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P-selectin glycoprotein ligand-1 (PSGL-1) is a cell surface glycoprotein that binds to P-, E-, and L-selectins to mediate the tethering and rolling of immune cells on the surface of the endothelium for cell migration into inflamed tissues. PSGL-1 has been identified as an interferon-γ (INF-γ)-regulated factor that restricts HIV-1 infectivity, and has recently been found to possess broad-spectrum antiviral activities. Here we report that the expression of PSGL-1 in virus-producing cells impairs the incorporation of SARS-CoV and SARS-CoV-2 spike (S) glycoproteins into pseudovirions and blocks pseudovirus attachment and infection of target cells. These findings suggest that PSGL-1 may potentially inhibit coronavirus replication in PSGL-1+ cells
Sijia He; Abdul A. Waheed; Brian Hetrick; Deemah Dabbagh; Ivan V. Akhrymuk; Kylene Kehn-Hall; Eric O. Freed; Yuntao Wu. PSGL-1 Inhibits the Incorporation of SARS-CoV and SARS-CoV-2 Spike Glycoproteins into Pseudovirions and Impairs Pseudovirus Attachment and Infectivity. Viruses 2020, 13, 46 .
AMA StyleSijia He, Abdul A. Waheed, Brian Hetrick, Deemah Dabbagh, Ivan V. Akhrymuk, Kylene Kehn-Hall, Eric O. Freed, Yuntao Wu. PSGL-1 Inhibits the Incorporation of SARS-CoV and SARS-CoV-2 Spike Glycoproteins into Pseudovirions and Impairs Pseudovirus Attachment and Infectivity. Viruses. 2020; 13 (1):46.
Chicago/Turabian StyleSijia He; Abdul A. Waheed; Brian Hetrick; Deemah Dabbagh; Ivan V. Akhrymuk; Kylene Kehn-Hall; Eric O. Freed; Yuntao Wu. 2020. "PSGL-1 Inhibits the Incorporation of SARS-CoV and SARS-CoV-2 Spike Glycoproteins into Pseudovirions and Impairs Pseudovirus Attachment and Infectivity." Viruses 13, no. 1: 46.
Host proteins with antiviral activity have evolved as first-line defenses to suppress viral replication. The HIV-1 accessory protein viral protein U (Vpu) enhances release of the virus from host cells by down-regulating the cell-surface expression of the host restriction factor tetherin. However, the exact mechanism of Vpu-mediated suppression of antiviral host responses is unclear. To further understand the role of host proteins in Vpu's function, here we carried out yeast two-hybrid screening and identified the V0 subunit C of vacuolar ATPase (ATP6V0C) as a Vpu-binding protein. To examine the role of ATP6V0C in Vpu-mediated tetherin degradation and HIV-1 release, we knocked down ATP6V0C expression in HeLa cells and observed that ATP6V0C depletion impairs Vpu-mediated tetherin degradation, resulting in defective HIV-1 release. We also observed that ATP6V0C overexpression stabilizes tetherin expression. This stabilization effect was specific to ATP6V0C, as overexpression of another subunit of the vacuolar ATPase, ATP6V0C″, had no effect on tetherin expression. ATP6V0C overexpression did not stabilize CD4, another target of Vpu-mediated degradation. Immunofluorescence localization experiments revealed that the ATP6V0C-stabilized tetherin is sequestered in a CD63– and lysosome-associated membrane protein 1 (LAMP1)–positive intracellular compartment. These results indicate that the Vpu-interacting protein ATP6V0C plays a role in down-regulating cell-surface expression of tetherin and thereby contributes to HIV-1 assembly and release.
Abdul A. Waheed; Maya Swiderski; Ali Khan; Ariana Gitzen; Ahlam Majadly; Eric O. Freed. The viral protein U (Vpu)-interacting host protein ATP6V0C down-regulates cell-surface expression of tetherin and thereby contributes to HIV-1 release. Journal of Biological Chemistry 2020, 295, 7327 -7340.
