Neutralization resistance of virological synapse-mediated HIV-1 Infection is regulated by the gp41 cytoplasmic tail.

Abstract

Human immunodeficiency virus type 1 (HIV-1) infection can spread efficiently from infected to uninfected T cells through adhesive contacts called virological synapses (VSs). In this process, cell-surface envelope glycoprotein (Env) initiates adhesion and viral transfer into an uninfected recipient cell. Previous studies have found some HIV-1-neutralizing patient sera to be less effective at blocking VS-mediated infection than infection with cell-free virus. Here we employ sensitive flow cytometry-based infection assays to measure the inhibitory potency of HIV-1-neutralizing monoclonal antibodies (MAb) and HIV-1-neutralizing patient sera against cell-free and VS-mediated infection. To various degrees, anti-Env MAbs exhibited significantly higher 50% inhibitory concentration (IC(50)s) against VS-mediated infection than cell-free infection. Notably, the MAb 17b, which binds a CD4-induced (CD4i) epitope on gp120, displayed a 72-fold reduced efficacy against VS-mediated inocula compared to cell-free inocula. A mutant with truncation mutation in the gp41 cytoplasmic tail (CT) which is unable to modulate Env fusogenicity in response to virus particle maturation but which can still engage in cell-to-cell infection was tested for the ability to resist neutralizing antibodies. The ΔCT mutation increased cell surface staining by neutralizing antibodies, significantly enhanced neutralization of VS-mediated infection, and had reduced or no effect on cell-free infection, depending upon the antibody. Our results suggest that the gp41 CT regulates the exposure of key neutralizing epitopes during cell-to-cell infection and plays an important role in immune evasion. Vaccine strategies should consider immunogens that reflect Env conformations exposed on the infected cell surface to enhance protection against VS-mediated HIV-1 spread.

• Authors: Natasha D Durham, Alice W Yewdall, Ping Chen, Rebecca Lee, Chati Zony, James E Robinson, Benjamin K Chen
• Journal: Journal of virology (J Virol) Vol. 86 Issue 14 Pg. 7484-95 (Jul 2012) ISSN: 1098-5514 [Electronic] United States
• PMID: 22553332 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Neutralizing
• CD4 Antigens
• Epitopes
• HIV Antibodies
• HIV Envelope Protein gp120
• HIV Envelope Protein gp41
• gp41 protein, Human immunodeficiency virus 1

Topics

• Antibodies, Monoclonal (immunology)
• Antibodies, Neutralizing (immunology)
• CD4 Antigens (immunology)
• Cell Line
• Epitopes (immunology)
• HIV Antibodies (immunology)
• HIV Envelope Protein gp120 (chemistry, immunology)
• HIV Envelope Protein gp41 (chemistry, genetics, immunology)
• HIV-1 (immunology)
• Humans
• Immune Evasion
• Mutation
• Virus Attachment