Stimulation of HIV-1 Replication in Immature Dendritic Cells in Contact with Primary CD4 T or B Lymphocytes

Abstract

Sexual transmission is the major route of HIV-1 infection worldwide. Dendritic cells (DCs) from the mucosal layers are considered to be the initial targets of HIV-1 and probably play a crucial role in HIV-1 transmission. We investigated the role of cell-to-cell contact between HIV-1-exposed immature DCs and various lymphocyte subsets in the stimulation of HIV-1 replication. We found that HIV-1 replication and production in DCs were substantially enhanced by the coculture of DCs with primary CD4 T or nonpermissive B lymphocytes but not with primary activated CD8 T lymphocytes or human transformed CD4 T lymphocytes. Most of the new virions released by cocultures of HIV-1-exposed immature DCs and primary B lymphocytes expressed the DC-specific marker CD1a and were infectious for both immature DCs and peripheral blood mononuclear cells (PBMCs). Cocultured DCs thus produced large numbers of infectious viral particles under these experimental conditions. The soluble factors present in the supernatants of the cocultures were not sufficient to enhance HIV-1 replication in DCs, for which cell-to-cell contact was required. The neutralizing monoclonal antibody IgG1b12 and polyclonal anti-HIV-1 sera efficiently blocked HIV-1 transfer to CD4 T lymphocytes but did not prevent the increase in viral replication in DCs. Neutralizing antibodies thus proved to be more efficient at blocking HIV-1 transfer than previously thought. Our findings show that HIV-1 exploits DC-lymphocyte cross talk to upregulate replication within the DC reservoir. We provide evidence for a novel mechanism that may facilitate HIV-1 replication and transmission. This mechanism may favor HIV-1 pathogenesis, immune evasion, and persistence.

Dendritic Cell-Lymphocyte Cross Talk Downregulates Host Restriction Factor SAMHD1 and Stimulates HIV-1 Replication in Dendritic Cells

“…Under these conditions, a significant proportion of virus particles released in DC-lymphocyte coculture were produced by DCs carried the DC-specific marker CD1a (36). Moreover, these newly synthesized virions were infectious, as they productively infected MoDCs and peripheral blood mononuclear cells (PBMCs) (36). Here, we demonstrated that the high HIV-1 replication observed in cocultured DCs was associated with a decreased expression of SAMHD1.…”

“…We observed that treatment with AZT strongly inhibited the percentage of infected cells (Fig. 3A, left panel) (36,38). In addition, significant viral p24 released was detected in the supernatants of coculture (Fig.…”

“…The interaction between adhesion molecule LFA-1 and its ligand ICAM-1 plays significant roles not only in the formation of immunological synapses and antigen-presenting cell-T cell interactions but also in cell-to-cell HIV-1 transmission (36,(41)(42)(43)(44). To investigate the functional role of DC-lymphocyte cross talk, we used an anti-ICAM-1 monoclonal antibody to prevent the formation of immunological synapse between immature MoDCs and autologous lymphocytes.…”

“…Here, we used a coculture model mimicking early mucosal HIV-1 infection and dissemination, in which DCs bind and take up the virus, which is then transferred to CD4 T lymphocytes (44,(54)(55)(56)(57)(58)(59). Under these conditions, a significant proportion of virus particles released in DC-lymphocyte coculture were produced by DCs carried the DC-specific marker CD1a (36). Moreover, these newly synthesized virions were infectious, as they productively infected MoDCs and peripheral blood mononuclear cells (PBMCs) (36).…”

“…We have previously demonstrated that HIV-1 replication in primary HIV-1 isolate-loaded immature DCs is enhanced when they are cocultured with autologous primary CD4 T or B lymphocytes (29,36). In this study, we investigated whether this enhanced HIV-1 replication in cocultured DCs was due to modulation of SAMHD1 expression.…”