Cell-Free versus Cell-to-Cell Infection by Human Immunodeficiency Virus Type 1 and Human T-Lymphotropic Virus Type 1: Exploring the Link among Viral Source, Viral Trafficking, and Viral Replication

Abstract

Human immunodeficiency virus type 1 (HIV-1) and human T-lymphotropic virus type 1 (HTLV-1) are complex retroviruses mainly infecting CD4(+) T lymphocytes. In addition, antigen-presenting cells such as dendritic cells (DCs) are targeted in vivo by both viruses, although to a lesser extent. Interaction of HIV-1 with DCs plays a key role in viral dissemination from the mucosa to CD4(+) T lymphocytes present in lymphoid organs. While similar mechanisms may occur for HTLV-1 as well, most HTLV-1 data were obtained from T-cell studies, and little is known regarding the trafficking of this virus in DCs. We first compared the efficiency of cell-free versus cell-associated viral sources of both retroviruses at infecting DCs. We showed that both HIV-1 and HTLV-1 cell-free particles are poorly efficient at productively infecting DCs, except when DC-SIGN has been engaged. Furthermore, while SAMHD-1 accounts for restriction of cell-free HIV-1 infection, it is not involved in HTLV-1 restriction. In addition, cell-free viruses lead mainly to a nonproductive DC infection, leading to trans-infection of T-cells, a process important for HIV-1 spread but not for that of HTLV-1. Finally, we show that T-DC cell-to-cell transfer implies viral trafficking in vesicles that may both increase productive infection of DCs ("cis-infection") and allow viral escape from immune surveillance. Altogether, these observations allowed us to draw a model of HTLV-1 and HIV-1 trafficking in DCs.

FIG 1

Cell-free virus entry determines the fate of infection in DCs. Cell-free viruses can use at least 3 nonexclusive pathways to enter DCs. (A) In the absence of DC-SIGN, viral binding in enriched lipid raft areas could lead to viral membrane fusion at the plasma membrane. Restriction factors in the cytoplasm will prevent viral replication. (B) In the presence of DC-SIGN in lipid rafts, its interaction with viral glycoproteins leads to signaling (shown as a dashed arrow) favoring the productive infection. DC-SIGN triggering leads to viral internalization in ill-identified vesicles (VCCs) (see the text for details), in which viral fusion could occur. (C) If viral capture occurs in the absence of a coreceptor and DC-SIGN, virions are internalized in clathrin-rich endosomes and directed toward degradation.

FIG 2

Infection after cell-cell contact: the viral synapse. The viral synapse is characterized by an intimate contact between the infected donor cell (left) and the target cell (right). The formation of the VS can be arbitrarily divided into 6 steps: 1, cell-cell contact is established through interactions between fusion-incompetent viral Env proteins (represented in yellow) and ICAM-1 on the donor cell side and viral receptor (represented in blue) and LFA-1 on the target cell; 2, adhesion leads to MTOC polarization and virion assembly at the cell-cell contact in the donor cell; 3, newly synthesized virions are released in the synaptic cleft; 4, polarized capture of virions by the target cell is driven by Env-receptor interaction; 5, captured virions are internalized through endocytosis in the target cell; and 6, Gag maturation in endosomes leads to Env-mediated viral fusion and release of viral capsids in the cytosol, allowing productive infection.

FIG 3

The infectious synapse between either cis-infected DCs or mature DCs that have captured virions and T cells. In contrast to the VS, the infectious synapse depends first on the formation of an immune synapse (1). This initial contact, which is independent of viral protein engagement, induces protrusions of T-cell membrane filopodia inside VCCs where viruses are stored, allowing virus capture at the tips of the protrusions (2), and/or VCC collapse (3) and release of viruses at the synapse, leading to T-cell infection (4).