AMA StyleAbdul A. Waheed, Maya Swiderski, Ali Khan, Ariana Gitzen, Ahlam Majadly, Eric O. Freed. The viral protein U (Vpu)-interacting host protein ATP6V0C down-regulates cell-surface expression of tetherin and thereby contributes to HIV-1 release. Journal of Biological Chemistry. 2020; 295 (21):7327-7340.
Chicago/Turabian StyleAbdul A. Waheed; Maya Swiderski; Ali Khan; Ariana Gitzen; Ahlam Majadly; Eric O. Freed. 2020. "The viral protein U (Vpu)-interacting host protein ATP6V0C down-regulates cell-surface expression of tetherin and thereby contributes to HIV-1 release." Journal of Biological Chemistry 295, no. 21: 7327-7340.
The HIV-1 accessory protein Vpu enhances virus release by down-regulating cell surface expression of the host restriction factor tetherin. To further understand the role of host proteins in Vpu function, we carried out yeast two-hybrid screening and identified the V0 subunit C of vacuolar ATPase (ATP6V0C) as a Vpu-binding protein. To examine the role of ATP6V0C in Vpu-mediated tetherin degradation and HIV-1 release, we knocked down ATP6V0C expression in HeLa cells and observed that ATP6V0C depletion impairs Vpu-mediated tetherin degradation, resulting in a defect in HIV-1 release. We also observed that overexpression of ATP6V0C stabilizes tetherin expression. This stabilization is specific to ATP6V0C, as overexpression of another subunit of the vacuolar ATPase, ATP6V0C”, had no effect on tetherin expression. ATP6V0C overexpression did not stabilize CD4, another target of Vpu-mediated degradation. Immunofluorescence localization studies showed that the ATP6V0C-stabilized tetherin is sequestered in a CD63- and LAMP1-positive intracellular compartment. These data demonstrate that the Vpu-interacting protein ATP6V0C plays a role in regulating tetherin expression and HIV-1 assembly and release.
Abdul A. Waheed; Maya Swiderski; Ali Khan; Ariana Gitzen; Ahlam Majadly; Eric O. Freed. The Vpu-interacting protein ATP6V0C regulates expression of tetherin and HIV-1 release. 2020, 1 .
AMA StyleAbdul A. Waheed, Maya Swiderski, Ali Khan, Ariana Gitzen, Ahlam Majadly, Eric O. Freed. The Vpu-interacting protein ATP6V0C regulates expression of tetherin and HIV-1 release. . 2020; ():1.
Chicago/Turabian StyleAbdul A. Waheed; Maya Swiderski; Ali Khan; Ariana Gitzen; Ahlam Majadly; Eric O. Freed. 2020. "The Vpu-interacting protein ATP6V0C regulates expression of tetherin and HIV-1 release." , no. : 1.
T cell SERINC proteins were recently identified as human immunodeficiency virus (HIV) restriction factors that diminish viral infectivity by incorporation into virions. Here we provide evidence that SERINC3 and SERINC5 perform additional antiviral activity by enhancing the type I interferon (IFN-I) and NF-κB signaling pathways. SERINC5 interacts with the mitochondrial antiviral-signaling (MAVS) and TRAF6 proteins, resulting in MAVS aggregation and TRAF6 polyubiquitination. Knockdown of SERINC5 in the target cell increases single-round HIV-1 infectivity, as well as infection by recombinant vesicular stomatitis virus (rVSV) bearing VSV-G or Ebola virus (EBOV) glycoprotein (GP). Infection by an endemic Asian strain of Zika virus (ZIKV) FSS13025 is also enhanced by SERINC5 knockdown, suggesting that SERINC5 has direct antiviral activity. Further experiments indicated that the antiviral activity of SERINC5 is IFN-I dependent. Altogether, our work uncovered a new function of SERINC proteins that promotes IFN-I and NF-B inflammatory signaling, thus contributing to SERINC-mediated antiviral activity.
Cong Zeng; Abdul A. Waheed; Tianliang Li; Jingyou Yu; Yi-Min Zheng; Jacob Yount; Haitao Wen; Eric O. Freed; Shan-Lu Liu. SERINC Proteins Potentiate Antiviral Type I IFN Induction and Proinflammatory Signaling Pathways. Proceedings 2020, 50, 1 .
