A Single Amino-Acid Change in a Highly Conserved Motif of gp41 Elicits HIV-1 Neutralization and Protects Against CD4 Depletion

Petitdemange, Caroline; Achour, Abla; Dispinseri, Stefania; Malet, Isabelle; Sennepin, Alexis; Fang, Raphaël Ho Tsong; Crouzet, J; Marcelin, Anne–Geneviève; Cálvez, Vincent; Scarlatti, Gabriella; Debré, Patrice; Vieillard, Vincent

doi:10.1093/cid/cit335

Cited by 15 publications

(37 citation statements)

References 36 publications

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“…This region has also been identified to be the target of various other antibody-mediated activities (42)(43)(44)(45)(46)(47)(48)(49)(50). Recent three-dimensional studies of gp140 trimers by crystallography and high-resolution cryo-electron microscopy show that this region lies in close proximity to the plasma membrane (28,29).…”

Section: Resultsmentioning

confidence: 99%

Identification of Human Anti-HIV gp160 Monoclonal Antibodies That Make Effective Immunotoxins

Pincus

Song

Maresh

et al. 2017

J Virol

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The envelope (Env) glycoprotein of HIV is the only intact viral protein expressed on the surface of both virions and infected cells. Env is the target of neutralizing antibodies (Abs) and has been the subject of intense study in efforts to produce HIV vaccines. Therapeutic anti-Env Abs can also exert antiviral effects via Fcmediated effector mechanisms or as cytotoxic immunoconjugates, such as immunotoxins (ITs). In the course of screening monoclonal antibodies (MAbs) for their ability to deliver cytotoxic agents to infected or Env-transfected cells, we noted disparities in their functional activities. Different MAbs showed diverse functions that did not correlate with each other. For example, MAbs against the external loop region of gp41 made the most effective ITs against infected cells but did not neutralize virus and bound only moderately to the same cells that they killed so effectively when they were used in ITs. There were also differences in IT-mediated killing among transfected and infected cell lines that were unrelated to the binding of the MAb to the target cells. Our studies of a well-characterized antigen demonstrate that MAbs against different epitopes have different functional activities and that the binding of one MAb can influence the interaction of other MAbs that bind elsewhere on the antigen. These results have implications for the use of MAbs and ITs to kill HIVinfected cells and eradicate persistent reservoirs of HIV infection.IMPORTANCE There is increased interest in using antibodies to treat and cure HIV infection. Antibodies can neutralize free virus and kill cells already carrying the virus. The virus envelope (Env) is the only HIV protein expressed on the surfaces of virions and infected cells. In this study, we examined a panel of human anti-Env antibodies for their ability to deliver cell-killing toxins to HIV-infected cells and to perform other antiviral functions. The ability of an antibody to make an effective immunotoxin could not be predicted from its other functional characteristics, such as its neutralizing activity. Anti-HIV immunotoxins could be used to eliminate virus reservoirs that persist despite effective antiretroviral therapy.

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Section: Resultsmentioning

confidence: 99%

Identification of Human Anti-HIV gp160 Monoclonal Antibodies That Make Effective Immunotoxins

Pincus

Song

Maresh

et al. 2017

J Virol

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“…An alanine-scanning assay within the 3S motif of the viral gp41 protein showed that a tryptophan residue at position 614 (W614) is crucial for the virus entry ( Petitdemange et al, 2013 ). The main reason could be that this region plays a key role in the formation of the six-helix bundled gp41 ectodomain core structure that imposes several kinetic and steric constraints responsible for the high degree of motif preservation, as previously reported ( Gallo et al, 2003 ).…”

Section: Introductionmentioning

confidence: 99%

“…Altogether, these data could explain the absence of detectable “3S” escape variants, and the remarkable conservation of the 3S motif within the gp41 ( Vieillard et al, 2005 , Potard et al, 2013 ). Next, we generated in mice a class of Abs against the 3S motif, called W614A-3S Ab that elicits neutralizing activity, against a panel of tier 1 and tier 2 viruses from clades A, B, C and E ( Petitdemange et al, 2013 ). More recently, these data were confirmed in rabbit and macaque models (unpublished data are from Vieillard et al).…”

Section: Introductionmentioning

confidence: 99%

Neutralizing Antibodies Against a Specific Human Immunodeficiency Virus gp41 Epitope are Associated With Long-term Non-progressor Status

Lucar

Potard

et al. 2017

EBioMedicine

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Antibodies (Abs) play a central role in human immunodeficiency virus (HIV) protection due to their multiple functional inhibitory activities. W614A-3S Abs recognize a specific form of a highly conserved motif of the gp41 envelope protein and can elicit viral neutralization to protect CD4+ T cells. Here, we describe in detail the neutralizing profile of W614A-3S Abs in untreated long-term non-progressor (LTNP) HIV-infected patients. W614A-3S Abs were detected in 23.5% (16/68) of untreated LTNP patients compared with < 5% (5/104) of HIV-1 progressor patients. The W614A-3S Abs had efficient neutralizing activity that inhibited transmitted founder primary viruses and exhibited Fc-mediated inhibitory functions at low concentrations in primary monocyte-derived macrophages. The neutralizing capacity of W614A-3S Abs was inversely correlated with viral load (r = − 0.9013; p < 0.0001), viral DNA (r = − 0.7696; p = 0.0005) and was associated the preservation of high CD4+ T-cell counts and T-cell responses. This study demonstrates that W614A-3S neutralizing Abs may confer a crucial advantage to LTNP patients. These results provide insights for both pathophysiological research and the development of vaccine strategies.

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“…At this time, it is not clear how much divergence in antibody epitopes is needed to escape from herd immunity. Studies with GII.4 human NoV, mouse NoV, and other RNA viruses have demonstrated significant changes in blockade or neutralization potential with only a single amino acid change (34,(49)(50)(51). It is possible that with an expanded panel of GII.2 blockade MAbs, we may have been able to more clearly antigenically differentiate the GII.2 VLPs.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Blockade Antibody Responses in GII.2.1976 Snow Mountain Virus-Infected Subjects

Swanstrom

Lindesmith

Donaldson

et al. 2014

J Virol

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A Single Amino-Acid Change in a Highly Conserved Motif of gp41 Elicits HIV-1 Neutralization and Protects Against CD4 Depletion

Abstract: These findings suggest that a specific substitution in a 3S-based immunogen might allow the generation of specific antibodies, providing a foundation for a rational vaccine that combine a capacity to neutralize HIV-1 and to protect CD4(+) T cells.

Cited by 15 publications

References 36 publications

Identification of Human Anti-HIV gp160 Monoclonal Antibodies That Make Effective Immunotoxins

Identification of Human Anti-HIV gp160 Monoclonal Antibodies That Make Effective Immunotoxins

Neutralizing Antibodies Against a Specific Human Immunodeficiency Virus gp41 Epitope are Associated With Long-term Non-progressor Status

Characterization of Blockade Antibody Responses in GII.2.1976 Snow Mountain Virus-Infected Subjects

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