HMGB1 AND HIV-1
Extracellular HMGB1: Putative Mechanisms of Interference with HIV-1 Infection.
HMGB1 may influence HIV infection at three levels at least. First, HMGB1 pro-inflammatory activity, alone or in combination with other factors, may elicit the production of numerous soluble factors - including TNF- α - that are known to modulate HIV-1 infection and/or replication [60].
Second, HMGB1 may play an important function during the early phase of HIV-1 infection, as a growing set of evidences indicates that it could link innate to adaptive immunity. Third, HMGB1 may act directly on the multiple HIV-1 target cells that have been shown to express RAGE, TLR-2 or TLR-4, such as the monocytes/macrophages, the CD4 T cells and the dendritic cells [61-63]. This is especially relevant for the control of HIV-1 expression since most if not all the signaling pathways induced by soluble HMGB1 converge to NF-kB, a well-known regulator of HIV-1 transcription [60,64].HMGB1, Natural Killer Cells and Dendritic Cells: When Innate Immunity Talks to the Adaptive Response
The sexual route is the main way of HIV-1 acquisition. During infection of the sexual mucosa, the first target cells encountered by the virus in the genital epithelium and sub-epithelium are the CCR5 expressing dendritic cells (DCs) and their subtypes the Langherans cells (LCs). These cells are professional antigen presenting cells (APCs) that can play an opposite (and not mutually exclusive) role during HIV infection.
On the first hand, they contribute to HIV-1 transmission to its main target, the CD4 T cells, since they migrate after their activation to the lymphoid tissues where they can find significant amounts of these major target cells. This is mainly due to the ability of HIV-1 to bind to the C-type lectins expressed at the surface of these cells, such as DC-SIGN for the DCs and langerin for the LCs even if a recent study suggests the lectin langerin might also protect LCs from infection [65].
One the other hand, these cells are also important to initiate specific immunity against the HIV-1. Migration of dendritic cells to the lymphoid compartment induces their maturation, allowing the priming of a specific immune response against the virus through the presentation of viral antigen to naive T cells. Maturation of DCs is also known to be essential for the subsequent orientation of CD4 T cell to a Th1 phenotype [66]. Therefore, DCs are located at the cross road between innate and specific immunity. Their fate has been recently linked to their interaction with another key actor of the innate immunity, the Natural Killer cells (NKs). Importantly, the reciprocal activation of these two cell types involves HMGB1. During DC-NK interaction, NKs trigger the polarized secretion of IL-18 at the synaptic space by immature DCs, whereas DC- activated NKs secrete in turn hyper-acetylated HMGB1 [33]. Many works demonstrated that HMGB1 can induce maturation of DCs [31,32,67] and it is now believed that this protein is a key actor of the DC-NK cross talk. Indeed HMGB1 secreted by NK matures DCs and triggers these cells to secrete the pro-inflammatory cytokines IL-1β and IL-12. Moreover, secreted HMGB1 at the NK-DC synapse also appears to induce the resistance displayed by matured DC to NK cells cytotoxicity [33].
A recent work investigated how this NK-DC cross-talk may impact the fate of infected DCs in the context of HIV-1 infection [68]. HIV-1 infected DCs retain their susceptibility to NK-induced maturation and this cross talk still involves the secretion of HMGB1 by both cell types. As for uninfected DCs, maturation of HIV-1 infected DCs by HMGB1 involves RAGE expression on these cells [67,68]. However, this cross-talk is not fully functional when DCs are infected by HIV-1, since infected DCs do not properly secrete IL-12 and IL-18 after their maturation via NKs interactions. These cytokines are important in the subsequent polarization of autologous CD4 T cell to a Th1 phenotype [66] and no increase in IFN-γ secreting T cells was indeed observed when naive CD4+CD45RO-T cells were co-cultured with autologous NKs and infected DCs [68].
The effective contribution of HIV to this defect is demonstrated by the restoration of the Th1 polarization upon addition of the reverse transcriptase inhibitor AZT to the co-cultures.Another consequence of the cross talk between activated NKs and infected DCs is an increased viral expression in DCs, as demonstrated by the percentage of positive p24 antigen expressing DCs, the p24 release in the co-cultures supernatants and the amount of viral DNA within the cells. Importantly, this increase in HIV expression in dependent on HMGB1 since it is alleviated by specific anti-HMGB1 antibodies or by glycyrrhizin, another direct inhibitor of HMGB1 [68].
This last result opens another very exciting field of work on HMGB1 and HIV-1 that is its impact on viral expression. Whereas an early work did demonstrate that intracellular expression of HMGB1 could inhibit HIV-1 LTR-directed transcription in a cell-specific manner [69], recent studies focused on the putative impact of extracellular HMGB1 on HIV-1 expression.