Next-Generation mRNA Sequencing Reveals Pyroptosis-Induced CD4+ T Cell Death in Early Simian Immunodeficiency Virus-Infected Lymphoid Tissues

Authors

Wuxun Lu, University of Nebraska—Lincoln
Andrew J. Demers, University of Nebraska—Lincoln
Fangrui Ma, University of Nebraska-LincolnFollow
Guobin Kang, University of Nebraska–LincolnFollow
Zhe Yuan, University of Nebraska-LincolnFollow
Yanmin Wan, University of Nebraska—LincolnFollow
Yue Li, University of Nebraska—Lincoln
Jiangqing Xu, Fudan University
Mark Lewis, BIOQUAL, Inc., Rockville, MD
Qingsheng Li, University of Nebraska-LincolnFollow

Date of this Version

11-2015

Document Type

Article

Citation

Journal of Virology, January 2016, Volume 90 Number 2, pp . 1080-1087

Comments

Copyright © 2016 by the American Society for Microbiology. Used by permission.

Abstract

Lymphoid tissues (LTs) are the principal sites where human immunodeficiency virus type 1 (HIV-1) replicates and virus-host interactions take place, resulting in immunopathology in the form of inflammation, immune activation, and CD4+ T cell death. The HIV-1 pathogenesis in LTs has been extensively studied; however, our understanding of the virus-host interactions in the very early stages of infection remains incomplete. We investigated virus-host interactions in the rectal draining lymph nodes (dLNs) of rhesus macaques at different times after intrarectal inoculation (days postinoculation [dpi]) with simian immunodeficiency virus (SIV). At 3 dpi, 103 differentially expressed genes (DEGs) were detected using next-generation mRNA sequencing (RNA-seq). At 6 and 10 dpi, concomitant with increased SIV replication, 366 and 1,350 DEGs were detected, respectively, including upregulation of genes encoding proteins that play a role in innate antiviral immune responses, inflammation, and immune activation. Notably, genes (IFI16, caspase-1, and interleukin 1β [IL-1β]) in the canonical pyroptosis pathway were significantly upregulated in expression. We further validated increased pyroptosis using flow cytometry and found that the number of CD4+ T cells expressing activated caspase-1 protein, the hallmark of ongoing pyroptosis, were significantly increased, which is correlated with decreased CD4+ T cells in dLNs. Our results demonstrated that pyroptosis contributes to the CD4+ T cell death in vivo in early SIV infection, which suggests that pyroptosis may play a pivotal role in the pathogenesis of SIV, and by extension, that of HIV-1, since pyroptosis not only induces CD4+ T cell death but also amplifies inflammation and immune activation. Thus, blocking CD4+ T cell pyroptosis could be a complementary treatment to antiretroviral therapy.