The fusion of IGF I with stromal cell-derived factor I or alpha1 proteinase inhibitor alters their mitogenic or chemotactic activities while keeping their ability to inhibit HIV-1-gp120 binding.

It has been previously reported that insulin-like growth factor I (IGF I) decreases in AIDS patients with wasting, a condition that is partially prevented by combined IGF I growth hormone therapy. By generating bifunctional proteins of IGF I and stromal cell-derived factor 1alpha (SDF-1alpha) or alpha1 proteinase inhibitor (API), two proteins known to prevent HIV infection, it may be possible to improve the therapeutic effectiveness of these compounds for the treatment of AIDS-mediated wasting. SDF-1alpha or the M351E-M358L mutant of API were attached at the C-terminal end of IGF I and synthesized by a stable insect cell expression technique. The IGF I-SDF-1alpha chimera reduced the enhancement of thymidine incorporation into bovine fetal erythroid cells observed in the presence of insect cell produced IGF I alone. It also decreased the SDF-1 and IGF I-stimulated hematopoietic cell migration, without losing the capacity to compete with the binding of HIV-1 (IIIB)-surface glycoprotein gp120. The IGF I-API chimera displayed the same mitogenic activity and a similar, but lower chemotactic activity than IGF I in the assays mentioned above. It had a comparable anti-elastase activity to that observed with a previously described IGF II-API fusion protein with the single mutation M351E. The binding of gp120 to a murine hematopoietic cell line was stimulated by human neutrophil elastase (25-100 nM) and inhibited by IGF I-API. In conclusion, the linkage of IGF I with SDF-1 or API can alter some biological functions of the single components of the chimera while keeping their ability to compete with HIV-1-gp120 binding.