AMA StyleCong Zeng, Abdul A. Waheed, Tianliang Li, Jingyou Yu, Yi-Min Zheng, Jacob Yount, Haitao Wen, Eric O. Freed, Shan-Lu Liu. SERINC Proteins Potentiate Antiviral Type I IFN Induction and Proinflammatory Signaling Pathways. Proceedings. 2020; 50 (1):1.
Chicago/Turabian StyleCong Zeng; Abdul A. Waheed; Tianliang Li; Jingyou Yu; Yi-Min Zheng; Jacob Yount; Haitao Wen; Eric O. Freed; Shan-Lu Liu. 2020. "SERINC Proteins Potentiate Antiviral Type I IFN Induction and Proinflammatory Signaling Pathways." Proceedings 50, no. 1: 1.
Tetherin is an interferon-inducible antiviral protein that inhibits the release of a broad spectrum of enveloped viruses by retaining virions at the surface of infected cells. While the role of specific tetherin domains in antiviral activity is clearly established, the role of glycosylation in tetherin function is not clear. In this study, we carried out a detailed investigation of this question by using tetherin variants in which one or both sites of N-linked glycosylation were mutated (N65A, N92A, and N65,92A), and chemical inhibitors that prevent glycosylation at specific stages of oligosaccharide were added or modified. The single N-linked glycosylation mutants, N65A and N92A, efficiently inhibited the release of Vpu-defective human immunodeficiency virus type 1 (HIV-1). In contrast, the non-glycosylated double mutant, N65,92A, lost its ability to block HIV-1 release. The inability of the N65,92A mutant to inhibit HIV-1 release is associated with a lack of cell-surface expression. A role for glycosylation in cell-surface tetherin expression is supported by tunicamycin treatment, which inhibits the first step of N-linked glycosylation and impairs both cell-surface expression and antiviral activity. Inhibition of complex-type glycosylation with kifunensine, an inhibitor of the oligosaccharide processing enzyme mannosidase 1, had no effect on either the cell-surface expression or antiviral activity of tetherin. These results demonstrate that high-mannose modification of a single asparagine residue is necessary and sufficient, while complex-type glycosylation is dispensable, for cell-surface tetherin expression and antiviral activity.
Abdul A. Waheed; Ariana Gitzen; Maya Swiderski; Eric O. Freed. High-Mannose But Not Complex-Type Glycosylation of Tetherin Is Required for Restriction of HIV-1 Release. Viruses 2018, 10, 26 .
AMA StyleAbdul A. Waheed, Ariana Gitzen, Maya Swiderski, Eric O. Freed. High-Mannose But Not Complex-Type Glycosylation of Tetherin Is Required for Restriction of HIV-1 Release. Viruses. 2018; 10 (1):26.
Chicago/Turabian StyleAbdul A. Waheed; Ariana Gitzen; Maya Swiderski; Eric O. Freed. 2018. "High-Mannose But Not Complex-Type Glycosylation of Tetherin Is Required for Restriction of HIV-1 Release." Viruses 10, no. 1: 26.
The HIV-1 accessory protein Vpu enhances virus release by counteracting the host restriction factor tetherin. To further understand the role of host cell proteins in Vpu function, we carried out yeast two-hybrid screening and identified a previously reported Vpu-interacting host factor, small glutamine-rich tetratricopeptide repeat-containing protein (SGTA). While RNAi-mediated depletion of SGTA did not significantly affect levels of tetherin or virus release efficiency, we observed that overexpression of SGTA inhibited HIV-1 release in a Vpu- and tetherin-independent manner. Overexpression of SGTA in the presence of Vpu, but not in its absence, resulted in a marked stabilization and cytosolic relocalization of a 23-kDa, non-glycosylated tetherin species. Coimmunoprecipitation studies indicated that non-glycosylated tetherin is stabilized through the formation of a ternary SGTA/Vpu/tetherin complex. This accumulation of non-glycosylated tetherin is due to inhibition of its degradation, independent of the ER-associated degradation (ERAD) pathway. Because the SGTA-stabilized tetherin species is partially localized to the cytosol, we propose that overexpression of SGTA in the presence of Vpu blocks the translocation of tetherin across the ER membrane, resulting in cytosolic accumulation of a non-glycosylated tetherin species. Although our results do not provide support for a physiological function of SGTA in HIV-1 replication, they demonstrate that SGTA overexpression regulates tetherin expression and stability, thus providing insights into the function of SGTA in ER translocation and protein degradation.
