AEGiS-15IAC: Impact of CXCL12 production by dendritic cells in HIV infection.

15th International AIDS Conference

Bangkok, Thailand - July 11-16, 2004

Impact of CXCL12 production by dendritic cells in HIV infection.

Int Conf AIDS 2004 Jul 11-16; 15:(abstract no. MoOrA1043)

Alcami J, Bermejo M, Pablos JL, Gonzalez N, Sanchez-Verde L, Baleux F, Arenzana F
AIDS Immunopathogenesis Unit. Centro Nacional de Microbiologia. Instituto de Salud Carlos III., Majadahonda. Madrid, Spain

BACKGROUND: Emergence of X4 HIV strains occurs late in the course of HIV infection, suggesting that a selective pressure interpheres with the switch from CCR5 to CXCR4 coreceptor use. On the other hand HIV infection is enhanced by the DC-SIGN molecule present in dendritic cells. We hypothesized that CXCL12 production by dendritic cells could be involved in the inhibition of X4 strain propagation "in vivo" and to this aim we have analyzed the expression of CXCL12 in lymphoid organs and cultured dendritic cells.

METHODS: Characterization of CXCL12 producing cells in paraffin-embedded lymphoid organs was analyzed by immunohistochemistry and in situ hybridization techniques. Expression of SDF-1 was also assessed in an "in vitro" model of dendritic cell differentiation using flow cytometry, immunofluorescence and RT-PCR techniques. CXCL12 activity was analyzed by chemotaxis assay. X4 and R5 HIV strains harboring a luciferase reporter gene were used in infection experiments. Specificity of CXCL12 effects was assessed using blocking peptides (T134) and CXCL12 neutralizing antibody (k15c).

RESULTS: CXCL12 was expressed by dendritic cells in tonsil crypts and in the parafollicular compartment of lymph nodes. CXCL12 expression was documented in differentiated dendritic cells "in vitro". CXCL12 was detected by ELISA in culture supernatants. Chemotaxis, induced by supernatants from cultured dendritic cells was specifically neutralized by T134 and k15c. Infection with an X4 HIV strain was partially blocked when lymphocytes were co-cultured with dendritic cells and this inhibition was dependent on SDF-1 production. In contrast, infection with R5 HIV strains was strongly enhanced in this co-culture model.

CONCLUSIONS: These results suggest that the production of CXCL12 by dendritic cells could account for the lack of emergence and low propagation of X4 HIV strains in early and chronic stages of infection.

Keywords: AEGIS, HIV Infections, Chemokines, CXC, Receptors, CXCR4, Receptors, CCR5, Dendritic Cells, HIV, Acquired Immunodeficiency Syndrome, Anti-HIV Agents, HIV Seropositivity, HIV Long Terminal Repeat, Cells, Cultured, stromal cell-derived factor-1alpha, In Vitro, economics, genetics

040711
MoOrA1043