HIV-1 exploits innate signaling by TLR8 and DC-SIGN for productive infection of dendritic cells

Gringhuis, S.I. et al. Nat. immunol. 11, 419-426 (2010)

Speaker: Pei-Huan Lee (李佩寰)                      Time: 13:00-14:00, Jan. 5, 2011

Commentator: Dr.Shainn-Wei Wang (王憲威老師)        Place: Room 601

Abstract:

Dendritic cells (DCs) express pattern-recognition receptors (PRRs) to sense invading pathogens and trigger immune response to clear them. It is reported that TLRs and C-type lectins are involved in HIV recognition . However, DCs also play an important role for transmission of HIV-1. But it is unclear whether innate signaling induced by inter­actions of HIV-1 with PRRs on DCs is involved in HIV-1 infection.

In this report, the authors demonstrated that HIV-1 subverts the innate signaling pathway by TLR8 and DC-SIGN for its infection in DCs. First , they found that binding of DC-SIGN by gp120 is essential for early HIV-1 transcription. HIV-1 infection triggers DC-SIGN to induce a Raf-1-dependent signaling pathway which is involved in HIV-1 replication.Raf-1 signaling regulates NF-κB activity that is linked to HIV-1 replication by binding to the LTR (long terminal repeats). In addition, NF-κB is also activated by HIV-1 ssRNA through the MyD88-dependent receptors TLR7 and TLR8 . Theauthors demonstrated HIV-1 ssRNA activated NF-κB through TLR8 and it was required for transcription initiation of the integrated HIV-1 genome by RNA polymerase II. On the other hand, DC-SIGN–HIV-1 interactions inducing phosphorylation of the NF-κB subunit p65 at Ser276 was Raf-1-dependent. Then, pTEF-b was recruited to the LTR by p65 phosphorylated at Ser276 ,which is essential for transcrip­tion elongation. Inhibition either of DC-SIGN or TLR8 induced signaling abrogates productive HIV-1 infection of DC . In conclusion, this article demonstrates that HIV-1 subverts the innate signaling pathways induced via TLR8 and DC-SIGN for its replication in DCs and subsequent transmission to T cell. These two innate signaling pathways exploited by HIV-1 for its replication might provide a molecular basis for new strategies to prevent HIV-1 transmission.

Reference

1. Gringhuis, S.I. et al. C-type lectin DC-SIGN modulates toll-like receptor signaling via Raf-1 kinase-dependent acetylation of transcription factor NF-κB. Immunity 26, 605–616 (2007).

2. Perkins, N.D. et al. A cooperative interaction between NF-κB and Sp1 is required for HIV-1 enhancer activation. EMBO J. 12, 3551–3558 (1993).