Abstract
Fibroblastic reticular cells (FRCs) are stromal cells in secondary lymphoid organs, the major sites for HIV-1 infection of CD4+ T cells. Although FRCs regulate T cell survival, proliferation, and migration, whether they play any role in HIV-1 spread has not been studied. Here, we show that FRCs enhance HIV-1 spread via trans-infection in which FRCs capture HIV-1 and facilitate infection of T cells that come into contact with FRCs. FRCs mediate trans-infection in both two- and three-dimensional culture systems and in a manner dependent on the virus producer cells. This producer cell dependence, which was also observed for virus spread in secondary lymphoid tissues ex vivo, is accounted for by CD44 incorporated into virus particles and hyaluronan bound to such CD44 molecules. This virus-associated hyaluronan interacts with CD44 expressed on FRCs, thereby promoting virus capture by FRCs. Overall, our results reveal a novel role for FRCs in promoting HIV-1 spread.
Highlights
Fibroblastic reticular cells (FRCs) are stromal cells in secondary lymphoid organs, the major sites for HIV-1 infection of CD4+ T cells
To investigate whether FRCs play any role in HIV-1 spread, we used FRCs isolated from human inguinal lymph nodes (LNs), which is commercially available as human lymphatic fibroblasts, and FRCs isolated from tonsils of healthy donors according to an established protocol[26]
To investigate the effect of lnFRCs on HIV-1 infection, we examined HIV-1 spread in T cell-lnFRC cocultures by p24 enzyme-linked immunosorbent assay (ELISA)
Summary
Fibroblastic reticular cells (FRCs) are stromal cells in secondary lymphoid organs, the major sites for HIV-1 infection of CD4+ T cells. FRCs mediate trans-infection in both two- and three-dimensional culture systems and in a manner dependent on the virus producer cells This producer cell dependence, which was observed for virus spread in secondary lymphoid tissues ex vivo, is accounted for by CD44 incorporated into virus particles and hyaluronan bound to such CD44 molecules. 1234567890():,; Secondary lymphoid organs (SLOs), including lymph nodes (LNs), play a central role in dissemination of HIV-1 In both SIV-infected rhesus macaques[1,2,3,4,5,6] and HIV-1-infected humans[7], a large number of infected CD4+ T cells are detectable in SLOs in contrast with peripheral blood. These findings reveal the presence of a novel trans-infection mechanism mediated by stromal cells in SLOs and suggest that the interaction of HA and CD44 could be a new target for anti-HIV therapeutic strategies
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