title: HIV envelope gp120 activates LFA-1 on CD4 T-lymphocytes and increases cell susceptibility to LFA-1-targeting leukotoxin (LtxA).
abstract: The cellular adhesion molecule LFA-1 and its ICAM-1 ligand play an important role in promoting HIV-1 infectivity and transmission. These molecules are present on the envelope of HIV-1 virions and are integral components of the HIV virological synapse. However, cellular activation is required to convert LFA-1 to the active conformation that has high affinity binding for ICAM-1. This study evaluates whether such activation can be induced by HIV itself. The data show that HIV-1 gp120 was sufficient to trigger LFA-1 activation in fully quiescent naïve CD4 T cells in a CD4-dependent manner, and these CD4 T cells became more susceptible to killing by LtxA, a bacterial leukotoxin that preferentially targets leukocytes expressing high levels of the active LFA-1. Moreover, virus p24-expressing CD4 T cells in the peripheral blood of HIV-infected subjects were found to have higher levels of surface LFA-1, and LtxA treatment led to significant reduction of the viral DNA burden. These results demonstrate for the first time the ability of HIV to directly induce LFA-1 activation on CD4 T cells. Although LFA-1 activation may enhance HIV infectivity and transmission, it also renders the cells more susceptible to an LFA-1-targeting bacterial toxin, which may be harnessed as a novel therapeutic strategy to deplete virus reservoir in HIV-infected individuals.
authors.affiliation: Department of Pathology, New York University School of Medicine, and Veterans Affairs New York Harbor Healthcare System, Manhattan Campus, New York, New York, United States of America. catarina.hioe@nyumc.org
authors.forename: Catarina E
authors.initials: CE
authors.lastname: Hioe
authors.forename: Michael
authors.initials: M
authors.lastname: Tuen
authors.forename: Gaia
authors.initials: G
authors.lastname: Vasiliver-Shamis
authors.forename: Yelina
authors.initials: Y
authors.lastname: Alvarez
authors.forename: Kathleen C
authors.initials: KC
authors.lastname: Prins
authors.forename: Sagarika
authors.initials: S
authors.lastname: Banerjee
authors.forename: Arthur
authors.initials: A
authors.lastname: Nádas
authors.forename: Michael W
authors.initials: MW
authors.lastname: Cho
authors.forename: Michael L
authors.initials: ML
authors.lastname: Dustin
authors.forename: Scott C
authors.initials: SC
authors.lastname: Kachlany
mesh_terms: D000199:Actins / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005098:Exotoxins / Q000494:pharmacology*; D005434:Flow Cytometry; D015699:HIV Envelope Protein gp120 / Q000378:metabolism*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000235:genetics / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D000199:Actins; D005098:Exotoxins; D015699:HIV Envelope Protein gp120; D016169:Lymphocyte Function-Associated Antigen-1; C018579:leukotoxin; D018799:Intercellular Adhesion Molecule-1