Journal
AIDS
Volume 27, Issue 16, Pages 2505-2517Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/01.aids.0000432455.06476.bc
Keywords
immune activation; IP-10; mDCs; monocytes; Toll-like receptor
Categories
Funding
- NIH/NIAID [R01 AI078784]
- Harvard University Center for AIDS Research (CFAR), NIH [P30 AI060354]
- NIAID
- NCI
- NICHD
- NHLBI
- NIDA
- NIMH NIA
- NCCAM
- FIC
- OAR
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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. (C) 2013 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins
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