Modulation of Dendritic Cell Chemotaxis by HIV-gp120.

Dendritic cells are essential antigen-presenting cells involved in the induction of T cell immunity against pathogens, such as Human Immunodeficiency Virus (HIV)-1. During the early stages of HIV infection, immature dendritic cells (iDCs) are the first cellular targets of HIV-1. These HIV-infected iDCs cross mucosal surfaces and facilitate transmission of the virus to nearby CD4+ T cells. To date, the effect of HIV envelope proteins such as gp120 on dendritic cell chemotaxis has not been well characterized. Thus, we studied the effect of recombinant gp120 on the chemotaxis of mature DCs (mDCs) and immature DCs. Immature DCs have been shown to express the CC chemokine receptor, CCR5. In contrast, mature DCs down-regulate CCR5 but upregulate CXCR4 as well as exhibit enhanced chemotaxis towards CXCL12. In our study, we analyzed the effect of soluble gp120 on the chemotaxis of DCs. We have shown that pre-treatment of DCs with M-tropic gp120 significantly inhibited the CCR5-induced chemotaxis of iDCs, whereas pre-treatment of DCs with T-tropic gp120 inhibited the CXCL12-induced chemotaxis of mDCs. In addition, we found that M-tropic gp120 itself induced the chemotaxis of iDCs in a dose-dependent manner, while T-tropic gp120 did not show any effect on iDC chemotaxis. We next analyzed the signaling mechanisms involved in the modulation of iDC chemotaxis by M-tropic gp120 and found that M-tropic gp120 increased the phosphorylation of Src kinase, paxillin, Erk, and Akt in these cells. Moreover, M-tropic gp120 induced an increased expression of Lymphocyte Specific Protein-1 (LSP1), which has been reported to regulate the chemotaxis of various immune cells. Taken together, these results suggest that HIV-gp120 plays an important role in modulating the chemotaxis of mDCs and iDCs. This study may help to elucidate the mechanisms of immune response and contribute to the development of vaccines against HIV.