Abdul A. Waheed; Scott Macdonald; Maisha Khan; Megan Mounts; Maya Swiderski; Yue Xu; Yihong Ye; Eric O. Freed. The Vpu-interacting Protein SGTA Regulates Expression of a Non-glycosylated Tetherin Species. Scientific Reports 2016, 6, 24934 .
AMA StyleAbdul A. Waheed, Scott Macdonald, Maisha Khan, Megan Mounts, Maya Swiderski, Yue Xu, Yihong Ye, Eric O. Freed. The Vpu-interacting Protein SGTA Regulates Expression of a Non-glycosylated Tetherin Species. Scientific Reports. 2016; 6 (1):24934.
Chicago/Turabian StyleAbdul A. Waheed; Scott Macdonald; Maisha Khan; Megan Mounts; Maya Swiderski; Yue Xu; Yihong Ye; Eric O. Freed. 2016. "The Vpu-interacting Protein SGTA Regulates Expression of a Non-glycosylated Tetherin Species." Scientific Reports 6, no. 1: 24934.
HIV-1 uses cellular machinery to bud from infected cells. This cellular machinery is comprised of several multiprotein complexes known as endosomal sorting complexes required for transport (ESCRTs). A conserved late domain motif, Pro-Thr-Ala-Pro (PTAP), located in the p6 region of Gag (p6 Gag ), plays a central role in ESCRT recruitment to the site of virus budding. Previous studies have demonstrated that PTAP duplications are selected in HIV-1-infected patients during antiretroviral therapy; however, the consequences of these duplications for HIV-1 biology and drug resistance are unclear. To address these questions, we constructed viruses carrying a patient-derived PTAP duplication with and without drug resistance mutations in the viral protease. We evaluated the effect of the PTAP duplication on viral release efficiency, viral infectivity, replication capacity, drug susceptibility, and Gag processing. In the presence of protease inhibitors, we observed that the PTAP duplication in p6 Gag significantly increased the infectivity and replication capacity of the virus compared to those of viruses bearing only resistance mutations in protease. Our biochemical analysis showed that the PTAP duplication, in combination with mutations in protease, enhances processing between the nucleocapsid and p6 domains of Gag, resulting in more complete Gag cleavage in the presence of protease inhibitors. These results demonstrate that duplication of the PTAP motif in p6 Gag confers a selective advantage in viral replication by increasing Gag processing efficiency in the context of protease inhibitor treatment, thereby enhancing the drug resistance of the virus. These findings highlight the interconnected role of PTAP duplications and protease mutations in the development of resistance to antiretroviral therapy. IMPORTANCE Resistance to current drug therapy limits treatment options in many HIV-1-infected patients. Duplications in a Pro-Thr-Ala-Pro (PTAP) motif in the p6 domain of Gag are frequently observed in viruses derived from patients on protease inhibitor (PI) therapy. However, the reason that these duplications arise and their consequences for virus replication remain to be established. In this study, we examined the effect of PTAP duplication on PI resistance in the context of wild-type protease or protease bearing PI resistance mutations. We observe that PTAP duplication markedly enhances resistance to a panel of PIs. Biochemical analysis reveals that the PTAP duplication reverses a Gag processing defect imposed by the PI resistance mutations in the context of PI treatment. The results provide a long-sought explanation for why PTAP duplications arise in PI-treated patients.
Angelica N. Martins; Abdul A. Waheed; Sherimay D. Ablan; Wei Huang; Alicia Newton; Christos J. Petropoulos; Rodrigo D. M. Brindeiro; Eric O. Freed. Elucidation of the Molecular Mechanism Driving Duplication of the HIV-1 PTAP Late Domain. Journal of Virology 2016, 90, 768 -779.
