title: Simian immunodeficiency virus and human immunodeficiency virus type 1 matrix proteins specify different capabilities to modulate B cell growth.
abstract: Exogenous HIV-1 matrix protein p17 (p17) deregulates the function of different cells after its N-terminal loop (AT20) binding to the chemokine receptors CXCR1 and CXCR2. One site within AT20 has been recently found to be the major determinant of viral fitness following transmission of simian immunodeficiency virus (SIV) to the human host. Therefore, we sought to determine whether SIV matrix protein (MA) was already capable of interacting with CXCR1 and CXCR2 and mimic p17 biological activities rather than this being a newly acquired function during host adaptation. We show here that SIV MA binds with the same affinity of p17 to CXCR1 and CXCR2 and displays both p17 proangiogenic on human primary endothelial cells and chemotactic activity on human primary monocytes and B cells. However, SIV MA exhibited a higher degree of plasticity than p17 in the C terminus, a region known to play a role in modulating B cell growth. Indeed, in contrast to p17, SIV MA was found to activate the phosphatidylinositol 3-kinase/Akt signaling pathway and strongly promote B cell proliferation and clonogenic activity. Interestingly, we have recently highlighted the existence of a Ugandan HIV-1 strain-derived p17 variant (S75X) with the same B cell growth-promoting activity of SIV MA. Computational modeling allowed us to hypothesize an altered C terminus/core region interaction behind SIV MA and S75X activity. Our findings suggest the appearance of a structural constraint in the p17 C terminus that controls B cell growth, which may help to elucidate the evolutionary trajectory of HIV-1.
  
  
  OBJECTIVE
  The HIV-1 matrix protein p17 (p17) deregulates the biological activities of different cells after binding to the chemokine receptors CXCR1 and CXCR2. The p17 functional domain responsible for receptors interaction includes an amino acid which is considered the major determinant of SIV replication in humans. Therefore, we sought to determine whether SIV matrix protein (SIV MA) already had the ability to bind to both chemokine receptors rather than being a function newly acquired during host adaptation. We show here that SIV MA binds to CXCR1 and CXCR2 and fully mimics the p17 proangiogenic and chemokine activity. However, it differs from p17 in its ability to signal into B cells and promote B cell growth and clonogenicity. Computational analysis suggests that the accumulation of mutations in the C-terminal region may have led to a further SIV MA adaptation to the human host. This finding in turn sheds light on the evolutionary trajectory of HIV-1.
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia Medical School, Brescia, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Caccuri
authors.forename: Cinzia
authors.initials: C
authors.lastname: Giagulli
authors.forename: Joachim
authors.initials: J
authors.lastname: Reichelt
authors.forename: Debora
authors.initials: D
authors.lastname: Martorelli
authors.forename: Stefania
authors.initials: S
authors.lastname: Marsico
authors.forename: Antonella
authors.initials: A
authors.lastname: Bugatti
authors.forename: Ines
authors.initials: I
authors.lastname: Barone
authors.forename: Marco
authors.initials: M
authors.lastname: Rusnati
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Guzman
authors.forename: Riccardo
authors.initials: R
authors.lastname: Dolcetti
authors.forename: Arnaldo
authors.initials: A
authors.lastname: Caruso
mesh_terms: D001402:B-Lymphocytes / Q000502:physiology / Q000821:virology*; D049109:Cell Proliferation; D015683:Gene Products, gag / Q000378:metabolism*; D015488:HIV Antigens / Q000378:metabolism*; D015497:HIV-1 / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D015398:Signal Transduction; D015302:Simian Immunodeficiency Virus / Q000502:physiology*; D014763:Viral Matrix Proteins / Q000378:metabolism*; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: D015683:Gene Products, gag; D015488:HIV Antigens; D014763:Viral Matrix Proteins; D054301:gag Gene Products, Human Immunodeficiency Virus; C054858:p17 protein, Human Immunodeficiency Virus Type 1; C077410:simian immunodeficiency virus matrix protein p17