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Deep transcriptional sequencing of mucosal challenge compartment from rhesus macaques acutely infected with simian immunodeficiency virus implicates loss of cell adhesion preceding immune activation.
Barrenas, Fredrik; Palermo, Robert E; Agricola, Brian; Agy, Michael B; Aicher, Lauri; Carter, Victoria; Flanary, Leon; Green, Richard R; McLain, Randy; Li, Qingsheng; Lu, Wuxun; Murnane, Robert; Peng, Xinxia; Thomas, Matthew J; Weiss, Jeffrey M; Anderson, David M; Katze, Michael G.
Afiliação
  • Barrenas F; Department of Microbiology, University of Washington, Seattle, Washington, USA Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden.
  • Palermo RE; Department of Microbiology, University of Washington, Seattle, Washington, USA.
  • Agricola B; Washington National Primate Research Center, University of Washington, Seattle, Washington, USA.
  • Agy MB; Washington National Primate Research Center, University of Washington, Seattle, Washington, USA.
  • Aicher L; Department of Microbiology, University of Washington, Seattle, Washington, USA.
  • Carter V; Department of Microbiology, University of Washington, Seattle, Washington, USA.
  • Flanary L; Washington National Primate Research Center, University of Washington, Seattle, Washington, USA.
  • Green RR; Department of Microbiology, University of Washington, Seattle, Washington, USA.
  • McLain R; Washington National Primate Research Center, University of Washington, Seattle, Washington, USA.
  • Li Q; Nebraska Center for Virology, School of Biological Sciences, University of Nebraska-Lincoln, Lincoln, Nebraska, USA.
  • Lu W; Nebraska Center for Virology, School of Biological Sciences, University of Nebraska-Lincoln, Lincoln, Nebraska, USA.
  • Murnane R; Washington National Primate Research Center, University of Washington, Seattle, Washington, USA.
  • Peng X; Department of Microbiology, University of Washington, Seattle, Washington, USA.
  • Thomas MJ; Department of Microbiology, University of Washington, Seattle, Washington, USA.
  • Weiss JM; Department of Microbiology, University of Washington, Seattle, Washington, USA.
  • Anderson DM; Washington National Primate Research Center, University of Washington, Seattle, Washington, USA.
  • Katze MG; Department of Microbiology, University of Washington, Seattle, Washington, USA Washington National Primate Research Center, University of Washington, Seattle, Washington, USA honey@u.washington.edu.
J Virol ; 88(14): 7962-72, 2014 Jul.
Article em En | MEDLINE | ID: mdl-24807713
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. Importance The HIV pandemic is one of the major threats to human health, causing over a million deaths per year. Recent studies have suggested that mucosal antiviral immune responses play an important role in preventing systemic infection after exposure to the virus. Yet, despite their potential role in decreasing transmission rates between individuals, these antiviral mechanisms are poorly understood. Here, we carried out the first deep mRNA sequencing analysis of mucosal host responses in the primary infection compartment during acute SIV infection. We found that during acute infection, a significant host response was mounted in the mucosa before inflammation was triggered. Our analysis indicated that the response has a detrimental effect on tissue integrity, causing increased permeability, tissue damage, and recruitment of SIV target cells. These results emphasize the importance of mucosal host responses preceding immune activation in preventing systemic SIV infection.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Reto / Adesão Celular / Vírus da Imunodeficiência Símia / Interações Hospedeiro-Patógeno / Mucosa Intestinal Limite: Animals Idioma: En Revista: J Virol Ano de publicação: 2014 Tipo de documento: Article País de afiliação: Suécia

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Reto / Adesão Celular / Vírus da Imunodeficiência Símia / Interações Hospedeiro-Patógeno / Mucosa Intestinal Limite: Animals Idioma: En Revista: J Virol Ano de publicação: 2014 Tipo de documento: Article País de afiliação: Suécia