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

作者：Schouest Blake; Weiler Andrea M.; Janaka Sanath Kumar; Myers Tereance A.; Das Arpita; Wilder Sarah C.; Furlott Jessica; Baddoo Melody; Flemington Erik K.; Rakasz Eva G.; Evans David T.; Friedrich Thomas C.; Maness Nicholas J.^*

来源：Journal of Virology, 2018, 92(5): UNSP e01822-17.

DOI：10.1128/JVI.01822-17

• CD4
• SERINC
• Tetherin
• viral escape
• evolution
• major histocompatibility complex
• simian immunodeficiency virus

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 Nef(195-203)MW9 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 Nef(195-203)MW9 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.

• 出版日期2018-3