Inhibitory Effect of Individual or Combinations of Broadly Neutralizing Antibodies and Antiviral Reagents against Cell-Free and Cell-to-Cell HIV-1 Transmission

Gombos, Randi; Kolodkin-Gal, Dror; Eslamizar, Leila; Owuor, Joshua; Mazzola, Emanuele; González, Ana María; Korioth-Schmitz, Birgit; Gelman, Rebecca; Montefiori, David C.; Haynes, Barton F.; Schmitz, Joern E.

doi:10.1128/jvi.00783-15

Cited by 37 publications

(46 citation statements)

References 82 publications

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“…bNAbs directed to the MPER have low efficacy against VSmediated viral transmission, even though they potently neutralize cell-free virus (19,(33)(34)(35)(36). To examine the role of the MPER in cell-free infection and cell-cell viral spread, an assay was developed to compare the spread of two well-characterized HIV-1 AD8 MPER mutants, W666A and I675A (Fig.…”

Section: Cell-associated Mper Mutant Viruses Retain the Ability To Inmentioning

confidence: 99%

“…For example, VS-mediated viral transmission is less sensitive to commonly used nucleoside reverse transcription inhibitors such as nevirapine, zidovudine, and tenofovir (29 -32). Importantly, VS-mediated HIV-1 transmission between CD4 ϩ T cells and between HIV-1-infected MDMs and uninfected CD4 ϩ T cells is less sensitive to neutralization by bNAbs, when compared with cell-free virus infections, indicating that this mode of spread may represent an obstacle to successful vaccine development and neutralizing antibody therapy (19,(33)(34)(35)(36). Although these differences between cell-to-cell and cell-free virus transmission can be explained in part by a higher local multiplicity of infection at the VS, it is also plausible that cell-free and cell-associated viruses possess structural differences that confer distinct functional advantages to the two viral forms.…”

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confidence: 99%

“…Z13 binds to and immobilizes the MPER hinge with little change in membrane orientation or conformation (37,51). bNAbs directed to the MPER have low efficacy against VS-mediated viral transmission, even though they potently neutralize cell-free virus (19,(33)(34)(35)(36). An understanding of the basis of the differential efficacy of MPER bNAbs in neutralizing cell-free versus cell-tocell viral transmission is needed to inform approaches for developing vaccines that target this highly conserved epitope.…”

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confidence: 99%

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Distinct functions for the membrane-proximal ectodomain region (MPER) of HIV-1 gp41 in cell-free and cell–cell viral transmission and cell–cell fusion

Narasimhulu

Bellamy-McIntyre

Laumaea

et al. 2018

Journal of Biological Chemistry

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HIV-1 is spread by cell-free virions and by cell-cell viral transfer. We asked whether the structure and function of a broad neutralizing antibody (bNAb) epitope, the membrane-proximal ectodomain region (MPER) of the viral gp41 transmembrane glycoprotein, differ in cell-free and cell-cell-transmitted viruses and whether this difference could be related to Ab neutralization sensitivity. Whereas cell-free viruses bearing W666A and I675A substitutions in the MPER lacked infectivity, cell-associated mutant viruses were able to initiate robust spreading infection. Infectivity was restored to cell-free viruses by additional substitutions in the cytoplasmic tail (CT) of gp41 known to disrupt interactions with the viral matrix protein. We observed contrasting effects on cell-free virus infectivity when W666A was introduced to two transmitted/founder isolates, but both mutants could still mediate cell-cell spread. Domain swapping indicated that the disparate W666A phenotypes of the cell-free transmitted/founder viruses are controlled by sequences in variable regions 1, 2, and 4 of gp120. The sequential passaging of an MPER mutant (W672A) in peripheral blood mononuclear cells enabled selection of viral revertants with loss-of-glycan suppressor mutations in variable region 1, suggesting a functional interaction between variable region 1 and the MPER. An MPER-directed bNAb neutralized cell-free virus but not cell-cell viral spread. Our results suggest that the MPER of cell-cell-transmitted virions has a malleable structure that tolerates mutagenic disruption but is not accessible to bNAbs. In cell-free virions, interactions mediated by the CT impose an alternative MPER structure that is less tolerant of mutagenic alteration and is efficiently targeted by bNAbs.

