Viral Source-Independent High Susceptibility of Dendritic Cells to Human T-Cell Leukemia Virus Type 1 Infection Compared to That of T Lymphocytes

Abstract

Human T-cell leukemia virus type 1 (HTLV-1)-infected CD4؉ T cells and dendritic cells (DCs) are present in peripheral blood from HTLV-1 carriers. While T-cell infection requires cell-cell contact, DCs might be infected with cell-free virus, at least in vitro. However, a thorough comparison of the susceptibilities of the two cell types to HTLV-1 infection using cell-associated and cell-free viral sources has not been performed. We first determined that human primary monocyte-derived dendritic cells (MDDCs) were more susceptible to HTLV-1 infection than their autologous lymphocyte counterparts after contact with chronically infected cells. Next, a comparison of infection efficiency using nonconcentrated or concentrated supernatants from infected cells as well as purified viral biofilm was performed. Integrated provirus was found after exposure of MDDCs or primary lymphocytes to viral biofilm but not to a viral supernatant. Using a large series of primary cell samples (n ‫؍‬ 21), we demonstrated a higher proviral load in MDDCs exposed to viral biofilm than in lymphocytes. This higher susceptibility is correlated to a higher expression of neuropilin-1 on MDDCs than on autologous activated T lymphocytes. Moreover, we show that MDDCs infected with viral biofilm can transmit the virus to lymphocytes. In conclusion, MDDCs are more susceptible to HTLV-1 infection than autologous lymphocytes in vitro, supporting a model in which DC infection might represent an important step during primoinfection in vivo. IMPORTANCEHTLV-1 is able to infect several cell types, but viral DNA is mainly found in T lymphocytes in vivo. This supports a model in which T lymphocytes are the main target of infection. However, during the primo-infection of new individuals, incoming viruses might first encounter dendritic cells (DCs), the specialized immune cells responsible for the antiviral response of the host. HTLV-1 cell-free purified viruses can infect dendritic cells in vitro, while T-cell infection is restricted to cell-to-cell transmission. In order to understand the sequence of HTLV-1 dissemination, we undertook a direct comparison of the susceptibilities of the two cell types using cell-associated and cell-free viral sources. We report here that MDDCs are more susceptible to HTLV-1 infection than autologous lymphocytes in vitro and are able to efficiently transmit the virus to lymphocytes. Our results suggest that DCs may represent a true viral reservoir, as the first cell type to be infected in vivo.H uman T-cell leukemia virus type 1 (HTLV-1) infects 5 to 20 million people worldwide (1) and is the etiological agent of both an aggressive CD4 ϩ T-cell leukemia named adult T-cell leukemia (ATL) (2) and a neurological disease named tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM) (3, 4). HTLV-1 is transmitted through contact with infected cells present in maternal milk, semen, or blood and is mainly found in CD4 ϩ T cells, but other cell types might also be infected or functionally altered in vivo and thus involv...

How Does Susceptibility to HTLV-1 Infection Varies With the Maturation State of Dendritic Cells?

“…These cell types include DCs, which are specialized antigen-presenting cells and essential mediators in shaping innate and adaptive immunity [8]. In vitro studies conducted by our lab and others confirmed that HTLV-1 productively infects myeloid blood DCs [7] and monocyte-derived DCs (MDDCs) [9][10][11]. Of note, exposure of target cells to cell-free viruses only leads to very low levels of productive infection [9], consistent with the observation that efficient infection of target cells requires close cell-to-cell contacts with infected donor cells [12].…”

“…Importantly, we demonstrated that primary MDDCs are more susceptible to productive HTLV-1 infection than their autologous T cells [9]. Given that productively infected MDDCs are able to transfer HTLV-1 to T cells [7,9,11], it is thus proposed that DCs might be important intermediaries for HTLV-1 spread to T cells in newly infected individuals.…”

“…In vitro studies conducted by our lab and others confirmed that HTLV-1 productively infects myeloid blood DCs [7] and monocyte-derived DCs (MDDCs) [9][10][11]. Of note, exposure of target cells to cell-free viruses only leads to very low levels of productive infection [9], consistent with the observation that efficient infection of target cells requires close cell-to-cell contacts with infected donor cells [12]. Viral entry in T cells requires expression of the HTLV-1 receptor complex, in other words, neuropilin-1 and heparan sulfate proteoglycans, used for binding [13], and the glucose transporter Glut-1, required for fusion [14], while viral binding to DCs was also shown to require DC-SIGN [11].…”

“…Given that productively infected MDDCs are able to transfer HTLV-1 to T cells [7,9,11], it is thus proposed that DCs might be important intermediaries for HTLV-1 spread to T cells in newly infected individuals.…”

“…Of note, exposure of target cells to cell-free viruses only leads to very low levels of productive infection [9], consistent with the observation that efficient infection of target cells requires close cell-to-cell contacts with infected donor cells [12]. Viral entry in T cells requires expression of the HTLV-1 receptor complex, in other words, neuropilin-1 and heparan sulfate proteoglycans, used for binding [13], and the glucose transporter Glut-1, required for fusion [14], while viral binding to DCs was also shown to require DC-SIGN [11].Importantly, we demonstrated that primary MDDCs are more susceptible to productive HTLV-1 infection than their autologous T cells [9]. Given that productively infected MDDCs are able to transfer HTLV-1 to T cells [7,9,11], it is thus proposed that DCs might be important intermediaries for HTLV-1 spread to T cells in newly infected individuals.…”