Abstract
BackgroundDendritic cells (DCs) are considered as key mediators of the early events in human immunodeficiency virus type 1 (HIV-1) infection at mucosal sites. Previous studies have shown that surface-bound virions and/or internalized viruses found in endocytic vacuoles of DCs are efficiently transferred to CD4+ T cells. Extracellular adenosine triphosphate (ATP) either secreted or released from necrotic cells induces a distorted maturation of DCs, transiently increases their endocytic capacity and affects their migratory capacity. Knowing that high extracellular ATP concentrations are present in situations of tissue injury and inflammation, we investigated the effect of ATP on HIV-1 transmission from DCs to CD4+ T lymphocytes.ResultsIn this study, we show that extracellular ATP reduces HIV-1 transfer from immature monocyte-derived DCs (iDCs) to autologous CD4+ T cells. This observed decrease in viral replication was related to a lower proportion of infected CD4+ T cells following transfer, and was seen with both X4- and R5-tropic isolates of HIV-1. Extracellular ATP had no effect on direct CD4+ T cell infection as well as on productive HIV-1 infection of iDCs. These observations indicate that extracellular ATP affects HIV-1 infection of CD4+ T cells in trans with no effect on de novo virus production by iDCs. Additional experiments suggest that extracellular ATP might modulate the trafficking pathway of internalized virions within iDCs leading to an increased lysosomal degradation, which could be partly responsible for the decreased HIV-1 transmission.ConclusionThese results suggest that extracellular ATP can act as a factor controlling HIV-1 propagation.
Highlights
Dendritic cells (DCs) are considered as key mediators of the early events in human immunodeficiency virus type 1 (HIV-1) infection at mucosal sites
These results suggest that extracellular adenosine triphosphate (ATP) can act as a factor controlling HIV-1 propagation
Extracellular ATP diminishes HIV-1 transfer from DCs to CD4+ T cells To study the possible consequences of ATP on HIV-1 capture by DCs and subsequent virus transfer to CD4+ T cells, immature DCs (iDCs) were first pulsed with R5-tropic NL4-3Balenv pro
Summary
Dendritic cells (DCs) are considered as key mediators of the early events in human immunodeficiency virus type 1 (HIV-1) infection at mucosal sites. The reported low levels of CD4 and chemokine co-receptors CXCR4 and CCR5 on DCs are probably responsible for their weaker susceptibility to productive HIV-1 infection in vitro as compared to CD4+ T cells [1,2] It has been demonstrated (page number not for citation purposes). A small fraction of such endocytosed virions will escape processing and retain their infectivity These viruses may be released to the cytoplasm, leading to DC infection [16], or remain protected from degradation in a low pH compartment lacking early or late endosomal markers and are later relocated to the virological synapse [9,13,17]. Little is known about the contribution of intracellular signal transducers in virus capture and transfer, it has been recently demonstrated that Src and Syk tyrosine kinases play a functional role in productive HIV-1 infection of iDCs [18]
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