The recently discovered connections between HIV infection, chemokines, and chemokine receptors collectively provide unprecedented opportunities for understanding HIV pathogenesis and immunological mechanisms for controlling infection in the blood. It is now established that certain chemokine receptors, also called HIV co-receptors, facilitate the entry of HIV into CD4+ host cells and that their cognate ligands, chemokines, suppress HIV infection as a result of normal receptor-ligand interactions. The known chemokine systems are used selectively by HIV depending on viral phenotype. Consequently, macrophage-tropic viruses that require CCR5 are suppressed by RANTES, MIP-1alpha and MIP-1beta while T cell tropic viruses that use CxCR4 are suppressed by SDF-1. However, our recent studies with the beta chemokine MDC suggest a novel relationship between chemokines and HIV infection. In contrast with other HIV suppressive chemokines MDC suppresses both macrophage tropic and T tropic virus isolates. The macrophage tropic isolates are inhibited in primary macrophages as well as PBMC. This activity is associated with a mixture of natural isoforms, each with a different N terminal truncation relative to the putative full length chemokine. Other evidence suggests that at least one isoform prefers an unidentified receptor that mediates HIV suppression. Based on these findings, our central hypothesis is that MDC forms part of a unique chemokine receptor-ligand system that mediates a novel mechanism of HIV suppression in the blood. There will be three specific aims to evaluate this hypothesis. In the first, we will express the MDC isoforms in baculovirus and identify ones with the most potent antiviral activities. These will be used in the second aim to elucidate the mechanism of HIV suppression mediated by this system. In the third aim, we will characterize alternative MDC receptors and define their roles in HIV infection. These studies promise to reveal a new mechanism for HIV suppression by chemokines, potentially involving a novel co-receptor, that is commonly related to the infection of macrophages as well as T cells.
