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

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.
AIDS (London, England) (Impact Factor: 5.55). 10/2013; 27(16):2505-2517. DOI: 10.1097/01.aids.0000432455.06476.bc
Source: PubMed


To study the cytokine/chemokine profiles in response to HIV-1 viremia, and elucidate the pathways leading to HIV-1-induced inflammation.
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.
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.
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.

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    • "The relation of CXCL10 with the viral load has been tested in viral diseases, and it was showed that there are differences, especially when fatal and nonfatal cases are compared. In a multivariate model on the cytokine/chemokine profiles in response to HIV-1 viremia, CXCL10 concentration was the most significant cytokine associated with the viral load [Simmons et al., 2013]; CXCL10 was elevated in acute non-fatal cases of Lassa fever, but it was low or undetectable in the fatal cases [Mahanty et al., 2001]. In contrast, CXCL10 rose rapidly in fatal Ebola cases, and reached very high levels 2 days before death, creating a " cytokine storm " [Wauquier et al., 2010]. "
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