Dissertation Defense Announcement
To:  The George Mason University Community

Candidate: Mark R. Spear

Program: PhD in Biosciences

Date:   Wednesday November 12, 2014

Time:   1:00 p.m.

Place:  George Mason University
             Prince William Campus<http://www.gmu.edu/resources/welcome/Directions-to-GMU.html>

             Occoquan Bldg, Room 203

Title: "The Elucidation of the Role of Arp2/3 in HIV-1 Replication in CD4 T Cells"
Thesis Director: Dr. Yuntao Wu
Thesis Committee:  Dr. Kylene Kehn-Hall, Dr. Jia Guo, Dr. Barney Bishop
A copy of the dissertation is available in the Mercer Library.  All are invited to attend the defense.
HIV-1-initiated receptor signaling and early actin dynamics are required for viral infection of resting CD4 T cells. WAVE2 is a component of a multiprotein complex linking receptor signaling to actin dynamics. WAVE2 directly activates Arp2/3, leading to actin nucleation and filament branching. Here we report that binding of HIV-1 to resting CD4 T cells and primary macrophages induces a rapid phosphorylation of WAVE2 at serine 351. This phosphorylation involves both Gαi-dependent and -independent pathways, and occurs in response to R5 and X4 viruses, suggesting that this signaling event is likely conserved in HIV infection. In addition, inhibition of WAVE2-mediated Apr2/3 activity through a specific Apr2/3 inhibitor, CK-548, inhibits both T cell chemotaxis and HIV-1 infection of CD4 T cells. Furthermore, inhibition of Arp2/3 through stable shRNA knockdown of Arp3 also inhibits HIV-1 infection of CD4 T cells. The inhibition is mainly at the level of viral nuclear migration. Our results suggest that WAVE2 and Arp2/3 are actively engaged by HIV-1 following viral binding, and that WAVE2-mediated Arp2/3 activity plays a critical role in mediating actin-based post-entry nuclear migration.