Abstract
Dendritic cells (DCs) are one of the earliest targets of HIV-1 infection acting as a "Trojan horse," concealing the virus from the innate immune system and delivering it to T cells via virological synapses (VS). To explicate how the virus is trafficked through the cell to the VS and evades degradation, a high-throughput small interfering RNA screen targeting membrane trafficking proteins was performed in monocyte-derived DCs. We identified several proteins including BIN-1 and RAB7L1 that share common roles in transport from endosomal compartments. Depletion of target proteins resulted in an accumulation of virus in intracellular compartments and significantly reduced viral trans-infection via the VS. By targeting endocytic trafficking and retromer recycling to the plasma membrane, we were able to reduce the virus's ability to accumulate at budding microdomains and the VS. Thus, we identify key genes involved in a pathway within DCs that is exploited by HIV-1 to traffic to the VS.IMPORTANCE The lentivirus human immunodeficiency virus (HIV) targets and destroys CD4+ T cells, leaving the host vulnerable to life-threatening opportunistic infections associated with AIDS. Dendritic cells (DCs) form a virological synapse (VS) with CD4+ T cells, enabling the efficient transfer of virus between the two cells. We have identified cellular factors that are critical in the induction of the VS. We show that ADP-ribosylation factor 1 (ARF1), bridging integrator 1 (BIN1), and Rab GTPases RAB7L1 and RAB8A are important regulators of HIV-1 trafficking to the VS and therefore the infection of CD4+ T cells. We found these cellular factors were essential for endosomal protein trafficking and formation of the VS and that depletion of target proteins prevented virus trafficking to the plasma membrane by retaining virus in intracellular vesicles. Identification of key regulators in HIV-1 trans-infection between DC and CD4+ T cells has the potential for the development of targeted therapy to reduce trans-infection of HIV-1 in vivo.
Highlights
Dendritic cells (DC) are key antigen-presenting cells that provide an important link between innate and adaptive immune systems, activating T-cells
In this study we identified a number of host factors involved in transinfection of Human Immunodeficiency Virus (HIV)-1 from DC to T-cells
By conducting a siRNA screen targeting membrane trafficking proteins we identified four genes involved in efficient transinfection from DC to T-cells
Summary
Dendritic cells (DC) are key antigen-presenting cells that provide an important link between innate and adaptive immune systems, activating T-cells (reviewed in [1, 2]). HIV-1 trans-infection has been shown to depend on the ability of the virus to ‘surf’ along the surface of the DC via actin rich dendrites, to promote trans-infection [12,13,14]. Several studies conducted in macrophages and DC located virus sequestered into plasma membrane invaginated compartments from which viral particles are released at the VS [15,16,17,18]. These compartments are thought to be surface accessible [15], there is evidence of a population becoming isolated from the cell surface [16]. It is established in macrophages and DC that these surface accessible compartments may have complex morphologies that require membrane trafficking regulation, such as the virus containing compartments found in macrophages [17]
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