Efficient Virus Transmission from Dendritic Cells to CD4+T Cells in Response to Antigen Depends on Close Contact through Adhesion Molecules

Abstract

Monocyte-derived cultured dendritic cells (DCs) are potent antigen-presenting cells (APCs) and are susceptible to HIV-1Lai infection. Compared to the low level of virus production by HIV-1-infected DCs alone, a level of virus two to three orders of magnitude higher was produced by cocultivation of HIV-1-infected DCs with autologous resting CD4+ T cells in the presence of a nominal antigen. In this coculture system, direct contact of HIV-1-infected DCs with T cells was crucial for efficient virus transmission and subsequent virus production. Blocking of the LFA-1/ICAM-1 or LFA-3/CD2 interaction between these cells substantially reduced virus production, without influence or IL-2 production by activated T cells. In contrast, cell-cell transmission of HIV between non-APCs and activated T cells was not blocked by an antibody against LFA-3. Since a low level of virus production by HIV-infected DCs was upregulated by cross-linking of CD40, it was suggested that not only focal adhesion, but also mutual activation of HIV-infected DCs and T cells through adhesion molecules, may potentiate virus transmission and production and that such activation signals to HIV may be distinct from signals responsible for IL-2 production in activated T cells.

Transcriptional regulation of HIV-1 LTR during antigen-dependent activation of primary T cells by dendritic cells

“…The virus production at days 10 and 14 of more than three individuals is depicted in Figure 3B. As we described previously [16], antigen-dependent activation of CD4 ϩ T cells by HIV-infected DCs induced a massive production of virus with rapid kinetics. At 10-14 days after infection, virus replication reached a peak, whereas in the case of CD4 ϩ T cells activated by PMA ϩ ionomycin, a maximum level of replication was achieved later, at 21 days after infection (Fig.…”

“…For the coculture of DCs and autologous resting CD4 ϩ T cells, DCs (1 ϫ 10 5 cells per well) and T cells (1 ϫ 10 6 cells per well) were mixed in 1 mL of RPMI medium and plated into 24-well culture plates. A nominal antigen, PPD, was always added to the coculture at 40 µg/mL to ensure a high level of T cell activation, as described previously [16]. Under this coculture condition, the supplementation of IL-2 was unnecessary because the level of endogenously produced IL-2 was high enough to maintain activated T cells until virus replication reached the maximum level.…”

“…In this respect, DCs provide the full costimulation signals to T cells through LFA-1/ICAMs, LFA-3/CD2, CD80/CD28, and CD40/CD40L interaction, which were shown to be important for virus transmission and activation [16]. It is possible that the highly impaired replication of Sp1-deletion mutant only in CD45RA ϩ T cells activated by DCs and antigen simply reflect delayed signaling events for IL-2 production in these subsets.…”

Directed Egress of Animal Viruses Promotes Cell-to-Cell Spread

“…However, while cell fusion may play a role in HIV disease, its extent and its significance in promoting virus spread in vivo are not clear (15,31,47). Studies with cultured T cells and macrophages or dendritic cells have provided evidence for cell-to-cell spread, without cell fusion, and apparently across junctions formed between cells (6,15,18,26,65,66,91,92).…”

“…However, CAMs, including LFA-1 and its ligands ICAM-1, -2, and-3, can contribute to both virus entry and cell-to-cell spread. ICAM-1 can be incorporated into the virion envelope, apparently affecting entry of extracellular virus (30,41,70), but can also cement cells together, promoting movement of HIV directly across cell junctions (26,92). It is likely that other T-cell or macrophage CAMs can similarly contribute to cell-to-cell spread of HIV.…”