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.
Sandoval
Carolyn
C
Endocrine Laboratory, McGill University Health Centre, 687 avenue des pins, ouest, Montreal, Que., Canada H3A 1A1.
Stojanova
Angelina
A
DiFalco
Marcos R
MR
Congote
L Fernando
LF
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001667:Binding, Competitive; D002417:Cattle; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects; D015699:HIV Envelope Protein gp120 / Q000187:drug effects*; D015497:HIV-1 / Q000737:chemistry; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007313:Insecta / Q000166:cytology; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008934:Mitogens / Q000494:pharmacology; D008969:Molecular Sequence Data; D011993:Recombinant Fusion Proteins / Q000378:metabolism / Q000494:pharmacology; D000515:alpha 1-Antitrypsin / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D015699:HIV Envelope Protein gp120; D008934:Mitogens; D011993:Recombinant Fusion Proteins; D000515:alpha 1-Antitrypsin; D007334:Insulin-Like Growth Factor I