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Differential regulation of toll-like receptor pathways in acute and chronic HIV-1 infection.

ABSTRACT: The objective of this study was to determine changes in toll-like receptor (TLR) responses of monocytes, myeloid dendritic cells and plasmacytoid dendritic cells during primary and chronic HIV-1 infection. TLRs serve as important innate receptors to sense pathogens, and have been implicated in mediating immune activation in HIV-1 infection. Studies assessing the consequences of HIV-1 infection on the ability of innate immune cells to respond to TLR stimulation have come to varying conclusions.Using intracellular flow cytometry, cytokine production by cryopreserved peripheral blood mononuclear cells from healthy controls and HIV-1-infected individuals were examined after TLR stimulation.We observed that the effect of HIV-1 infection on TLR responses not only depended on the stage of HIV-1 infection, but was also dependent on the individual receptor and cell type examined. Monocyte and myeloid dendritic cell responses to TLR8 stimulation were associated with HIV-1 viral load and CD4 T-cell count, whereas plasmacytoid dendritic cell responses to TLR7 stimulation were not. Responses to TLR2 stimulation were not affected by HIV-1 infection, whereas responses to TLR9 stimulation were universally decreased in all HIV-1-infected individuals examined regardless of treatment or clinical parameters.Responsiveness to TLR7/8 stimulation, which have been shown to recognize HIV-1 ssRNA, did not decrease in chronic infection, and may represent a contributing factor to ongoing T-cell immune activation in the setting of chronic viremic HIV-1 infection.

SUBMITTER: Chang JJ

PROVIDER: S-EPMC3738004 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Differential regulation of toll-like receptor pathways in acute and chronic HIV-1 infection.

Chang J Judy JJ Lacas Aurore A Lindsay Robert J RJ Doyle Erin H EH Axten Karen L KL Pereyra Florencia F Rosenberg Eric S ES Walker Bruce D BD Allen Todd M TM Altfeld Marcus M

AIDS (London, England) 20120301 5

<h4>Objective and design</h4>The objective of this study was to determine changes in toll-like receptor (TLR) responses of monocytes, myeloid dendritic cells and plasmacytoid dendritic cells during primary and chronic HIV-1 infection. TLRs serve as important innate receptors to sense pathogens, and have been implicated in mediating immune activation in HIV-1 infection. Studies assessing the consequences of HIV-1 infection on the ability of innate immune cells to respond to TLR stimulation have c ...[more]

PMID: 22210629

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Project description:Viral engagement with macrophages activates Toll-Like-Receptors (TLRs) and viruses must contend with the ensuing inflammatory responses to successfully complete their replication cycle. To date, known counter-strategies involve the use of viral-encoded proteins that often employ mimicry mechanisms to block or redirect the host response to benefit the virus. Whether viral regulatory DNA sequences provide an opportunistic strategy by which viral enhancer elements functionally mimic innate immune enhancers is unknown. Here we find that host innate immune genes and the prototypical viral enhancer of cytomegalovirus (CMV) have comparable expression kinetics, and positively respond to common TLR agonists. In macrophages but not fibroblasts we show that activation of NFκB at immediate-early times of infection is independent of virion-associated protein, M45. We find upon virus infection or transfection of viral genomic DNA the TLR-agonist treatment results in significant enhancement of the virus transcription-replication cycle. In macrophage time-course infection experiments we demonstrate that TLR-agonist stimulation of the viral enhancer and replication cycle is strictly delimited by a temporal gate with a determined half-maximal time for enhancer-activation of 6 h; after which TLR-activation blocks the viral transcription-replication cycle. By performing a systematic siRNA screen of 149 innate immune regulatory factors we identify not only anticipated anti-viral and pro-viral contributions but also new factors involved in the CMV transcription-replication cycle. We identify a central convergent NFκB-SP1-RXR-IRF axis downstream of TLR-signalling. Activation of the RXR component potentiated direct and indirect TLR-induced activation of CMV transcription-replication cycle; whereas chromatin binding experiments using wild-type and enhancer-deletion virus revealed IRF3 and 5 as new pro-viral host transcription factor interactions with the CMV enhancer in macrophages. In a series of pharmacologic, siRNA and genetic loss-of-function experiments we determined that signalling mediated by the TLR-adaptor protein MyD88 plays a vital role for governing the inflammatory activation of the CMV enhancer in macrophages. Downstream TLR-regulated transcription factor binding motif disruption for NFκB, AP1 and CREB/ATF in the CMV enhancer demonstrated the requirement of these inflammatory signal-regulated elements in driving viral gene expression and growth in cells as well as in primary infection of neonatal mice. Thus, this study shows that the prototypical CMV enhancer, in a restricted time-gated manner, co-opts through DNA regulatory mimicry elements, innate-immune transcription factors to drive viral expression and replication in the face of on-going pro-inflammatory antiviral responses in vitro and in vivo and; suggests an unexpected role for inflammation in promoting acute infection and has important future implications for regulating latency.

Dataset Information

Differential regulation of toll-like receptor pathways in acute and chronic HIV-1 infection.

Publications

Differential regulation of toll-like receptor pathways in acute and chronic HIV-1 infection.

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