Elevated Basal Pre-infection CXCL10 in Plasma and in the Small Intestine after Infection Are Associated with More Rapid HIV/SIV Disease Onset

PLoS Pathog. 2016 Aug 10;12(8):e1005774. doi: 10.1371/journal.ppat.1005774. eCollection 2016 Aug.

Abstract

Elevated blood CXCL10/IP-10 levels during primary HIV-1 infection (PHI) were described as an independent marker of rapid disease onset, more robust than peak viremia or CD4 cell nadir. IP-10 enhances the recruitment of CXCR3+ cells, which include major HIV-target cells, raising the question if it promotes the establishment of viral reservoirs. We analyzed data from four cohorts of HIV+ patients, allowing us to study IP-10 levels before infection (Amsterdam cohort), as well as during controlled and uncontrolled viremia (ANRS cohorts). We also addressed IP-10 expression levels with regards to lymphoid tissues (LT) and blood viral reservoirs in patients and non-human primates. Pre-existing elevated IP-10 levels but not sCD63 associated with rapid CD4 T-cell loss upon HIV-1 infection. During PHI, IP-10 levels and to a lesser level IL-18 correlated with cell-associated HIV DNA, while 26 other inflammatory soluble markers did not. IP-10 levels tended to differ between HIV controllers with detectable and undetectable viremia. IP-10 was increased in SIV-exposed aviremic macaques with detectable SIV DNA in tissues. IP-10 mRNA was produced at higher levels in the small intestine than in colon or rectum. Jejunal IP-10+ cells corresponded to numerous small and round CD68neg cells as well as to macrophages. Blood IP-10 response negatively correlated with RORC (Th17 marker) gene expression in the small intestine. CXCR3 expression was higher on memory CD4+ T cells than any other immune cells. CD4 T cells from chronically infected animals expressed extremely high levels of intra-cellular CXCR3 suggesting internalization after ligand recognition. Elevated systemic IP-10 levels before infection associated with rapid disease progression. Systemic IP-10 during PHI correlated with HIV DNA. IP-10 production was regionalized in the intestine during early SIV infection and CD68+ and CD68neg haematopoietic cells in the small intestine appeared to be the major source of IP-10.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / immunology
  • Cell Separation
  • Chemokine CXCL10 / metabolism*
  • Disease Progression
  • Flow Cytometry
  • HIV Infections / immunology*
  • HIV-1 / immunology
  • Humans
  • Immunohistochemistry
  • Intestine, Small / immunology*
  • Macaca
  • Polymerase Chain Reaction
  • Simian Acquired Immunodeficiency Syndrome / immunology*
  • Simian Immunodeficiency Virus / immunology
  • Viral Load / immunology
  • Viremia / immunology

Substances

  • Chemokine CXCL10

Grants and funding

This work was supported by Fondation AREVA, the ANRS, SIDACTION and Institut Pasteur. MJP was the recipient of an ANRS postdoctoral fellowship and a SIDACTION Young Investigator fellowship. SPJ received a PhD fellowship from the French Ministry of Higher Education and Research. CP received an ANRS postdoctoral fellowship. NH received a postdoctoral fellowship from the French Vaccine Research Institute (Créteil, France). The National Center for Infectious Disease Models and Innovative Therapies (IDMIT) is funded by "Programme investissements d’avenir” under grant agreement N° ANR-11-INBS-0008). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.