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Maintenance of AP-2-Dependent Functional Activities of Nef Restricts Pathways of Immune Escape from CD8 T Lymphocyte Responses.

Authors
  • Schouest, Blake1
  • Weiler, Andrea M2
  • Janaka, Sanath Kumar3
  • Myers, Tereance A1
  • Das, Arpita1
  • Wilder, Sarah C1
  • Furlott, Jessica2
  • Baddoo, Melody4
  • Flemington, Erik K4, 5
  • Rakasz, Eva G2
  • Evans, David T2, 3
  • Friedrich, Thomas C2, 6
  • Maness, Nicholas J7, 8
  • 1 Division of Microbiology, Tulane National Primate Research Center, Covington, Louisiana, USA.
  • 2 Wisconsin National Primate Research Center, Madison, Wisconsin, USA.
  • 3 Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA.
  • 4 Tulane Cancer Center, New Orleans, Louisiana, USA.
  • 5 Department of Pathology, Tulane University School of Medicine, New Orleans, Louisiana, USA.
  • 6 Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, Wisconsin, USA.
  • 7 Division of Microbiology, Tulane National Primate Research Center, Covington, Louisiana, USA [email protected]
  • 8 Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, Louisiana, USA.
Type
Published Article
Journal
Journal of Virology
Publisher
American Society for Microbiology
Publication Date
Mar 01, 2018
Volume
92
Issue
5
Identifiers
DOI: 10.1128/JVI.01822-17
PMID: 29237831
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Nef-specific CD8+ T lymphocytes (CD8TL) are linked to extraordinary control of primate lentiviral replication, but the mechanisms underlying their efficacy remain largely unknown. The immunodominant, Mamu-B*017:01+-restricted Nef195-203MW9 epitope in SIVmac239 partially overlaps a sorting motif important for interactions with host AP-2 proteins and, hence, downmodulation of several host proteins, including Tetherin (CD317/BST-2), CD28, CD4, SERINC3, and SERINC5. We reasoned that CD8TL-driven evolution in this epitope might compromise Nef's ability to modulate these important molecules. Here, we used deep sequencing of SIV from nine B*017:01+ macaques throughout infection with SIVmac239 to characterize the patterns of viral escape in this epitope and then assayed the impacts of these variants on Nef-mediated modulation of multiple host molecules. Acute variation in multiple Nef195-203MW9 residues significantly compromised Nef's ability to downregulate surface Tetherin, CD4, and CD28 and reduced its ability to prevent SERINC5-mediated reduction in viral infectivity but did not impact downregulation of CD3 or major histocompatibility complex class I, suggesting the selective disruption of immunomodulatory pathways involving Nef AP-2 interactions. Together, our data illuminate a pattern of viral escape dictated by a selective balance to maintain AP-2-mediated downregulation while evading epitope-specific CD8TL responses. These data could shed light on mechanisms of both CD8TL-driven viral control generally and on Mamu-B*017:01-mediated viral control specifically.IMPORTANCE A rare subset of humans infected with HIV-1 and macaques infected with SIV can control the virus without aid of antiviral medications. A common feature of these individuals is the ability to mount unusually effective CD8 T lymphocyte responses against the virus. One of the most formidable aspects of HIV is its ability to evolve to evade immune responses, particularly CD8 T lymphocytes. We show that macaques that target a specific peptide in the SIV Nef protein are capable of better control of the virus and that, as the virus evolves to escape this response, it does so at a cost to specific functions performed by the Nef protein. Our results help show how the virus can be controlled by an immune response, which could help in designing effective vaccines. Copyright © 2018 American Society for Microbiology.

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