Next-generation mRNA sequencing reveals pyroptosis-induced CD4+ T cell death in early simian immunodeficiency virus-infected lymphoid tissues

Wuxun Lu, Andrew J. Demers, Fangrui Ma, Guobin Kang, Zhe Yuan, Yanmin Wan, Yue Li, Jianqing Xu, Mark Lewis, Qingsheng Li

Research output: Contribution to journalArticle

3 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1080-1087
Number of pages8
JournalJournal of virology
Volume90
Issue number2
DOIs
StatePublished - Jan 1 2016

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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