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Section: Cell-associated Mper Mutant Viruses Retain the Ability To Inmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Distinct functions for the membrane-proximal ectodomain region (MPER) of HIV-1 gp41 in cell-free and cell–cell viral transmission and cell–cell fusion

Narasimhulu

Bellamy-McIntyre

Laumaea

et al. 2018

Journal of Biological Chemistry

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“…Cell-to-cell infection is mediated by adhesive cell-cell contacts that form between infected and uninfected CD4 ϩ T cells (called "virological synapses" [VS]). Cell-to-cell infection through VS is more efficient than cell-free infection in vitro (1,2) and has been found to resist neutralizing antibodies (NAbs) to a greater extent than infection by the same viral clone when it is presented as cell-free virus (1,(3)(4)(5)(6)(7)(8)(9)(10)(11).…”

Section: Importancementioning

confidence: 99%

Reduced Potency and Incomplete Neutralization of Broadly Neutralizing Antibodies against Cell-to-Cell Transmission of HIV-1 with Transmitted Founder Envs

Zony

Chen

et al. 2017

J Virol

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Broadly neutralizing antibodies (bNAbs) have been isolated from HIV-1 patients and can potently block infection of a wide spectrum of HIV-1 subtypes. These antibodies define common epitopes shared by many viral isolates. While bNAbs potently antagonize infection with cell-free virus, inhibition of HIV-1 transmission from infected to uninfected CD4 ϩ T cells through virological synapses (VS) has been found to require greater amounts of antibody. In this study, we examined two well-studied molecular clones and two transmitted/founder (T/F) clones for their sensitivities to a panel of bNAbs in cell-free and cell-to-cell infection assays. We observed resistance of cell-to-cell transmission to antibody neutralization that was reflected not only by reductions of antibody potency but also by decreases in maximum neutralization capacity relative to the levels seen with cell-free infections. BNAbs targeting different epitopes exhibited incomplete neutralization against cellassociated virus with T/F Envs, which was not observed with the cell-free form of the same virus. We further identified the membrane-proximal internal tyrosine-based sorting motif as a determinant that can affect the incomplete neutralization of these T/F clones in cell-to-cell infection. These findings indicate that the signal that affects surface expression and/or internalization of Env from the plasma membrane can modulate the presentation of neutralizing epitopes on infected cells. These results highlight that a fraction of virus can escape from high concentrations of antibody through cell-to-cell infection while remaining sensitive to neutralization in cell-free infection. The ability to fully inhibit cell-to-cell transmission may represent an important consideration in the development of antibodies for treatment or prophylaxis.

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“…Even a slight decrease in susceptibility in vivo could result in a substantial effect on virus production in amplification over multiple rounds of replication. Studies have consistently shown that HIV-1 broadly neutralizing antibodies can block cell-to-cell infection but that much higher concentrations or bnAb combinations are frequently required (33)(34)(35)(36)(37). All of those studies reported that differences between cell-free neutralization and cell-associated neutralization were seen across virus strains and antibody epitopes.…”

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confidence: 99%

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

Smith

Derdeyn

2017

J Virol

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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.

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Inhibitory Effect of Individual or Combinations of Broadly Neutralizing Antibodies and Antiviral Reagents against Cell-Free and Cell-to-Cell HIV-1 Transmission

Cited by 37 publications

References 82 publications

Distinct functions for the membrane-proximal ectodomain region (MPER) of HIV-1 gp41 in cell-free and cell–cell viral transmission and cell–cell fusion

Distinct functions for the membrane-proximal ectodomain region (MPER) of HIV-1 gp41 in cell-free and cell–cell viral transmission and cell–cell fusion

Reduced Potency and Incomplete Neutralization of Broadly Neutralizing Antibodies against Cell-to-Cell Transmission of HIV-1 with Transmitted Founder Envs

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

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