studies help illuminate the pathways through which chemokine receptors are coupled in primary macrophages, and provide a mechanistic basis for effects that HIV has on macrophage function. These signaling responses may play a role in the pathogenesis of organ dysfunction such as HIV encephalopathy and lymphocytic interstitial pneumonitis where macrophages are the principal infected cell type and inappropriate immune activation plays a central role.