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

Benjamin J Burwitz1, Juan Pablo Giraldo-Vela2, Jason Reed1, Laura P Newman2, Alexander T Bean2, Francesca A Nimityongskul2, Philip A Castrovinci2, Nicholas J Maness3, Enrique J Leon1, Richard Rudersdorf2 and Jonah B Sacha14*

  • * Corresponding author: Jonah B Sacha sacha@ohsu.edu

  • † Equal contributors

Author Affiliations

1 Vaccine and Gene Therapy Institute, Oregon Health and Science University, 505 NW 185th, Beaverton, OR, 97006, USA

2 Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI, 53706, USA

3 Division of Microbiology, Tulane National Primate Research Center, Covington, LA, 70433, USA

4 Division of Pathobiology and Immunology, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR, 97006, USA

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Retrovirology 2012, 9:91  doi:10.1186/1742-4690-9-91

Published: 6 November 2012

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.

Keywords:
HIV; Cytolytic CD4+ T cells; Immune evasion