Abstract
The gastrointestinal tract is a principal route of entry and site of persistence of human immunodeficiency virus type 1 (HIV-1). The intestinal mucosa, being rich of cells that are the main target of the virus, represents a primary site of viral replication and CD4+ T-cell depletion. Here, we show both in vitro and ex vivo that HIV-1 of R5 but not X4 phenotype is capable of selectively triggering dendritic cells (DCs) to migrate within 30 min between intestinal epithelial cells to sample virions and transfer infection to target cells. The engagement of the chemokine receptor 5 on DCs and the viral envelope, regardless of the genetic subtype, drive DC migration. Viruses penetrating through transient opening of the tight junctions likely create a paracellular gradient to attract DCs. The formation of junctions with epithelial cells may initiate a haptotactic process of DCs and at the same time favour cell-to-cell viral transmission. Our findings indicate that HIV-1 translocation across the intestinal mucosa occurs through the selective engagement of DCs by R5 viruses, and may guide the design of new prevention strategies.
Highlights
The mucosal surface of the gastrointestinal tract is the main route of entry of human immunodeficiency virus type 1 (HIV-1) during mother-to-child transmission (MTCT) via ingestion of infected biological fluids as well as during anal sexual intercourses
R5 HIV-1 induce migration of dendritic cells (DCs) through a tight monolayer of intestinal epithelial cells To test the hypothesis that HIV-1 can gain access into the intestinal mucosa by inducing DCs to send cellular projections across the epithelial cell monolayer and sample luminal virions, we developed a dual-chamber Caco-2/DCs in vitro co-culture system
To determine the amount of DCs that migrated across the epithelium, we calculated the area occupied by DCs at the apical (Fig 1G) and medial (Fig 1H) level of the Caco-2 cells monolayer
Summary
The mucosal surface of the gastrointestinal tract is the main route of entry of human immunodeficiency virus type 1 (HIV-1) during mother-to-child transmission (MTCT) via ingestion of infected biological fluids as well as during anal sexual intercourses. Regardless of the route of transmission, the intestinal tissue, being a major site of viral replication, is rapidly affected by a conspicuous CD4þ T-cell depletion after primary infection (Mattapallil et al, 2005; Schneider et al, 1995; Wang et al, 2007). CD4þ T cells fail to fully repopulate the gastrointestinal tract despite an effective antiretroviral therapy (ART) (Chun et al, 2008), and the virus is detected in the small and large intestines absent from blood circulation (1) Unit of Viral Evolution and Transmission, DITID, San Raffaele Scientific Institute, Milan, Italy (2) Department of Experimental Oncology, European Institute of Oncology, Milan, Italy (Ling et al, 2010). Primary jejunal epithelial cells incubated with HIV-1 carry over only R5 viruses to receptive target cells (Meng et al, 2002), whereas M cells transport selectively X4 viral variants through a chemokine-receptor mediated mechanism (Fotopoulos et al, 2002).
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