The multiple facets of HIV attachment to dendritic cell lectins

Abstract

Entry of enveloped viruses into host cells depends on the interactions of viral surface proteins with cell surface receptors. Many enveloped viruses maximize the efficiency of receptor engagement by first binding to attachment-promoting factors, which concentrate virions on target cells and thus increase the likelihood of subsequent receptor engagement. Cellular lectins can recognize glycans on viral surface proteins and mediate viral uptake into immune cells for subsequent antigen presentation. Paradoxically, many viral and non-viral pathogens target lectins to attach to immune cells and to subvert cellular functions to promote their spread. Thus, it has been proposed that attachment of HIV to the dendritic cell lectin DC-SIGN enables the virus to hijack cellular transport processes to ensure its transmission to adjacent T cells. However, recent studies show that the consequences of viral capture by immune cell lectins can be diverse, and can entail negative and positive regulation of viral spread. Here, we will describe key concepts proposed for the role of lectins in HIV attachment to host cells, and we will discuss recent findings in this rapidly evolving area of research.

Figure 1

Consequences of HIV attachment to DC‐SIGN on dendritic cells. Engagement of DC‐SIGN on dendritic cells can promote infection of adjacent target cells in two ways. First, DC‐SIGN can augment productive infection of dendritic cells, a process termed cis‐infection, and progeny virions released from the dendritic cells can infect nearby target cells. Second, dendritic cells can transfer captured virus (input virus) to adjacent target cells without becoming productively infected, a pathway termed trans‐infection. Trans‐infection occurs at infectious synapses, contact points between dendritic cells and T cells, and HIV might traffic to infectious synapses via intracellular and extracellular routes. The latter trafficking pathway might involve transport of HIV in intracellular but surface connected compartments. In addition, viruses bound to DC‐SIGN can be internalized and processed for MHC presentation. Finally, DC‐SIGN engagement can trigger signal transduction, which modulates TLR‐dependent cytokine production.

Figure 2

HIV induces signalling via DC‐SIGN, which promotes dendritic cell infection and release of immunosuppressive cytokines. Triggering TLR‐3 or TLR‐7 induces NFκB activation. Concomitant engagement of DC‐SIGN by HIV triggers Raf‐1‐dependent signalling, which results in phosphorylation of Ser276 of the NFκB subunit p65. Phosphorylation of Ser276 in turn induces acetylation of lysines in p65, which increases and prolongs transcription of the IL‐10 gene. IL‐10 inhibits the Th1‐mediated response and incapacitates the antigen presentation capabilities of dendritic cells. Induction of TLR‐8 signalling by HIV activates NFκB and allows synthesis of short HIV transcripts. Parallel triggering of DC‐SIGN signalling by HIV induces phosphorylation of the p65 subunit of NFκB at Ser276. This phosphorylation event allows recruitment of the transcription‐elongation factor pTEF‐b to the HIV promoter, which phosphorylates RNA polymerase II at Ser2. Phosphorylation increases processivity of the enzyme and thus allows synthesis of full‐length HIV transcripts.