title: Productive entry of HIV-1 during cell-to-cell transmission via dynamin-dependent endocytosis.
abstract: HIV-1 can be transmitted as cell-free virus or via cell-to-cell contacts. Cell-to-cell transmission between CD4(+) T cells is the more efficient mode of transmission and is predominant in lymphoid tissue, where the majority of virus resides. Yet the cellular mechanisms underlying productive cell-to-cell transmission in uninfected target cells are unclear. Although it has been demonstrated that target cells can take up virus via endocytosis, definitive links between this process and productive infection remain undefined, and this route of transmission has been proposed to be nonproductive. Here, we report that productive cell-to-cell transmission can occur via endocytosis in a dynamin-dependent manner and is sensitive to clathrin-associated antagonists. These data were obtained in a number of CD4(+) T-cell lines and in primary CD4(+) T cells, using both CXCR4- and CCR5-tropic virus. However, we also found that HIV-1 demonstrated flexibility in its use of such endocytic pathways as certain allogeneic transmissions were seen to occur in a dynamin-dependent manner but were insensitive to clathrin-associated antagonists. Also, depleting cells of the clathrin accessory protein AP180 led to a viral uptake defect associated with enhanced infection. Collectively, these data demonstrate that endosomal uptake of HIV-1 during cell-to-cell transmission leads to productive infection, but they are also indicative of a flexible model of viral entry during cell-to-cell transmission, in which the virus can alter its entry route according to the pressures that it encounters.
authors.affiliation: McGill University AIDS Centre, Lady Davis Institute-Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Sloan
authors.forename: Björn D
authors.initials: BD
authors.lastname: Kuhl
authors.forename: Thibault
authors.initials: T
authors.lastname: Mesplède
authors.forename: Jan
authors.initials: J
authors.lastname: Münch
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Donahue
authors.forename: Mark A
authors.initials: MA
authors.lastname: Wainberg
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D034281:Dynamins / Q000378:metabolism*; D004705:Endocytosis / Q000502:physiology*; D057809:HEK293 Cells; D015658:HIV Infections / Q000635:transmission*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D007963:Leukocytes, Mononuclear; D008954:Models, Biological; D034041:Monomeric Clathrin Assembly Proteins / Q000172:deficiency; D034622:RNA Interference; D053586:Virus Internalization
chemical_list: D034041:Monomeric Clathrin Assembly Proteins; C439023:clathrin assembly protein AP180; D034281:Dynamins