Evidence of dysregulation of dendritic cells in primary HIV infection.

Myeloid and plasmacytoid dendritic cells (DCs) are important mediators of both innate and adaptive immunity against pathogens such as HIV. During the course of HIV infection, blood DC numbers fall substantially. In the present study, we sought to determine how early in HIV infection the reduction occurs and whether the remaining DC subsets maintain functional capacity. We find that both myeloid DC and plasmacytoid DC levels decline very early during acute HIV infection. Despite the initial reduction in numbers, those DCs that remain in circulation retain their function and are able to stimulate allogeneic T-cell responses, and up-regulate maturation markers plus produce cytokines/chemokines in response to stimulation with TLR7/8 agonists. Notably, DCs from HIV-infected subjects produced significantly higher levels of cytokines/chemokines in response to stimulation with TLR7/8 agonists than DCs from uninfected controls. Further examination of gene expression profiles indicated in vivo activation, either directly or indirectly, of DCs during HIV infection. Taken together, our data demonstrate that despite the reduction in circulating DC numbers, those that remain in the blood display hyperfunctionality and implicates a possible role for DCs in promoting chronic immune activation.

Dendritic cell numbers in the blood of HIV-1 infected patients before and after changes in antiretroviral therapy.

Antigen presenting dendritic cells (DCs) can serve as sites for HIV replication and as vehicles for transmission of the virus to T cells. It is known that the numbers of DCs in blood is reduced during HIV-1 infection. Here we monitored the two major subsets of blood DCs in 12 individuals undergoing a change, primarily initiation, of highly active antiretroviral therapy. The numbers of plasmacytoid DCs were reliably higher on therapy, although in the 1-3 month interval we followed, these numbers did not return to those seen in HIV uninfected controls. An increase in plasmacytoid DCs was accompanied by an increase in IFN-alpha production in response to a standard challenge in culture with UV-inactivated herpes simplex virus. The levels of myeloid DCs also demonstrated an increase while on HAART, and these numbers become comparable to the HIV uninfected controls. The numbers of plasmacytoid and myeloid DCs varied inversely with the levels of plasma HIV viremia. These longitudinal studies extend prior work showing that virus infection with HIV leads to a decrease in the number of dendritic cells in blood, and that this can be reversed at least in part by therapy.