Mechanisms of loss of functional dendritic cells in HIV-1 infection.

Dendritic cells (DC) are lost from blood and skin during injection with HIV-1; those remaining show a reduced capacity to stimulate T cell proliferation [S. C. Knight, AIDS 10, 807-817]. Our recent studies investigate mechanisms underlying these effects. DC exposed to HIV-1 vitro can act as targets for cytotoxic T cells, although optimal killing was not obtained until DC were exposed to HIV-1 for 3 days. This cytotoxicity may provide a feedback mechanism by which DC that have presented antigens are removed. However, this effect could also contribute to the reduction in DC during persistent infection. We have also investigated the effect of exposure to HIV-1 on DC function. DC exposed to HIV-1 IIIB virus for 2 h stimulated primary proliferative and cytotoxic T cell responses in vitro; these effects may be similar to those occurring during the early activation of protective antiviral immunity in vivo. After exposure of DC to virus for 5 days, stimulation of allogeneic T cells was reduced. However, a different situation applied when using DC developed from CD34+ cord blood stem cells under the influence of granulocyte-macrophage colony-stimulating factor and tumor necrosis factor alpha that were exposed at 24 h to the same virus. These DC showed low levels of infection similar to peripheral blood DC but in contrast stimulated normal allogeneic T cell proliferation. The capacity of DC exposed to HIV-1 to stimulate T cell proliferation or to show a blocked stimulatory capacity may thus depend not only on the length of the exposure to virus but also on the maturational state of the DC. Loss in DC numbers and function on exposure to HIV-1 may result in lower levels of stimulation of T cells, which in turn may be instrumental in reduction of T cell numbers.