HIV-1 infection induces strong production of IP-10 through TLR7/9-dependent pathways

Rachel P. Simmons, Eileen P. Scully, Erin E. Groden, Kelly B. Arnold, J. Judy Chang, Kim Lane, Jeff Lifson, Eric Rosenberg, Douglas A. Lauffenburger, Marcus Altfeld

Research output: Contribution to journalArticle

Abstract

OBJECTIVE: To study the cytokine/chemokine profiles in response to HIV-1 viremia, and elucidate the pathways leading to HIV-1-induced inflammation. DESIGN/METHODS: Plasma levels of 19 cytokines in individuals with early HIV-1 infection and individuals undergoing treatment interruptions were evaluated via multiplex assay. To investigate the cellular sources of relevant cytokines, sorted cells from HIV-1 infected individuals were assessed for mRNA expression. Relevant signaling pathways were assessed by comparing cytokine production patterns of peripheral blood mononuclear cells stimulated with intact HIV-1 or specific Toll-like receptor (TLR) stimulants with and without a TLR7/9 antagonist. RESULTS: IP-10 plasma concentration was most significantly associated with HIV-1 viral load and was the most significant contributor in a multivariate model. IP-10 mRNA was highly expressed in monocytes and mDCs and these cells were the dominant producers after in-vitro stimulation with TLR7/8 ligands (CL097 and ssRNAGag1166), AT-2 HIV-1, and HIV-1NL43 virus. Partial least square discriminant analysis of culture supernatants revealed distinct cytokine/chemokine secretion profiles associated with intact viruses compared with TLR7/8 ligands alone, with IP-10 production linked to the former. A TLR7/9 antagonist blocked IP-10 production following whole virus stimulation, suggesting the involvement of TLR7/9 in the recognition of HIV-1 by these cells. CONCLUSION: Monocytes and mDCs produce significant amounts of IP-10 in response to HIV-1 viremia and after in-vitro stimulation with HIV-1. Stimulation with HIV-1-derived TLR7/8-ligands versus HIV-1 resulted in distinct cytokine/chemokine profiles, indicating additional pathways other than TLR7/8 that lead to the activation of innate immune cells by HIV-1.

Original languageEnglish (US)
Pages (from-to)2505-2517
Number of pages13
JournalAIDS
Volume27
Issue number16
DOIs
StatePublished - Oct 23 2013
Externally publishedYes

Keywords

  • IP-10
  • Toll-like receptor
  • immune activation
  • mDCs
  • monocytes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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  • Cite this

    Simmons, R. P., Scully, E. P., Groden, E. E., Arnold, K. B., Chang, J. J., Lane, K., Lifson, J., Rosenberg, E., Lauffenburger, D. A., & Altfeld, M. (2013). HIV-1 infection induces strong production of IP-10 through TLR7/9-dependent pathways. AIDS, 27(16), 2505-2517. https://doi.org/10.1097/01.aids.0000432455.06476.bc