Differential HIV-1 endocytosis and susceptibility to virus infection in human macrophages correlate with cell activation status.
HIV-1 is an enveloped virus that enters target cells by fusion either directly at the plasma membrane or at the endosomal membrane. The latter mechanism follows a rapid engulfment of HIV-1 after its receptor engagement at the cell surface, and its scale depends on cellular endocytosis/degradation rates and virus fusion kinetics. HIV-1 has recently been shown to exploit a novel Pak1-dependent macropinocytosis mechanism as a way to productively infect macrophages. However, macrophages are highly heterogeneous cells that can adapt functionally to their changing environment, and their endosomal/lysosomal pathway is highly regulated upon cell activation. These changes might impact the ability of HIV-1 to exploit endocytosis as a way to productively infect macrophages. In this study, we compared HIV-1 endocytosis/degradation rates in nonactivated, M1-activated, and M2a-activated monocyte-derived macrophages (MDMs). We found that the rate of HIV-1 endocytosis was increased in M1-activated but decreased in M2a-activated MDMs. However, both M1 and M2a activations of MDMs led specifically to a greater clathrin-mediated endocytosis of HIV-1, which was independent of CD4 and CCR5 binding. Furthermore, clathrin-mediated endocytosis is unlikely to result in productive HIV-1 infection, given that it leads to increased viral degradation. Therefore, we suggest that viral fusion following endocytosis is restricted in activated macrophages.
Centre de Recherche en Infectiologie, Centre Hospitalier Universitaire de Québec-CHUL, Canada.
Lise-Andrée
LA
Gobeil
Robert
R
Lodge
Michel J
MJ
Tremblay
D015704:CD4 Antigens / Q000096:biosynthesis; D002462:Cell Membrane / Q000821:virology; D002470:Cell Survival; D002966:Clathrin / Q000378:metabolism; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D015658:HIV Infections / Q000097:blood* / Q000821:virology; D015497:HIV-1 / Q000201:enzymology*; D006367:HeLa Cells; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000378:metabolism / Q000821:virology*; D008957:Models, Genetic; D019713:Receptors, CCR5 / Q000378:metabolism
D015704:CD4 Antigens; D002966:Clathrin; D019713:Receptors, CCR5