Infection of Dendritic Cells (DCs), Not DC-SIGN-Mediated Internalization of Human Immunodeficiency Virus, Is Required for Long-Term Transfer of Virus to T Cells

Abstract

The C-type lectin DC-SIGN expressed on immature dendritic cells (DCs) captures human immunodeficiency virus (HIV) particles and enhances the infection of CD4؉ T cells. This process, known as trans-enhancement of T-cell infection, has been related to HIV endocytosis. It has been proposed that DC-SIGN targets HIV to a nondegradative compartment within DCs and DC-SIGN-expressing cells, allowing incoming virus to persist for several days before infecting target cells. In this study, we provide several lines of evidence suggesting that intracellular storage of intact virions does not contribute to HIV transmission. We show that endocytosis-defective DC-SIGN molecules enhance T-cell infection as efficiently as their wild-type counterparts, indicating that DC-SIGN-mediated HIV internalization is dispensable for trans-enhancement. Furthermore, using immature DCs that are genetically resistant to infection, we demonstrate that several days after viral uptake, HIV transfer from DCs to T cells requires viral fusion and occurs exclusively through DC infection and transmission of newly synthesized viral particles. Importantly, our results suggest that DC-SIGN participates in this process by cooperating with the HIV entry receptors to facilitate cis-infection of immature DCs and subsequent viral transfer to T cells. We suggest that such a mechanism, rather than intracellular storage of incoming virus, accounts for the long-term transfer of HIV to CD4 ؉ T cells and may contribute to the spread of infection by DCs.

Gap Junctions Mediate Human Immunodeficiency Virus-Bystander Killing in Astrocytes

“…Despite low infection and viral replication, cytokines described in NeuroAIDS that are released by inflammatory cells, such as TNF-␣, IL-1␤, and/or IFN-␥, can induce reactivation of viral replication and transfer the virus to cells that support high viral replication (Brack-Werner, 1999;Schweighardt and Atwood, 2001). This mechanism of crossinfection is termed dissemination in trans (Geijtenbeek et al, 2000;Burleigh et al, 2006). We propose that HIV-infected astrocytes may participate in this trans process.…”

The C-type lectin surface receptor DCIR acts as a new attachment factor for HIV-1 in dendritic cells and contributes to trans- and cis-infection pathways

“…45 Assuming that DCIR allows HIV-1 to gain access to nondegradative endosomal organelles, this might allow the virus to persist for a sufficiently long time to be transported from mucosal surfaces to the T-cell compartment in lymphoid tissues, as it has been proposed for DC-SIGN. 46,47 Moreover, storage in endosomes could lead to fusion between viral and endosomal membranes and productive infection, as reported in macrophages. 48 Finally, it can be proposed that the interaction between HIV-1 and DCIR will initiate intracellular biochemical events that can reverse to some extent the various blocks responsible for the limited virus infection seen in DCs compared with CD4 ϩ T cells (reviewed in Piguet and Steinman 49 ).…”

Syndecan-3 is a dendritic cell-specific attachment receptor for HIV-1

“…Syndecans and C-type lectin receptors do not mediate entry of HIV-1 (11,21). However, these receptors enhance infection in cis by serving as attachment receptors (22,29,30). To investigate the role of syndecan-3 in DC infection, cells were pretreated with heparinase III before HIV-1 exposure.…”