Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• AIDS (London), 2013-10, Vol.27 (16), p.2505-2517

Ort / Verlag

Hagerstown, MD: Lippincott Williams & Wilkins, Inc

Erscheinungsjahr

2013

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.