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

Abstract

Follicular dendritic cells (FDCs) represent a major reservoir of HIV, and active infection occurs surrounding these cells, suggesting that this microenvironment is highly conducive to virus transmission. Because CD4 T cells around FDCs in germinal centers express the HIV coreceptor, CXCR4, whereas CD4 lymphocytes in many other sites do not, it prompted the hypothesis that FDCs may increase CXCR4 expression on CD4 T cells, thereby facilitating infection. To test this, HIV receptor/coreceptor expression was determined on CD4 T cells cultured with or without FDCs, and its consequence to infection was assessed by measuring virus binding and entry. FDCs had little effect on CCR5 or CD4 expression but increased CXCR4 expression on CD4 T cells. FDC-mediated up-regulation of CXCR4 on CD4 T cells occurred by 24 h and was sustained for at least 96 h in vitro, and FDC-CD4 T cell contact was necessary. Importantly, increased CXCR4 expression directly correlated with increased binding and entry of HIV-1 X4 isolates. Furthermore, CD4+CD57+ germinal center T cells expressed high levels of CXCR4 and supported enhanced entry of X4 HIV compared with other CD4 T cells from the same tissue. Thus, in addition to serving as a reservoir of infectious virus, FDCs render surrounding germinal center T cells highly susceptible to infection with X4 isolates of HIV-1.

Single and Coexpression of CXCR4 and CXCR5 Identifies CD4 T Helper Cells in Distinct Lymph Node Niches during Influenza Virus Infection

“…Further proof of this concept will require the inducible depletion of CXCR4 expression upon CD4 T cell activation, as CXCR4 is required for the proper maturation of T cells within the thymus (19). An induction or strong enhancement of the expression of CXCR4 by CD4 T cells after their entry into germinal centers would also be consistent with data from previous studies demonstrating that human FDC modulate CXCR4 expression on T cells in vitro (14) and our studies showing low but detectable levels of CXCR4 in the few T GC present in SAP Ϫ/Ϫ mice by immunofluorescent microscopy (Fig. 6).…”

Follicular Dendritic Cells and Human Immunodeficiency Virus Type 1 Transcription in CD4+T Cells

“…FDCs were isolated from human tonsils as previously described (11,33). Briefly, tonsils were cut into small pieces and digested with an enzyme cocktail containing Blendzyme (Roche Applied Science; Indianapolis, IN) and DNase I (Sigma, St. Louis, MO).…”

“…Moreover, when FDCs are present, HIV infection can occur even in the presence of potent neutralizing antibodies (18). FDCs also interact with adjacent GC T cells to increase their expression of the HIV coreceptor CXC chemokine receptor 4 (CXCR4) (11). As a consequence of increased CXCR4, these GC T cells are sensitive to infection with concentrations of X4-tropic HIV that do not appear to infect other CD4 T cells, and analysis of these cells indicates that they frequently carry provirus (13,20).…”

Adsorption and Infectivity of Human Immunodeficiency Virus Type 1 Are Modified by the Fluidity of the Plasma Membrane for Multiple‐Site Binding

“…(B) Temperature dependence of the order parameter (S) and effect of anti-HLA-II antibody on the MT-2 membrane fluidity. One ml of MT-2 cells (5ϫ10 6 ) was treated with 2 µg/ml of anti-HLA-II antibody at 37 C for 40 min and then mixed with 1 ml of 90 µg/ml of 5-doxyl stearic acid in PBS. After incubating at 37 C for 20 min, the cells were washed 3 times with PBS and applied to ESR spectroscopy.…”

“…One volume (5ϫ10 6 ) of GHOST/CXCR4 or MT-2 cells was mixed with the same volume of 5-doxyl stearic acid at a final concentration of 45 µg/ml. Stock solution of doxyl stearic acid was at 20 mg/ml in ethanol.…”