Abstract
Toll-like receptors (TLR) represent the best characterized receptor family transducing innate immune responses, the first line of defense against microbial invaders. This study was designed to investigate whether responses through TLR inhibit HIV-1 replication in its primary target cells. Primary human macrophages and lymphocytes from several different donors and HIV-1 infection in tissue culture were used exclusively in this work. We report that ligands of three different TLR: LPS, R848, and double stranded RNA, induce a common antiviral response in macrophages as assayed by measurement of HIV-1 p24 protein, gag DNA, and entry into cells. HIV-1 infection is arrested after efficient entry but prior to reverse transcription. TLR-ligand activated cells secrete antiviral factors that induce a similar restriction. HIV-1 infection of lymphocytes is not affected by exposure to TLR ligands or to antiviral factors secreted by activated macrophages. TBK1, but neither NF-κB nor JAK-STAT activity, is required in macrophages to mount this antiviral response; the combination of p38 MAPK and JNK are partially required for induction of antiviral activity. Based on transcriptional induction and inhibition, the TLR-linked antiviral activity is different from APOBEC3 A or G, interferon-β, NAMPT, or p21Cip1. The cell-type specificity, site of action, and requirement for signaling intermediates suggest that the TLR-linked antiviral activity is novel.
Highlights
Macrophages perform dual roles during HIV-1 infection [1]
A recent study shows that HIV-1 infection of lymphoid tissue is affected differently by different Toll-like receptor (TLR) ligands [11], so we investigated whether HIV-1 infection of purified human peripheral blood lymphocytes (PBL) is affected by exposure to ligands of TLR3, 4, or 7/8
We find that upon triggering any of three TLR, monocyte-derived macrophages (MDM) mount an innate immune response that inhibits HIV-1 infection, they secrete factor(s) that induce a similar antiviral state in untreated MDM
Summary
Macrophages perform dual roles during HIV-1 infection [1]. Like CD4-bearing T lymphocytes, they are a prominent target for virus replication. As major effectors of innate immunity, they have the potential to mount antiviral responses within hours of systemic infection. The salience of such immediate reaction to HIV-1 infection has been demonstrated in the intense cytokine cascade detected in the plasma of HIV-1 infected people that precedes the peak of viremia seen early after virus transmission [2]. Innate immune responses can be initiated by triggering pattern recognition receptors (PRR) that bind classes of molecules expressed by pathogens [3,4]. TLR ligation activates distinct signal transduction pathways resulting in transcription of many effector molecules including TNF-a, IL-6, and type I interferons [4]
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