HIV-1 Coreceptor CXCR4 Antagonists Promote Clonal Expansion of Viral Epitope-Specific CD8+ T Cells During Acute SIV Infection in Rhesus Monkeys In Vivo. (1st June 2015) - Ding, Qing
Abstract : Background: The underlying molecular mechanisms and the kinetics of T cell receptor (TCR) repertoire selection during administration of CXCR4 or CCR5 inhibitors in infection of AIDS viruses in vivo have remained largely unexplored. Viral epitope-specific CD8 + T lymphocytes play a dominant role in the control of HIV and simian immunodeficiency virus (SIV). We hypothesized that blockade of CXCR4 or CCR5 might influence the clonal expansion of epitope-specific CD8 + T cells, contributing to antiviral immune responses in vivo. Methods: We measured frequencies of the dominant epitope p11C-specific CD8 + T cells and analyzed the TCR repertoire of those cells in SIV-infected rhesus monkeys treated by CXCR4 or CCR5 inhibitors and vMIP-II, which binds multiple chemokine receptors. Results: A significantly increase in the levels of epitope-specific CD8 + T cells was observed after blockade of CXCR4 or CCR5 compared with untreated control groups. Those CD8 + T cells exhibited selected usage of TCR Vβ families and complementarity-determining region 3 (CDR3) segments. The clonal expansion of distinct Vβ populations could efficiently inhibit SIV replication in vitro, and CXCR4 inhibitor induced more expansion of epitope-specific CD8 + T cells than CCR5 antagonist ( P < 0.01), whereas vMIP-II treatment showed the most marked augmentation of p11C-specific CD8 + T cells. Conclusions: Antagonists of HIV coreceptors, particularly CXCR4, play an important role in the clonal expansion of SIV epitope-specific CD8 + T cells in vivo, thus inhibitors of chemokine receptors such as CXCR4 or CCR5 may contribute to the ability of epitope-specific CD8 + T cells to inhibit SIV or HIV infection.