Follicular dendritic cells (FDC) in retroviral infection: host/pathogen perspectives

Abstract

Follicular dendritic cells (FDC) are found in the follicles of virtually all secondary lymphoid tissues. In health, these cells trap and retain antigens (Ag) in the form of immune complexes and preserve them for months in their native conformation. FDC thus serve as a long-term repository of extracellular Ag important for induction and maintenance of memory responses. In retroviral infection, FDC trap and retain large numbers of retroviral particles with profound effects on FDC. FDC-trapped retrovirus induces follicular hyperplasia, and conventional Ag trapped prior to infection are lost and new Ag cannot be trapped. Concomitantly, antibody-forming cells (AFC) specific for Ag lost from FDC decrease followed by loss of specific serum antibody (Ab). Eventually, FDC die and follicular lysis occurs. From the pathogen perspective, binding to FDC is remarkably beneficial, bringing together virus and activated target cells that are highly susceptible to infection. Furthermore, FDC permit HIV to infect surrounding cells even in the presence of a vast excess of neutralizing Ab. Preliminary data suggest that FDC maintain virus infectivity-even when the virus cannot replicate. Thus retrovirus infection monopolizes FDC networks, thereby transforming the FDC Ag repository into a highly infectious retroviral reservoir.

Follicular Dendritic Cell-Mediated Up-Regulation of CXCR4 Expression on CD4 T Cells and HIV Pathogenesis

“…That the needed FDC-CD4 T cell contact can occur in vivo seems likely because Yuda et al (46) showed that CD4 T cells in the light zone of secondary lymphoid follicles appear to be in direct contact with FDCs. This contact may facilitate both B and T cell contributions to GCs because FDCs provide both Ag-dependent and Ag-independent signals to lymphocytes that are believed to be important to induction of optimal T-dependent humoral immune responses (10,16,47,48). FDC-mediated up-regulation of CXCR4 on CD4 T cells is both Ag independent and primary as evidenced by the observation that both autologous (data not shown) and allogeneic FDCs ( Figs.…”

“…Our recent studies have indicated that FDCs maintain HIV infectivity in vivo for many months in the complete absence of viral infection and/or replication (15). Additionally, FDCs appear to increase the production of virus in CD4 lymphocytes (16). Thus, secondary lymphoid tissues, in particular the GC microenvironment, bring together a reservoir of trapped, infectious virus on FDCs, CD4-bearing target cells, and an environment of high cellular activation creating an ideal site for HIV infection.…”

Persistence of Infectious HIV on Follicular Dendritic Cells

“…The amount of viral DNA or p24 detected depends not only on the amount of infectious virus present on added FDCs, but also on the amount of secondary or costimulatory signaling provided by the FDCs (16). In our hands, this signaling augments HIV infection/replication (33). This FDC costimulation is optimal at a ratio of 1 FDC per 10 lymphocytes.…”

Influence of follicular dendritic cells on decay of HIV during antiretroviral therapy

“…However, protein antigens, which are quickly degraded in blood, remain intact on FDCs for months to years (33). Also, it has been shown in short-term experiments that HIV-1 on FDCs is infectious (34) and that target cells become infected when cocultured with FDC isolated from mice that were inoculated with HIV-1 42 d earlier (35) and even 9 mo earlier (G. F. Burton, personal communication).…”