CD8+ and CD4+ cytotoxic T cell escape mutations precede breakthrough SIVmac239 viremia in an elite controller

Benjamin Burwitz, Juan P. Giraldo-Vela, Jason Reed, Laura P. Newman, Alexander T. Bean, Francesca A. Nimityongskul, Philip A. Castrovinci, Nicholas J. Maness, Enrique J. Leon, Richard Rudersdorf, Jonah Sacha

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Background: Virus-specific T cells are critical components in the containment of immunodeficiency virus infections. While the protective role of CD8+ T cells is well established by studies of CD8+ T cell-mediated viral escape, it remains unknown if CD4+ T cells can also impose sufficient selective pressure on replicating virus to drive the emergence of high-frequency escape variants. Identifying a high frequency CD4+ T cell driven escape mutation would provide compelling evidence of direct immunological pressure mediated by these cells.Results: Here, we studied a SIVmac239-infected elite controller rhesus macaque with a 1,000-fold spontaneous increase in plasma viral load that preceded disease progression and death from AIDS-related complications. We sequenced the viral genome pre- and post-breakthrough and demonstrate that CD8+ T cells drove the majority of the amino acid substitutions outside of Env. However, within a region of Gag p27CA targeted only by CD4+ T cells, we identified a unique post-breakthrough mutation, Gag D205E, which abrogated CD4+ T cell recognition. Further, we demonstrate that the Gag p27CA-specific CD4+ T cells exhibited cytolytic activity and that SIV bearing the Gag D205E mutation escapes this CD4+ T cell effector function ex vivo.Conclusions: Cumulatively, these results confirm the importance of virus specific CD8+ T cells and demonstrate that CD4+ T cells can also exert significant selective pressure on immunodeficiency viruses in vivo during low-level viral replication. These results also suggest that further studies of CD4+ T cell escape should focus on cases of elite control with spontaneous viral breakthrough.

Original languageEnglish (US)
Article number91
JournalRetrovirology
Volume9
DOIs
StatePublished - Nov 6 2012

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Viremia
T-Lymphocytes
Mutation
Viruses
Viral Genome
Virus Diseases
Amino Acid Substitution
Cellular Structures
Macaca mulatta
Viral Load
Disease Progression
Acquired Immunodeficiency Syndrome

Keywords

  • Cytolytic CD4+ T cells
  • HIV
  • Immune evasion

ASJC Scopus subject areas

  • Virology
  • Infectious Diseases

Cite this

CD8+ and CD4+ cytotoxic T cell escape mutations precede breakthrough SIVmac239 viremia in an elite controller. / Burwitz, Benjamin; Giraldo-Vela, Juan P.; Reed, Jason; Newman, Laura P.; Bean, Alexander T.; Nimityongskul, Francesca A.; Castrovinci, Philip A.; Maness, Nicholas J.; Leon, Enrique J.; Rudersdorf, Richard; Sacha, Jonah.

In: Retrovirology, Vol. 9, 91, 06.11.2012.

Research output: Contribution to journalArticle

Burwitz, B, Giraldo-Vela, JP, Reed, J, Newman, LP, Bean, AT, Nimityongskul, FA, Castrovinci, PA, Maness, NJ, Leon, EJ, Rudersdorf, R & Sacha, J 2012, 'CD8+ and CD4+ cytotoxic T cell escape mutations precede breakthrough SIVmac239 viremia in an elite controller', Retrovirology, vol. 9, 91. https://doi.org/10.1186/1742-4690-9-91
Burwitz, Benjamin ; Giraldo-Vela, Juan P. ; Reed, Jason ; Newman, Laura P. ; Bean, Alexander T. ; Nimityongskul, Francesca A. ; Castrovinci, Philip A. ; Maness, Nicholas J. ; Leon, Enrique J. ; Rudersdorf, Richard ; Sacha, Jonah. / CD8+ and CD4+ cytotoxic T cell escape mutations precede breakthrough SIVmac239 viremia in an elite controller. In: Retrovirology. 2012 ; Vol. 9.
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AU - Newman, Laura P.

AU - Bean, Alexander T.

AU - Nimityongskul, Francesca A.

AU - Castrovinci, Philip A.

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AU - Rudersdorf, Richard

AU - Sacha, Jonah

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AB - Background: Virus-specific T cells are critical components in the containment of immunodeficiency virus infections. While the protective role of CD8+ T cells is well established by studies of CD8+ T cell-mediated viral escape, it remains unknown if CD4+ T cells can also impose sufficient selective pressure on replicating virus to drive the emergence of high-frequency escape variants. Identifying a high frequency CD4+ T cell driven escape mutation would provide compelling evidence of direct immunological pressure mediated by these cells.Results: Here, we studied a SIVmac239-infected elite controller rhesus macaque with a 1,000-fold spontaneous increase in plasma viral load that preceded disease progression and death from AIDS-related complications. We sequenced the viral genome pre- and post-breakthrough and demonstrate that CD8+ T cells drove the majority of the amino acid substitutions outside of Env. However, within a region of Gag p27CA targeted only by CD4+ T cells, we identified a unique post-breakthrough mutation, Gag D205E, which abrogated CD4+ T cell recognition. Further, we demonstrate that the Gag p27CA-specific CD4+ T cells exhibited cytolytic activity and that SIV bearing the Gag D205E mutation escapes this CD4+ T cell effector function ex vivo.Conclusions: Cumulatively, these results confirm the importance of virus specific CD8+ T cells and demonstrate that CD4+ T cells can also exert significant selective pressure on immunodeficiency viruses in vivo during low-level viral replication. These results also suggest that further studies of CD4+ T cell escape should focus on cases of elite control with spontaneous viral breakthrough.

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