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High-multiplicity HIV-1 infection and neutralizing antibody evasion mediated by the macrophage-T cell virological synapse

Lookup NU author(s): Dr Christopher Duncan

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Abstract

Macrophage infection is considered to play an important role in HIV-1 pathogenesis and persistence. Using a primary cell-based coculture model, we show that monocyte-derived macrophages (MDM) efficiently transmit a high-multiplicity HIV-1 infection to autologous CD4+ T cells through a viral envelope glycoprotein (Env) receptor- and actin-dependent virological synapse (VS), facilitated by interactions between ICAM-1 and LFA-1. Virological synapse (VS)-mediated transmission by MDM results in high levels of T cell HIV-1 integration and is 1 to 2 orders of magnitude more efficient than cell-free infection. This mode of cell-to-cell transmission is broadly susceptible to the activity of CD4 binding site (CD4bs) and glycan or glycopeptide epitope-specific broadly neutralizing monoclonal antibodies (bNMAbs) but shows resistance to bNMAbs targeting the Env gp41 subunit membrane-proximal external region (MPER). These data define for the first time the structure and function of the macrophage-to-T cell VS and have important implications for bNMAb activity in HIV-1 prophylaxis and therapy.IMPORTANCE The ability of HIV-1 to move directly between contacting immune cells allows efficient viral dissemination with the potential to evade antibody attack. Here, we show that HIV-1 spreads from infected macrophages to T cells via a structure called a virological synapse that maintains extended contact between the two cell types, allowing transfer of multiple infectious events to the T cell. This process allows the virus to avoid neutralization by a class of antibody targeting the gp41 subunit of the envelope glycoproteins. These results have implications for viral spread in vivo and the specificities of neutralizing antibody elicited by antibody-based vaccines.


Publication metadata

Author(s): Duncan CJ, Williams JP, Schiffner T, Gartner K, Ochsenbauer C, Kappes J, Russell RA, Frater J, Sattentau QJ

Publication type: Article

Publication status: Published

Journal: Journal of Virology

Year: 2014

Volume: 88

Issue: 4

Pages: 2025-2034

Print publication date: 03/02/2014

Online publication date: 03/02/2014

Acceptance date: 26/11/2013

ISSN (print): 0022-538X

ISSN (electronic): 1098-5514

Publisher: American Society for Microbiology

URL: https://doi.org/10.1128/JVI.03245-13

DOI: 10.1128/JVI.03245-13

PubMed id: 24307588

Notes: epub:04/12/2013


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