AMA StyleAngelica N. Martins, Abdul A. Waheed, Sherimay D. Ablan, Wei Huang, Alicia Newton, Christos J. Petropoulos, Rodrigo D. M. Brindeiro, Eric O. Freed. Elucidation of the Molecular Mechanism Driving Duplication of the HIV-1 PTAP Late Domain. Journal of Virology. 2016; 90 (2):768-779.
Chicago/Turabian StyleAngelica N. Martins; Abdul A. Waheed; Sherimay D. Ablan; Wei Huang; Alicia Newton; Christos J. Petropoulos; Rodrigo D. M. Brindeiro; Eric O. Freed. 2016. "Elucidation of the Molecular Mechanism Driving Duplication of the HIV-1 PTAP Late Domain." Journal of Virology 90, no. 2: 768-779.
The interferon-inducible cellular protein tetherin (CD317/BST-2) inhibits the release of a broad range of enveloped viruses. The HIV-1 accessory protein Vpu enhances virus particle release by counteracting this host restriction factor. While the antagonism of human tetherin by Vpu has been associated with both proteasomal and lysosomal degradation, the link between Vpu-mediated tetherin degradation and the ability of Vpu to counteract the antiviral activity of tetherin remains poorly understood. Here, we show that human tetherin is expressed at low levels in African green monkey kidney (COS) cells. However, Vpu markedly increases tetherin expression in this cell line, apparently by sequestering it in an internal compartment that bears lysosomal markers. This stabilization of tetherin by Vpu requires the transmembrane sequence of human tetherin. Although Vpu stabilizes human tetherin in COS cells, it still counteracts the ability of tetherin to suppress virus release. The enhancement of virus release by Vpu in COS cells is associated with a modest reduction in cell-surface tetherin expression, even though the overall expression of tetherin is higher in the presence of Vpu. This study demonstrates that COS cells provide a model system in which Vpu-mediated enhancement of HIV-1 release is uncoupled from Vpu-mediated tetherin degradation.
Abdul A. Waheed; Nishani D. Kuruppu; Kathryn L. Felton; Darren D’Souza; Eric O. Freed. In COS Cells Vpu Can Both Stabilize Tetherin Expression and Counteract Its Antiviral Activity. PLOS ONE 2014, 9, e111628 .
AMA StyleAbdul A. Waheed, Nishani D. Kuruppu, Kathryn L. Felton, Darren D’Souza, Eric O. Freed. In COS Cells Vpu Can Both Stabilize Tetherin Expression and Counteract Its Antiviral Activity. PLOS ONE. 2014; 9 (10):e111628.
Chicago/Turabian StyleAbdul A. Waheed; Nishani D. Kuruppu; Kathryn L. Felton; Darren D’Souza; Eric O. Freed. 2014. "In COS Cells Vpu Can Both Stabilize Tetherin Expression and Counteract Its Antiviral Activity." PLOS ONE 9, no. 10: e111628.
Previously, we reported the conversion of the 12-mer linear and cell-impermeable peptide CAI to a cell-penetrating peptide NYAD-1 by using an i,i + 4 hydrocarbon stapling technique and confirmed its binding to the C-terminal domain (CTD) of the HIV-1 capsid (CA) protein with an improved affinity (Kd ~ 1 μM) compared to CAI (Kd ~ 15 μM). NYAD-1 disrupts the formation of both immature- and mature-like virus particles in in vitro and cell-based assembly assays. In addition, it displays potent anti-HIV-1 activity in cell culture against a range of laboratory-adapted and primary HIV-1 isolates.
Hongtao Zhang; Francesca Curreli; Abdul A Waheed; Peter Y Mercredi; Mansi Mehta; Pallavi Bhargava; Daniel Scacalossi; Xiaohe Tong; Shawn Lee; Alan Cooper; Michael F Summers; Eric O Freed; Asim K Debnath. Dual-acting stapled peptides target both HIV-1 entry and assembly. Retrovirology 2013, 10, 136 -136.
