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He Wangxiao; Campilongo,, Federica; Caccuri,, Francesca; Yuan,, Weirong; Varney,, Kristen; Caruso,, Arnaldo; Gallo,, Robert; Lu, Wuyuan
JAIDS Journal of Acquired Immune Deficiency Syndromes: January 2016
doi: 10.1097/01.qai.0000479626.70515.0c
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Background:The HIV-1 matrix protein p17 of 132 amino acid residues is a structural protein essential for viral assembly and maturation. Recent studies suggest that p17 and certain variants in particular are functionally associated with non-Hodgkin's lymphoma (NHL) in HIV-1 infected individuals as they promote the growth of transformed B cells and induce angiogenesis and lymphangiogenesis of vascular and lymphatic endothelial cells in vitro and in vivo; these growth-promoting effects are mediated by the chemokine receptors CXCR1 and/or CXCR2. Despite these findings, the structural basis of how p17 promotes lymphoma development remains unknown.

Results:By analyzing folding and stability of various p17 variants using a battery of biophysical techniques, we found that their B cell growth-promoting activity is strongly correlated with protein destabilization and/or unfolding. Thus, we hypothesize that a mutation-induced conformational change endows p17 with an acquired or enhanced ability to promote receptor-mediated lymphomagenesis. To test this hypothesis, we forced two highly conserved Cys residues, 10 Å away in the native structure of an inactive p17 from HIV-1 clade B isolate BH10, to form an intra-molecular disulfide bond. This disulfide- constrained p17 protein in a non-native conformation was, as expected, significantly destabilized and less structured, but fully active in promoting clonogenic growth of transformed B cells.

Conclusions:We have identified disulfide bonding as a conformational switch in p17 that turns on its lymphomagenic activity. Since HIV-1 associated NHL strongly correlates with viral replication and p17 is prone to mutate and persists in the germinal centers of lymph nodes long after HAART suppression of HIV, this conformational and functional switch, controlled by mutation-induced protein destabilization in an oxidizing environment, may underlie critical molecular events leading ultimately to the development of NHL in HIV/AIDS patients.

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