title: Lineage-Specific Differences between the gp120 Inner Domain Layer 3 of Human Immunodeficiency Virus and That of Simian Immunodeficiency Virus.
abstract: Binding of human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV) gp120 exterior envelope glycoprotein to CD4 triggers conformational changes in gp120 that promote its interaction with one of the chemokine receptors, usually CCR5, ultimately leading to gp41-mediated virus-cell membrane fusion and entry. We previously described that topological layers (layer 1, layer 2, and layer 3) in the gp120 inner domain contribute to gp120-trimer association in the unliganded state but also help secure CD4 binding. Relative to layer 1 of HIV-1 gp120, the SIVmac239 gp120 layer 1 plays a more prominent role in maintaining gp120-trimer association but is minimally involved in promoting CD4 binding, which could be explained by the existence of a well-conserved tryptophan at position 375 (Trp 375) in HIV-2/SIVsmm. In this study, we investigated the role of SIV layer 3 in viral entry, cell-to-cell fusion, and CD4 binding. We observed that a network of interactions involving some residues of the β8-α5 region in SIVmac239 layer 3 may contribute to CD4 binding by helping shape the nearby Phe 43 cavity, which directly contacts CD4. In summary, our results suggest that layer 3 in SIV has a greater impact on CD4 binding than in HIV-1. This work defines lineage-specific differences in layer 3 from HIV-1 and that from SIV.
  
  
  OBJECTIVE
  CD4-induced conformational changes in the gp120 inner domain involve rearrangements between three topological layers. While the role of layers 1 to 3 for HIV-1 and layers 1 and 2 for SIV on gp120 transition to the CD4-bound conformation has been reported, the role of SIV layer 3 remains unknown. Here we report that SIV layer 3 has a greater impact on CD4 binding than does layer 3 in HIV-1 gp120. This work defines lineage-specific differences in layer 3 from HIV-1 and SIV.
authors.affiliation: Centre de Recherche du CHUM, Montreal, QC, Canada.|Department of Microbiology, Infection and Immunology, Université de Montréal, Montreal, QC, Canada.
authors.forename: Shilei
authors.initials: S
authors.lastname: Ding
authors.affiliation: Centre de Recherche du CHUM, Montreal, QC, Canada.|Department of Microbiology, Infection and Immunology, Université de Montréal, Montreal, QC, Canada.
authors.forename: Halima
authors.initials: H
authors.lastname: Medjahed
authors.affiliation: Centre de Recherche du CHUM, Montreal, QC, Canada.|Department of Microbiology, Infection and Immunology, Université de Montréal, Montreal, QC, Canada.
authors.forename: Jérémie
authors.initials: J
authors.lastname: Prévost
authors.affiliation: Centre de Recherche du CHUM, Montreal, QC, Canada.|Department of Microbiology, Infection and Immunology, Université de Montréal, Montreal, QC, Canada.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Coutu
authors.affiliation: Nebraska Center for Virology, School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, Nebraska, USA.
authors.forename: Shi-Hua
authors.initials: SH
authors.lastname: Xiang
authors.affiliation: Centre de Recherche du CHUM, Montreal, QC, Canada andres.finzi@umontreal.ca.|Department of Microbiology, Infection and Immunology, Université de Montréal, Montreal, QC, Canada.|Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada.
authors.forename: Andrés
authors.initials: A
authors.lastname: Finzi
mesh_terms: D015704:CD4 Antigens / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D015700:HIV Envelope Protein gp41 / Q000378:metabolism; D015658:HIV Infections / Q000821:virology; D015497:HIV-1 / Q000378:metabolism*; D015498:HIV-2 / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D011487:Protein Conformation; D019713:Receptors, CCR5 / Q000378:metabolism; D015302:Simian Immunodeficiency Virus / Q000378:metabolism*; D014759:Viral Envelope Proteins / Q000378:metabolism*; D053586:Virus Internalization
chemical_list: D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; D008562:Membrane Glycoproteins; D019713:Receptors, CCR5; D014759:Viral Envelope Proteins; C069623:gp120 protein, Simian immunodeficiency virus