SDF-1/CXCL12: A Chemokine in the Life Cycle of HIV

Since 1986, the beginning of our involvement in HIV research, our major interest was focused on the regulation of HIV-1 replication by the transcriptional host cell machinery. Thus, we successively investigated the consequences of inflammatory and specific responses in HIV replication in primary monocytes and memory CD4 + T cells, and explored with special emphasis the role played by the transcriptional factors NF-kB and the viral trans-activator Tat in the induction and maintaining of the activity of HIV-1 promoter region, while in parallel we elucidated some of the critical mechanisms leading to the activation of NF-kB factors. Our initial interest in chemokines was based on our hypothesis that they could act both as chemoattractants for HIV-1 target cells and inducers of HIV-1 transcription and replication. During our early chemokine studies, the group of Paolo Lusso reported in 1995 that the CC chemokines CCL5/RANTES, CCL3/MIP-1α, and CCL4/Mip-1β, isolated from an immortalized CD8 + T lym-phocyte clone, blocked infection of a CD4 + T cell line susceptible to primary HIV-1 isolates and some HIV-2 and SIV isolates (1). Based on the tight relationship between T cell activation and HIV replication, the blockade of HIV infection by these factors was in an apparent contradiction with the strong and recently reported potent antigen-independent activation in T lymphocytes by RANTES. The Converging Paths of HIV-1 Entry and Chemokine Research The HIV inhibitory effect of the chemokines identified by Paolo Lusso's group was associated to the previously known, although poorly characterized, suppressive effect of CD8 + T lymphocytes culture supernatants (1, 2). However, the hypothesis of a possible interference of this mechanism on HIV entry was not raised in the report. HIV entry in CD4 T lymphocytes was known to critically rely on the interaction of the HIV envelope glycoproteins (surface subunit gp120) with CD4, a viral receptor and a critical determinant of viral tropism, in that gp120 binding to CD4 eventually leads to viral/target cell membrane fusion and entry of viral replication machinery. Importantly, this early research clearly established that an essential cofactor for HIV entry was missing as CD4 alone did not support HIV infection. While many teams all over the world were trying unsuccessfully to identify such CD4 cofactor(s) enabling productive infection by HIV, scientist working in the field of chemokines were making tremendous progress identifying new chemokines and receptors and elucidating their biological roles. Among them, Bernhard Moser at the Theodor-Kocher Institute in Bern, directed by Marco Baggiolini, had isolated the cDNA for the orphan receptor LESTR, which shared typical characteristics of G protein-coupled receptors (GPCRs) (2). Although the ligand for LESTR could not be identified among a large number of identified chemotactic cytokines, the high expression in white blood cells and the marked sequence relation to CXCR1/IL-8R1 and CXCR2/IL-8R2 suggested that LESTR may be a novel receptor for an unknown chemokine. In a collaboration with Conrad Bleul, a post-doctoral scientist in Tim Springer's laboratory at Harvard University, Bernhard obtained