Abstract
Incorporation of intercellular adhesion molecule 1 (ICAM-1) into HIV-1 particles is known to markedly enhance the virus binding and infection of cells expressing lymphocyte function-associated antigen-1 (LFA-1). At the same time, ICAM-1 has been reported to exert a less pronounced effect on HIV-1 fusion with lymphoid cells. Here we examined the role of ICAM-1/LFA-1 interactions in productive HIV-1 entry into lymphoid cells using a direct virus-cell fusion assay. ICAM-1 promoted HIV-1 attachment to cells in a temperature-dependent manner. It exerted a marginal effect on virus binding in the cold, but enhanced binding up to 4-fold at physiological temperature. ICAM-1-independent attachment in the cold was readily reversible upon subsequent incubation at elevated temperature, whereas ICAM-1-bearing particles were largely retained by cells. The better virus retention resulted in a proportional increase in HIV-1 internalization and fusion, suggesting that ICAM-1 did not specifically accelerate endocytosis or fusion steps. We also measured the rates of CD4 engagement, productive endocytosis and HIV-endosome fusion using specific fusion inhibitors. These rates were virtually independent of the presence of ICAM-1 in viral particles. Importantly, irrespective of the presence of ICAM-1, HIV-1 escaped from the low temperature block, which stopped virus endocytosis and fusion, much later than from a membrane-impermeant fusion inhibitor targeting surface-accessible particles. This result, along with the complete inhibition of HIV-1 fusion by a small molecule dynamin inhibitor, implies this virus enters lymphoid cells used in this study via endocytosis and that this pathway is not altered by the viral ICAM-1. Our data highlight the role of ICAM-1 in stabilizing the HIV-1 attachment to LFA-1 expressing cells, which leads to a proportional enhancement of the receptor-mediated uptake and fusion with endosomes.
Highlights
HIV-1 Env glycoprotein initiates infection by fusing the viral envelope membrane with a target cell membrane
We found that intercellular adhesion molecule 1 (ICAM-1)-independent binding was reversible, as the majority of virions were lost from cells, whereas ICAM-1/lymphocyte function-associated antigen-1 (LFA-1) interactions prevented virus dissociation from cells without significantly altering the probability of virus internalization or fusion
ICAM-1/LFA-1 interactions play an essential role in immune activation through stabilization of immunological synapse [63], as well as in cell-cell transmission of HIV-1 through their involvement in the formation of virological synapses [64]
Summary
HIV-1 Env glycoprotein initiates infection by fusing the viral envelope membrane with a target cell membrane. Sequential binding of Env to CD4 and coreceptors (CXCR4 or CCR5) [1,2,3,4] induces conformational changes in its transmembrane subunit, gp, which promotes membrane fusion upon refolding into the six-helix bundle structure [5,6]. Entry and fusion of cell-free HIV1 is inefficient, whereas cell-to-cell transmission provides a much more effective platform for virus dissemination [7,8,9]. Accumulating evidence suggests that the apparent low efficiency of HIV-1 infection is primarily due to poor binding to target cells and not to an inherently low specific infectivity [16,17,18]. Stable adhesion to cells is emerging as an essential factor in HIV-1 entry
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