title: Rab5 and Rab7, but not ARF6, govern the early events of HIV-1 infection in polarized human placental cells.
abstract: Trophoblasts, the structural cells of the placenta, are thought to play a determinant role in in utero HIV type 1 (HIV-1) transmission. We have accumulated evidence suggesting that HIV-1 infection of these cells is associated with uptake by an unusual clathrin/caveolae-independent endocytic pathway and that endocytosis is followed by trafficking through multiple organelles. Furthermore, part of this trafficking involves the transit of HIV-1 from transferrin-negative to EEA1 and transferrin-positive endosomes, suggesting a merger from nonclassical to classical endocytic pathways in these cells. In the present article, the relationship between the presence of HIV-1 within specific endosomes and infection was studied. We demonstrate that viral infection is virtually lost when endosome inhibitors are added shortly after exposure to HIV-1. Thus, contrary to what is seen in CD4+ T lymphocytes, the initial presence of HIV-1 within the endosomes is mandatory for infection to take place. Importantly, this process is independent of the viral envelope proteins gp120 and gp41. The Rab family of small GTPases coordinates the vesicular transport between the different endocytic organelles. Experiments performed with various expression vectors indicated that HIV-1 infection in polarized trophoblasts relies on Rab5 and Rab7 without the contribution of Arf6 or Rab11. Furthermore, we conclude that Rab5 drives movements from raft-rich region to early endosomes, and this transit is required for subsequently reaching late endosomes via Rab7. This complex trafficking is mandatory for HIV-1 infection to proceed in human polarized trophoblasts.
authors.affiliation: Research Center in Infectious Diseases, Centre Hospitalier de l'Université Laval Research Center, and Faculty of Medicine, Laval University, Quebec City, Quebec, Canada.
authors.forename: Gaël
authors.initials: G
authors.lastname: Vidricaire
authors.forename: Michel J
authors.initials: MJ
authors.lastname: Tremblay
mesh_terms: D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000378:metabolism*; D000730:Androstadienes / Q000494:pharmacology; D001483:Base Sequence; D002460:Cell Line; D016764:Cell Polarity; D004279:DNA, Viral / Q000235:genetics; D004705:Endocytosis; D011992:Endosomes / Q000187:drug effects / Q000821:virology; D005260:Female; D016655:HIV Core Protein p24 / Q000096:biosynthesis; D015658:HIV Infections / Q000209:etiology* / Q000276:immunology / Q000635:transmission / Q000821:virology; D015497:HIV-1 / Q000235:genetics; D006801:Humans; D010920:Placenta / Q000276:immunology / Q000821:virology*; D011247:Pregnancy; D013601:T-Lymphocytes / Q000821:virology; D014327:Trophoblasts / Q000821:virology; D000077191:Wortmannin; D020691:rab GTP-Binding Proteins / Q000378:metabolism*; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism*; D000090802:rab7 GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins
chemical_list: D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors; D000730:Androstadienes; D004279:DNA, Viral; D016655:HIV Core Protein p24; D000077191:Wortmannin; D020691:rab GTP-Binding Proteins; D020696:rab5 GTP-Binding Proteins; D000090802:rab7 GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; C000715348:ARF6 protein, human