Mechanisms of HIV-1 Resistance to ADCC David Evans

Mechanisms of HIV-1 Resistance to ADCC David Evans

Mechanisms of HIV-1 Resistance to ADCC David Evans University of Wisconsin-Madison July 26, 2017 No conflicts of interest to declare Perspective

HIV-1 has evolved to replicate continuously in the presence of active host immune responses, and has therefore acquired mechanisms to overcome all immune responses in most infected individuals. The ability of neutralizing antibodies to block HIV-1 infectivity is dependent on their capacity to bind to native conformations of the viral envelope glycoprotein as they exist on the surface of virions. ADCC Assay Antibody Env

CD16 NK Cell HIV-1 Tat LTR Luc.

la No p sma irus No v Serial antibody dilutions 0% 100%

Alpert et al. J. Virol. 2012 Env Expression on the Surface of HIV-infected is Tightly Regulated Gardiner et al. J. Virol. 2016 % MAX

% RLU Env Internalization Protects HIV-infected Cells from ADCC Env HIVIG (g/ml) HIV-1 gp41 tail 710

WT: NRVRQGYSPL SFQTHLPIPR Y710G: ......G... .......... Y710F: ......F... .......... von Bredow et al. J. Virol. 2015 Tetherin Adapted from Gottlinger. 2008. Nature

Vpu Downregulates and Degrades Tetherin Tetherin bTrCP-2 Vpu Lysosomal Degradation

Neil et al. 2008. Nature Vpu Protects HIV-infected Cells from ADCC RNAi Knockdown of Tetherin, but not CD4 or NTB-A, Increases Resistance to ADCC Tetherin CD4

NTB-A Arias et al. PNAS. 2014 CD4 Downmodulation by Nef and Vpu Ab CD4 Env

Vpu Nef Downregulation & Degradation CD4 Env

CD4 Downmodulation Prevents the Exposure of CD4-Inducible Epitopes Sensitivity of Wildtype versus Nef- and Vpu-Deleted HIV-1 CH77 T/F to Plasma from HIV+ Donors HIV-1 Env Trimer Glycan Shield

CD4 Binding Site (CD4bs) V3 gp120 CD4bs gp41

MPER Viral Membrane or Infected Cell Membrane Burton et al. Cell Host & Microbe. 2012 % RLU Broadly Neutralizing Antibodies

mAb (g/ml) von Bredow et al. J. Virol. 2016 % RLU Non-Neutralizing Antibodies mAb (g/ml)

von Bredow et al. J. Virol. 2016 ADCC Correlates with Neutralization Conclusions There is little Env on the surface of HIV-infected cells due to trafficking signals in cytoplasmic tail of gp41. Tetherin antagonism by Vpu protects HIV-infected cells from ADCC by preventing the accumulation of captured virions on the cell surface.

CD4 downmodulation by Nef and Vpu protects HIV-infected cells from ADCC by preventing the exposure of CD4-inducible epitopes in Env. Many of the same structural features of the Env trimer that afford resistance to neutralizing antibodies also afford resistance to ADCC. Acknowledgements University of Wisconsin Benjamin von Bredow Juan Fernando Arias Lisa Heyer

Michael Alpert University of Montreal Andres Finzi Jaye Gardiner Nathan Sherer New York University Susan Zolla-Pazner

Scripps Research Institute Dennis Burton Tulane University James Robinson AI121135 CD4 Downmodulation by Vpu and Nef Prevents the Exposure

of CD4-Inducible Epitopes on the Surface HIV-infected Cells Veillette et al. J. Virol. 2014 CD4 Downmodulation by Vpu and Nef Protects HIV-infected Cells from ADCC Veillette et al. J. Virol. 2015 ADCC Correlates with Binding to Env on the Surface

of Infected Cells and with Virus Neutralization von Bredow et al. J. Virol. 2016 Tetherin/BST-2/CD317 Kupzig et al. 2003. Traffic Klimkait & Orenstein. 1990. J. Virol.

interferon-inducible transmembrane protein that interferes with the release of vpu-deleted HIV-1 from restrictive cells - Neil et al. 2008. Nature Van Damme et al. 2008. Cell Host & Microbe IFNa Treatment of HIV-infected Cells Increases their Susceptibility to ADCC

Arias et al. PNAS. 2014 Vpu Substitutions Differentiate Tetherin Antagonism from CD4- and NTB-downmodulation Tetherin Vpu A14L X S52NbTrCP S56N X X

X Sequestration X Degradation A14L blocks binding to tetherin, but does not affect CD4 I46K blocks CD4 binding S52N, prevents tetherin degradation,

S56N but not tetherin sequestration does not affect NTB-A Arias et al. PNAS. 2014 CD4 Binding Exposes Surfaces of the Inner Domain of gp120 Recognized by Non-neutralizing Antibodies Veillette et al. J. Virol. 2014

% RLU ExceptionsGp41 MPER-Specific bNAbs and 2G12 mAb (g/ml) Sensitivity of Wildtype versus Nef- and Vpu-Deleted HIV-1 CH77 T/F to Monoclonal Antibodies Mechanisms of HIV-1 Resistance to ADCC

Env internalization Tetherin antagonism CD4 downmodulation Structural features of the Env trimer Antibody-Dependent Cell-mediated Cytotoxicity (ADCC) NK cell

Antibody Env CD16 Granules Perforin Granzyme SIV or HIV infected cell

Acknowledgements University of Wisconsin Benjamin von Bredow Juan Fernando Arias Lisa Heyer Michael Alpert University of Montreal Andres Finzi

Jaye Gardiner Nathan Sherer New York University Susan Zolla-Pazner Scripps Research Institute Dennis Burton

Tulane University James Robinson AI121135

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