Abstract
Virus transmission can occur either by a cell-free mode through the extracellular space or by cell-to-cell transmission involving direct cell-to-cell contact. The factors that determine whether a virus spreads by either pathway are poorly understood. Here, we assessed the relative contribution of cell-free and cell-to-cell transmission to the spreading of the human immunodeficiency virus (HIV). We demonstrate that HIV can spread by a cell-free pathway if all the steps of the viral replication cycle are efficiently supported in highly permissive cells. However, when the cell-free path was systematically hindered at various steps, HIV transmission became contact-dependent. Cell-to-cell transmission overcame barriers introduced in the donor cell at the level of gene expression and surface retention by the restriction factor tetherin. Moreover, neutralizing antibodies that efficiently inhibit cell-free HIV were less effective against cell-to-cell transmitted virus. HIV cell-to-cell transmission also efficiently infected target T cells that were relatively poorly susceptible to cell-free HIV. Importantly, we demonstrate that the donor and target cell types influence critically the extent by which cell-to-cell transmission can overcome each barrier. Mechanistically, cell-to-cell transmission promoted HIV spread to more cells and infected target cells with a higher proviral content than observed for cell-free virus. Our data demonstrate that the frequently observed contact-dependent spread of HIV is the result of specific features in donor and target cell types, thus offering an explanation for conflicting reports on the extent of cell-to-cell transmission of HIV.
Highlights
Viruses can spread either by a cell-free mode through the extracellular space or by cell-to-cell transmission through direct cell-cell contact [1,2,3,4]
We choose HEK293 cells as donor cells because they support high viral gene expression and fulfilled the donor cell criteria required for efficient transmission by a cell-free mode
Our results do not exclude the contribution of cell-cell contact for the infection of these target cells because the co-culture is a mix of cell-free as well as cell-to-cell transmission, our results demonstrate that human immunodeficiency virus (HIV) can spread relatively efficiently by a cellfree mode under the combination of highly permissive donor and target cells
Summary
Viruses can spread either by a cell-free mode through the extracellular space or by cell-to-cell transmission through direct cell-cell contact [1,2,3,4]. Many bacteriophages and some Alphaviruses are highly infectious in their cell-free form and a single viral particle can enter a cell and cause an infection [5,6] If these viruses use cell-cell contact to spread is unknown. The infectivity to particle ratio of other viruses can be very poor despite the observation of efficient spreading in tissue cultures [7,8,9]. This observation prompted the study of cell-to-cell transmission. The ability of neurotropic viruses to spread along neurons or the ability of Vaccinia virus to induce actin tails that could propel viral particles to neighboring cells supported viral spread by cell-cell contact [15,16,17,18,19]
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