HIV envelope gp120 activates LFA-1 on CD4 T-lymphocytes and increases cell susceptibility to LFA-1-targeting leukotoxin (LtxA)

• Published in: PloS one 2011-08, Vol.6 (8), p.e23202-e23202
• Main Authors: Hioe, Catarina E, Tuen, Michael, Vasiliver-Shamis, Gaia, Alvarez, Yelina, Prins, Kathleen C, Banerjee, Sagarika, Nádas, Arthur, Cho, Michael W, Dustin, Michael L, Kachlany, Scott C
• Format: Article
• Language: English
• Subjects: Acquired immune deficiency syndrome; Actins - genetics; AIDS; Antiretroviral drugs; Biology; CD4 antigen; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - metabolism; Cell activation; Cell adhesion molecules; Cell Survival - drug effects; Cells, Cultured; Conformation; Data processing; Deoxyribonucleic acid; Disease transmission; DNA; Envelopes; Exotoxins - pharmacology; Flow Cytometry; Glycoprotein gp120; Health aspects; HIV; HIV Envelope Protein gp120 - metabolism; Human immunodeficiency virus; Human immunodeficiency virus 1; Humans; Immunological synapses; Infectivity; Intercellular adhesion molecule 1; Intercellular Adhesion Molecule-1 - metabolism; Kinases; Leukocytes; LFA-1 antigen; Lymphocyte Function-Associated Antigen-1 - genetics; Lymphocyte Function-Associated Antigen-1 - metabolism; Lymphocytes; Lymphocytes T; Medicine; Microscopy, Fluorescence; Peripheral blood; Real-Time Polymerase Chain Reaction; Risk factors; Synapses; T cells; Toxins; Virions; Viruses
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0023202

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.