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Molecular Mechanisms of HIV Nef-induced Src Kinase Activation and Survival Signaling in Myeloid Cells

Choi, Hyun-Jung (2004) Molecular Mechanisms of HIV Nef-induced Src Kinase Activation and Survival Signaling in Myeloid Cells. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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The nef gene of HIV encodes a small myristylated protein that is required for viral replication and pathogenesis. Nef lacks intrinsic catalytic activity and has been postulated to function through binding to cellular proteins and altering signaling pathways. Nef binds to the macrophage-specific Src family member Hck through its SH3 domain with the highest affinity reported for an SH3-mediated protein-protein interaction. Studies presented in this dissertation characterized the interface constituting this unusually strong interaction by comparing the ability of different Nef alleles to bind and activate Hck in cells. By aid of molecular modeling and mutational analysis, we found the residues in the Nef hydrophobic pocket critically contributing to high affinity interaction with Hck. This is the first study to show that the HIV-1 Nef hydrophobic pocket is critical for SH3-mediated Hck activation in vivo and identified the pocket as a rational target for drug design to selectively disrupt Nef-Hck signaling in HIV-infected cells. We also investigated the role of HIV Nef in survival signaling in myeloid cells, which is a more relevant cell type for HIV infection. Recently, Nef has been demonstrated to be an important factor in promoting the survival of HIV-infected T cells. Since macrophages serve as HIV viral reservoirs, suppression of apoptosis of infected macrophages could have more impact on persistent virus infection in the host. In this study, we demonstrate that Nef protects the macrophage precursor cell line, TF-1 from apoptosis by upregulating the anti-apoptotic gene, Bcl-XL. In addition, the survival signal and Bcl-XL induction by Nef require Erk MAPK activation. This study provides the first evidence that Nef generates anti-apoptosis signals in cells of the myelomonocytic lineage and adds important evidence to the hypothesis that Nef may contribute to the establishment and maintenance of an HIV reservoir by conferring a survival advantage on HIV-infected macrophages


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Choi, Hyun-Junghycst5@pitt.eduHYCST5
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairSmithgall, Thomas Etsmithga@pitt.eduTSMITHGA
Committee MemberRajasekaran, Baskaranbask@pitt.eduBASK
Committee Member Prochownik,
Committee MemberSchmidt, Martin Cmcs2@pitt.eduMCS2
Committee MemberReinhart, Toddreinhar@pitt.eduREINHAR
Committee Member Kodama, Toshiakitoshik@pitt.eduTOSHIK
Date: 28 October 2004
Date Type: Completion
Defense Date: 18 October 2004
Approval Date: 28 October 2004
Submission Date: 25 October 2004
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Biochemistry and Molecular Genetics
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Bcl-XL; Erk MAPK; Hck; HIV Nef; Hydrophobic pocket; Myeloid cells
Other ID:, etd-10252004-162624
Date Deposited: 10 Nov 2011 20:03
Last Modified: 15 Nov 2016 13:50


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