Deep transcriptional sequencing of mucosal challenge compartment from rhesus macaques acutely infected with simian immunodeficiency virus implicates loss of cell adhesion preceding immune activation

Fredrik Barrenas, Robert E. Palermo, Brian Agricola, Michael B. Agy, Lauri Aicher, Victoria Carter, Leon Flanary, Richard R. Green, Randy McLain, Qingsheng Li, Wuxun Lu, Robert Murnane, Xinxia Peng, Matthew J. Thomas, Jeffrey M. Weiss, David M. Anderson, Michael G. Katze

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Pathology resulting from human immunodeficiency virus (HIV) infection is driven by protracted inflammation; the primary loss of CD4+ T cells is caused by activation-driven apoptosis. Recent studies of nonhuman primates (NHPs) have suggested that during the acute phase of infection, antiviral mucosal immunity restricts viral replication in the primary infection compartment. These studies imply that HIV achieves systemic infection as a consequence of a failure in host antiviral immunity. Here, we used high-dose intrarectal inoculation of rhesus macaques with simian immunodeficiency virus (SIV) SIVmac251 to examine how the mucosal immune system is overcome by SIV during acute infection. The host response in rectal mucosa was characterized by deep mRNA sequencing (mRNA-seq) at 3 and 12 days postinoculation (dpi) in 4 animals for each time point. While we observed a strong host transcriptional response at 3 dpi, functions relating to antiviral immunity were absent. Instead, we observed a significant number of differentially expressed genes relating to cell adhesion and reorganization of the cytoskeleton. We also observed downregulation of genes encoding members of the claudin family of cell adhesion molecules, which are coexpressed with genes associated with pathology in the colorectal mucosa, and a large number of noncoding transcripts. In contrast, at 12 dpi the differentially expressed genes were enriched in those involved with immune system functions, in particular, functions relating to T cells, B cells, and NK cells. Our findings indicate that host responses that negatively affect mucosal integrity occur before inflammation. Consequently, when inflammation is activated at peak viremia, mucosal integrity is already compromised, potentially enabling rapid tissue damage, driving further inflammation.

Original languageEnglish (US)
Pages (from-to)7962-7972
Number of pages11
JournalJournal of virology
Volume88
Issue number14
DOIs
StatePublished - Jul 2014

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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    Barrenas, F., Palermo, R. E., Agricola, B., Agy, M. B., Aicher, L., Carter, V., Flanary, L., Green, R. R., McLain, R., Li, Q., Lu, W., Murnane, R., Peng, X., Thomas, M. J., Weiss, J. M., Anderson, D. M., & Katze, M. G. (2014). Deep transcriptional sequencing of mucosal challenge compartment from rhesus macaques acutely infected with simian immunodeficiency virus implicates loss of cell adhesion preceding immune activation. Journal of virology, 88(14), 7962-7972. https://doi.org/10.1128/JVI.00543-14