HIV Envelope Protein gp120 Stimulates Expression of Specific Chemokines in Lymphatic Endothelial Cells.

Lymphoid organs are the major anatomical home of HIV, where the virus replicates during both the acute and chronic phases of infections. In this regard, there are significantly more infected cells in lymph nodes (LNs) than in circulating blood, and these infected cells are a major reservoir of infectious HIV. Certain chemokines like CCL19 (MIP-3β) and CCL21 (SLC) play key roles in immune cell trafficking to LNs. They induce specific homing of naïve T cells and dendritic cells into the T cell zone of secondary lymphoid organs. There, the T cells become activated by the dendritic cells. A network of channels composed of lymphatic endothelium exists in LNs that provides a route for this dendritic cell and T cell movement. To date, how this lymphatic endothelium may contribute to the pathogenesis of HIV infection has not been studied. This prompted us to investigate whether HIV may alter immune cell trafficking via interaction with this lymphatic network. Lymphatic endothelial cells (LEC) were separated from primary dermal microvascular endothelial cells. The phenotype of LEC was confirmed by immunostaining with specific lymphatic markers including VEGFR-3, LYVE-1, and podoplanin. Since HIV envelope proteins are presented to endothelial cells in the microenvironment, we studied the effects of X4 gp120 on LEC. Using a pathway specific cDNA array, we detected enhanced expression of a restricted repertoire of chemokines in LEC upon HIV-1 gp120 stimulation. Gp120 upregulated expression of the chemokine genes GRO-α, GRO-γ, MIP-3β, and SDF-1α and β in LEC. These chemokines can act to enhance T cell and dendritic cell homing to LNs. Furthermore, we also detected GRO-α, SDF-1, and SLC proteins in culture supernatants of the gp120-treated LEC. We did not observe upregulation of the chemokines RANTES and MCP-1 upon gp120 stimulation. Since dendritic cells mediate the HIV infectivity of CD4⁺ T cells by presenting HIV particles, our study suggests that HIV-1 gp120-induced production of a restricted repertoire of chemokines in LEC may accelerate the trafficking of infected dendritic cells to LNs and foster HIV infection in this reservoir.