Neutralizing antibodies evolve to exploit vulnerable sites in the HCV envelope glycoprotein E2 and mediate spontaneous clearance of infection

Frumento, Nicole; Sinnis-Bourozikas, Ariadne; Paul, Harry T.; Stavrakis, Georgia; Zahid, Muhammad N.; Wang, Shuyi; Ray, Stuart C.; Flyak, Andrew I.; Shaw, George M.; Cox, Andrea L.; Bailey, Justin R.

doi:10.1016/j.immuni.2023.12.004

Cited by 10 publications

(3 citation statements)

References 54 publications

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“…Plasma neutralization activity was also boosted in resolvers upon reinfection, as reported by previous studies ( 16 , 20 , 21 , 52 ), and is probably mediated by the higher titers of anti-E2. Indeed, our observations are in line with a recently reported mechanism in which early NAbs exert selection pressure that leads to E2 substitutions followed by loss of viral fitness contributing to clearance of HCV ( 15 , 53 ). Virus sequencing may resolve some of these questions; however, the low-level viremia and rapid clearance upon reinfection remain a major obstacle to this approach.…”

Section: Discussionsupporting

confidence: 91%

“…Early expansion of HCV-specific MBCs and the production of neutralizing antibodies (NAbs) are associated with clearance of acute primary HCV infection and reinfection ( 11 , 12 , 15 – 21 ). NAbs with exceptionally high neutralization breadth and potency were identified in HCV elite neutralizers and are associated with the use of the VH1–69 heavy-chain gene segment ( 22 , 23 ).…”

Section: Introductionmentioning

confidence: 99%

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Coordinated expansion of memory T follicular helper and B cells mediates spontaneous clearance of HCV reinfection

Eisa,

Gomez-Escobar,

Bédard

et al. 2024

Front. Immunol.

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IntroductionFollicular helper T cells are essential for helping in the maturation of B cells and the production of neutralizing antibodies (NAbs) during primary viral infections. However, their role during recall responses is unclear. Here, we used hepatitis C virus (HCV) reinfection in humans as a model to study the recall collaborative interaction between circulating CD4 T follicular helper cells (cTfh) and memory B cells (MBCs) leading to the generation of NAbs.MethodsWe evaluated this interaction longitudinally in subjects who have spontaneously resolved primary HCV infection during a subsequent reinfection episode that resulted in either another spontaneous resolution (SR/SR, n = 14) or chronic infection (SR/CI, n = 8).ResultsBoth groups exhibited virus-specific memory T cells that expanded upon reinfection. However, early expansion of activated cTfh (CD4+CXCR5+PD-1+ICOS+FoxP3−) occurred in SR/SR only. The frequency of activated cTfh negatively correlated with time post-infection. Concomitantly, NAbs and HCV-specific MBCs (CD19+CD27+IgM−E2-Tet+) peaked during the early acute phase in SR/SR but not in SR/CI. Finally, the frequency of the activated cTfh1 (CXCR3+CCR6−) subset correlated with the neutralization breadth and potency of NAbs.ConclusionThese results underscore a key role for early activation of cTfh1 cells in helping antigen-specific B cells to produce NAbs that mediate the clearance of HCV reinfection.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Coordinated expansion of memory T follicular helper and B cells mediates spontaneous clearance of HCV reinfection

Eisa,

Gomez-Escobar,

Bédard

et al. 2024

Front. Immunol.

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“…The relative importance and interdependence of antibody-producing B cells and CD8 T cells in the control of chronic viral infection remains a subject of active investigation and controversial debate 25,41,44,46,47,[49][50][51][79][80][81][82][83][84] . To address these questions, we treated mice with AAV-aCD20, AAV-aCD8 or AAV-ctrl or with a combination of the first two vectors (combo), followed by chronic LCMV infection one week later (Fig.…”

Section: Antiviral Antibodies Suppress Chronic Viremia To Enable Cd8 ...mentioning

confidence: 99%

Permanent lymphocyte subset elimination upon a single dose of AAV-delivered depletion antibody dissects immune control of chronic viral infection

Kastner,

Marx,

Dimitrova

et al. 2024

Preprint

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To interrogate the role of specific immune cells in infection, cancer and autoimmunity, immunologists commonly use monoclonal depletion antibodies (depletion-mAbs) or genetically engineered mouse models (GEMMs). To generate a tool that combines specific advantages and avoids select drawbacks of the two methods we engineer adeno-associated viral vectors expressing depletion-mAbs (depletion-AAVs). Single-dose depletion-AAV administration permanently eliminates lymphocyte subsets in mice while avoiding accessory deficiencies of GEMMs such as marginal zone defects in B cell-deficient animals. Depletion-AAVs can be used irrespective of the animals’ genetic background, and multiple depletion-AAVs can readily be combined. Exploiting depletion-AAV technology, we show that B cells are required for unimpaired CD4 and CD8 T cell responses to chronic viral infection. Importantly, CD8 T cells fail to suppress viremia when B cells are depleted, and they only help resolving chronic infection if antibodies suppress viral loads. Our study positions depletion-AAVs as a versatile tool for immunological research.

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Research progress in Fc‐effector functions against SARS‐CoV‐2

Gao,

Feng,

Sheng

et al. 2024

Journal of Medical Virology

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The severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) pandemic has caused more than 676 million cases in the global human population with approximately 7 million deaths and vaccination has been proved as the most effective countermeasure in reducing clinical complications and mortality rate of SARS‐CoV‐2 infection in people. However, the protective elements and correlation of protection induced by vaccination are still not completely understood. Various antibodies with multiple protective mechanisms can be induced simultaneously by vaccination in vivo, thereby complicating the identification and characterization of individual correlate of protection. Recently, an increasing body of observations suggests that antibody‐induced Fc‐effector functions play a crucial role in combating SARS‐CoV‐2 infections, including neutralizing antibodies‐escaping variants. Here, we review the recent progress in understanding the impact of Fc‐effector functions in broadly disarming SARS‐CoV‐2 infectivity and discuss various efforts in harnessing this conserved antibody function to develop an effective SARS‐CoV‐2 vaccine that can protect humans against infections by SARS‐CoV‐2 virus and its variants of concern.

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Neutralizing antibodies evolve to exploit vulnerable sites in the HCV envelope glycoprotein E2 and mediate spontaneous clearance of infection

Cited by 10 publications

References 54 publications

Coordinated expansion of memory T follicular helper and B cells mediates spontaneous clearance of HCV reinfection

Coordinated expansion of memory T follicular helper and B cells mediates spontaneous clearance of HCV reinfection

Permanent lymphocyte subset elimination upon a single dose of AAV-delivered depletion antibody dissects immune control of chronic viral infection

Research progress in Fc‐effector functions against SARS‐CoV‐2

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