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.
aSection of Infectious Diseases, Boston University
bRagon Institute of MGH, MIT, and Harvard, Massachusetts General Hospital, Boston
cDepartment of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts
dAIDS and Cancer Virus Program, Science Applications International Corporation-Frederick, National Cancer Institute, Frederick, Maryland
eDivision of Infectious Diseases, Massachusetts General Hospital, Boston
fDivision of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
gHeinrich-Pette-Institut, Leibniz Institute for Experimental Virology, Hamburg, Germany.
*Rachel P. Simmons and Eileen P. Scully contributed equally to the writing of the article.
Correspondence to Marcus Altfeld, MD/PhD, Professor, Harvard Medical School, Ragon Institute of MGH, MIT and Harvard, 400 Technology Square, Cambridge, MA 02139, USA. Tel: +1 857 268 7001; e-mail: email@example.com
Received 5 December, 2012
Revised 24 May, 2013
Accepted 11 June, 2013
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