New Connections: Cell-to-Cell HIV-1 Transmission, Resistance to Broadly Neutralizing Antibodies, and an Envelope Sorting Motif

Abstract

HIV-1 infection from cell-to-cell may provide an efficient mode of viral spread in vivo and could therefore present a significant challenge for preventative or therapeutic strategies based on broadly neutralizing antibodies. Indeed, Li et al. (H. Li, C. Zony, P. Chen, and B. K. Chen, J. Virol. 91:e02425-16, 2017, https://doi.org/ 10.1128/JVI.02425-16) showed that the potency and magnitude of multiple HIV-1 broadly neutralizing antibody classes are decreased during cell-to-cell infection in a context-dependent manner. A functional motif in gp41 appears to contribute to this differential susceptibility by modulating exposure of neutralization epitopes.KEYWORDS broadly neutralizing antibody, human immunodeficiency virus, viral envelope, virological synapse T he best-understood process by which HIV-1 mediates infection of susceptible CD4 ϩ target cells is via cell-free virions. Independent virions attach to the target cell membrane, bind CD4 and the coreceptor, mediate membrane fusion at neutral pH, and deposit the nucleocapsid into the new host cell to initiate de novo replication. However, HIV-1 can also mediate infection via virological synapses, where direct cell-to-cell contact between the envelope (Env) glycoprotein gp120 subunit expressed on the infected CD4 ϩ T cell surface interacts with the CD4 receptor on nearby uninfected T cells (reviewed in reference 1). This mode of virus transfer is known as a virological synapse, whereas an immunological synapse mediates transfer from a virus-harboring antigen-presenting cell to an uninfected CD4 ϩ T cell. Cell-to-cell HIV-1 infection was described as early as 1989, including one study that also established the relative levels of resistance of this transmission mode to neutralizing antibody (nAb) and the nucleoside reverse transcriptase inhibitor AZT (2, 3). Cell-to-cell HIV-1 infection has also been estimated to be several orders of magnitude more efficient than cell-free infection (3-6). Although it could represent a predominant mode of viral spread in vivo, cell-tocell transmission has not been studied to the same depth as cell-free infection, as almost all in vitro neutralization assays and in vivo broadly neutralizing antibody (bnAb) protection experiments have been performed using cell-free virus.

Viral cell-to-cell spread: Conventional and non-conventional ways

“…Moreover, cell-to-cell transmission of retroviruses through the VS has been shown to play a critical role in viral dissemination in vivo ( Murooka et al, 2012 ; Sewald et al, 2015 ). In this context, studies that examined the accessibility of the VS to entry inhibitors have concluded that synapse-mediated spread is less sensitive than cell-free particle spread to neutralizing antibodies in vitro and vivo ( Abela et al, 2012 ; Gombos et al, 2015 ; Smith and Derdeyn, 2017 ; Zhong et al, 2013 ). Cell-to-cell contact sites have additionally been described as the main route of viral dissemination for the murine leukemia virus (MLV) by using live-cell imaging ( Jin et al, 2009 ).…”

Synergistic inhibition of cell-to-cell HIV-1 infection by combinations of single chain variable fragments and fusion inhibitors

“…It is possible that conformational changes of envelope trimers [39] induced by binding to scFvs may allow fusion inhibitors to interact with gp41 [30]. Moreover, mutations within the cytoplasmic tail of gp41 may play a crucial role in exposure of key neutralizing epitopes during cell-to-cell infection [40,41].…”

HIV-1 virological synapse formation enhances infection spread by dysregulating Aurora Kinase B

“…To differentiate the two cell lines in mass spectrometry, SupT1 target cells were labeled for eight doublings with "heavy" amino acids, with ~100% incorporation of 13 C arginine and C 15 N lysine confirmed by mass spectroscopy, while the Jurkat producer cells were grown in normal "light" media (Fig 1A). To further focus analysis on cell contact-induced changes in producer cells and minimize downstream effects on signaling pathways [34] from cell-free infection, we transfected Jurkat producer cells with a plasmid carrying an HIV-1 provirus [38,72] expressing a GFP-NanoLuc luciferase fusion gene (Promega), and an HIV-1 Env and Nef expression plasmid [40].…”

“…In cultured cells, spread by cell-cell transfer between T cells is 100-1,000-fold more efficient than cell-free infection through the extracellular space [5][6][7][8][9]. Increasing evidence shows that direct cell-cell spread confers multiple replicative advantages to HIV-1 and may allow HIV-1 to evade aspects of the humoral immune response, innate antiviral restriction factors such as tetherin, and antiretroviral drugs [8,[10][11][12][13]. VS formation promotes infection of the target cell by focusing virion assembly and release at sites of cell-cell contact, leading to efficient HIV-1 integration and high viral gene expression in the target cell [14][15][16][17][18].…”