AMA StyleHongtao Zhang, Francesca Curreli, Abdul A Waheed, Peter Y Mercredi, Mansi Mehta, Pallavi Bhargava, Daniel Scacalossi, Xiaohe Tong, Shawn Lee, Alan Cooper, Michael F Summers, Eric O Freed, Asim K Debnath. Dual-acting stapled peptides target both HIV-1 entry and assembly. Retrovirology. 2013; 10 (1):136-136.
Chicago/Turabian StyleHongtao Zhang; Francesca Curreli; Abdul A Waheed; Peter Y Mercredi; Mansi Mehta; Pallavi Bhargava; Daniel Scacalossi; Xiaohe Tong; Shawn Lee; Alan Cooper; Michael F Summers; Eric O Freed; Asim K Debnath. 2013. "Dual-acting stapled peptides target both HIV-1 entry and assembly." Retrovirology 10, no. 1: 136-136.
Abdul A. Waheed; Abraham L. Brass; Suryaram Gummuluru; Gilda Tachedjian. Host-Pathogen Interactions of Retroviruses. Molecular Biology International 2012, 2012, 1 -4.
AMA StyleAbdul A. Waheed, Abraham L. Brass, Suryaram Gummuluru, Gilda Tachedjian. Host-Pathogen Interactions of Retroviruses. Molecular Biology International. 2012; 2012 ():1-4.
Chicago/Turabian StyleAbdul A. Waheed; Abraham L. Brass; Suryaram Gummuluru; Gilda Tachedjian. 2012. "Host-Pathogen Interactions of Retroviruses." Molecular Biology International 2012, no. : 1-4.
The Gag proteins of HIV-1 are central players in virus particle assembly, release, and maturation, and also function in the establishment of a productive infection. Despite their importance throughout the replication cycle, there are currently no approved antiretroviral therapies that target the Gag precursor protein or any of the mature Gag proteins. Recent progress in understanding the structural and cell biology of HIV-1 Gag function has revealed a number of potential Gag-related targets for possible therapeutic intervention. In this review, we summarize our current understanding of HIV-1 Gag and suggest some approaches for the development of novel antiretroviral agents that target Gag.
Abdul A. Waheed; Eric O. Freed. HIV Type 1 Gag as a Target for Antiviral Therapy. AIDS Research and Human Retroviruses 2012, 28, 54 -75.
AMA StyleAbdul A. Waheed, Eric O. Freed. HIV Type 1 Gag as a Target for Antiviral Therapy. AIDS Research and Human Retroviruses. 2012; 28 (1):54-75.
Chicago/Turabian StyleAbdul A. Waheed; Eric O. Freed. 2012. "HIV Type 1 Gag as a Target for Antiviral Therapy." AIDS Research and Human Retroviruses 28, no. 1: 54-75.
The C-terminal domain (CTD) of HIV-1 capsid (CA), like full-length CA, forms dimers in solution and CTD dimerization is a major driving force in Gag assembly and maturation. Mutations of the residues at the CTD dimer interface impair virus assembly and render the virus non-infectious. Therefore, the CTD represents a potential target for designing anti-HIV-1 drugs.
Hongtao Zhang; Francesca Curreli; Xihui Zhang; Shibani Bhattacharya; Abdul A Waheed; Alan Cooper; David Cowburn; Eric O Freed; Asim K Debnath. Antiviral activity of α-helical stapled peptides designed from the HIV-1 capsid dimerization domain. Retrovirology 2011, 8, 28 -28.
AMA StyleHongtao Zhang, Francesca Curreli, Xihui Zhang, Shibani Bhattacharya, Abdul A Waheed, Alan Cooper, David Cowburn, Eric O Freed, Asim K Debnath. Antiviral activity of α-helical stapled peptides designed from the HIV-1 capsid dimerization domain. Retrovirology. 2011; 8 (1):28-28.
Chicago/Turabian StyleHongtao Zhang; Francesca Curreli; Xihui Zhang; Shibani Bhattacharya; Abdul A Waheed; Alan Cooper; David Cowburn; Eric O Freed; Asim K Debnath. 2011. "Antiviral activity of α-helical stapled peptides designed from the HIV-1 capsid dimerization domain." Retrovirology 8, no. 1: 28-28.