Role of the natural CXCR4 antagonist ALB408-423 in health and disease

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The CXCR4/CXCL12 signaling pair plays an essential role in homeostasis and, if deregulated, it is associated with a variety of pathophysiological conditions like metastasis or chronic inflammatory processes. Furthermore, the G protein-coupled receptor (GPCR) CXCR4 serves as cofactor for HIV-1 entry. In human blood, we identified a fragment of serum albumin, ALB408-423, that dose-dependently blocks CXCR4- but not CCR5-tropic HIV-1 infection. We provide evidence that ALB408-423 competes with binding of CXCL12 to CXCR4 thereby blocking signaling via the receptor. ALB408-423 inhibits CXCL12-induced calcium mobilization, receptor internalization and tumour cell migration. Importantly, a single administration of ALB408-423 induced stem cell mobilization in mice, demonstrating its in vivo activity. In sum, ALB408-423 is an endogenous antagonist of CXCR4 and likely represents an as-yet-unknown key regulator of CXCR4 function. Therefore, I propose a research project that aims to determine the role of ALB408-423 in health and disease. Within this proposal we aim at 1) establishing means to easily quantify ALB408-423 in body fluids and other specimens; 2) clarifying its role in HIV-1 pathogenicity and transmission; 3) investigating its generation from the precursor albumin; 4) studying whether CXCR4 antagonism by ALB408-423 is a conserved mechanism in mammals; and finally 5) generating optimized ALB-based CXCR4 antagonists for the treatment of CXCR4-linked diseases or the mobilization of stem cells. The work proposed herein will provide fundamental new insights into the regulation of the pivotal CXCR4 receptor and might pave the way for a better understanding of AIDS pathogenesis or the development of new therapeutic strategies for CXCR4-linked diseases.