The CH1α domain of mucosal gp41 IgA contributes to antibody specificity and antiviral functions in HIV-1 highly exposed Sero-Negative individuals

Khamassi, Marwa; Lin, Xu; Rey, Julien; Duchemin, Maxence; Bouceba, Tahar; Tufféry, Pierre; Tudor, Daniela; Bomsel, Morgane

doi:10.1371/journal.ppat.1009103

Cited by 13 publications

(10 citation statements)

References 63 publications

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“…Such high-risk subjects are referred to as HIV-exposed seronegative (HESN) individuals and include sex workers, HIV-status discordant couples, intravenous drug users, and children born to untreated HIV-infected mothers. Relative resistance to HIV infection is likely multi-factorial and several studies have identified innate immune and anti-inflammatory factors, HIV-specific T-and B-cell responses, increased regulatory T-and B-cell activity as well as genetic and epigenetic correlates to this phenotype [2][3][4][5][6][7][8][9][10][11][12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

HIV-Exposed Seronegative Sex Workers Express Low T-Cell Activation and an Intact Ectocervical Tissue Microenvironment

et al. 2021

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Immunological correlates of natural resistance to HIV have been identified in HIV-exposed seronegative (HESN) individuals and include a low-inflammatory genital mucosal status. The cervicovaginal epithelium has not been studied for such correlates despite constituting an important barrier against sexual HIV transmission. To fill this gap in knowledge, we collected samples of blood, cervical mononuclear cells, cervicovaginal lavage, and ectocervical tissue from Kenyan HESN sex workers (n = 29) and controls (n = 33). The samples were analyzed by flow cytometry, protein profiling, 16S rRNA gene sequencing, in situ image analysis, and tissue-based RNA sequencing. A significantly higher relative proportion of regulatory T cells in blood (B7+CD25hiFoxP3+CD127loCD4+ and B7+Helios+FoxP3+CD4+), and a significantly lower proportion of activated cervical T cells (CCR5+CD69+CD4+ and CCR5+CD69+CD8+), were found in the HESN group compared with the controls. In contrast, there were no statistically significant differences between the study groups in cervicovaginal protein and microbiome compositions, ectocervical epithelial thickness, E-cadherin expression, HIV receptor expression, and tissue RNA transcriptional profiles. The identification of an intact ectocervical microenvironment in HESN individuals add new data to current knowledge about natural resistance to sexual transmission of HIV.

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Section: Introductionmentioning

confidence: 99%

HIV-Exposed Seronegative Sex Workers Express Low T-Cell Activation and an Intact Ectocervical Tissue Microenvironment

et al. 2021

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“…The mucosal humoral responses in BAL contain secretory IgA and IgG, produced locally in the mucosa prior to secretion in the alveolar space, and have an antigenic repertoire distinct from the serum humoral response ( 14 , 26 , 60 ). We found that both SARS-CoV-2-specific IgA and IgG responses developed simultaneously after a week of infection when the virus replicates in BAL.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, nasal vaccination could not only be used for initial vaccination but also as a boost ( 85 , 86 ). Hence, anti-spike/N IgA could also eliminate virally infected cells by ADCC ( 87 ) or ADCP ( 77 ) as shown in other mucosal viral diseases ( 14 , 26 , 60 ) using innate immune cells expressing Fcα-receptor and acting as second-chance protection.…”

Section: Discussionmentioning

confidence: 99%

Persistent but dysfunctional mucosal SARS-CoV-2-specific IgA and low lung IL-1β associate with COVID-19 fatal outcome: A cross-sectional analysis

Ruiz

Siracusano²,

Cottignies-Calamarte

et al. 2022

Front. Immunol.

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The role of the mucosal pulmonary antibody response in coronavirus disease 2019 (COVID-19) outcome remains unclear. Here, we found that in bronchoalveolar lavage (BAL) samples from 48 patients with severe COVID-19-infected with the ancestral Wuhan virus, mucosal IgG and IgA specific for S1, receptor-binding domain (RBD), S2, and nucleocapsid protein (NP) emerged in BAL containing viruses early in infection and persist after virus elimination, with more IgA than IgG for all antigens tested. Furthermore, spike-IgA and spike-IgG immune complexes were detected in BAL, especially when the lung virus has been cleared. BAL IgG and IgA recognized the four main RBD variants. BAL neutralizing titers were higher early in COVID-19 when virus replicates in the lung than later in infection after viral clearance. Patients with fatal COVID-19, in contrast to survivors, developed higher levels of mucosal spike-specific IgA than IgG but lost neutralizing activities over time and had reduced IL-1β in the lung. Altogether, mucosal spike and NP-specific IgG and S1-specific IgA persisting after lung severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) clearance and low pulmonary IL-1β correlate with COVID-19 fatal outcome. Thus, mucosal SARS-CoV-2-specific antibodies may have adverse functions in addition to protective neutralization.HighlightsMucosal pulmonary antibody response in COVID-19 outcome remains unclear. We show that in severe COVID-19 patients, mucosal pulmonary non-neutralizing SARS-CoV-2 IgA persit after viral clearance in the lung. Furthermore, low lung IL-1β correlate with fatal COVID-19. Altogether, mucosal IgA may exert harmful functions beside protective neutralization.

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“…Furthermore, the role of the Fab isotype, including that of the CH1 domain, also remains a parameter to be studied. In this respect, we revealed that the CH1 domain plays a crucial role in Fab antigen recognition (both in affinity and specificity) with a superiority of CH1α over CH1γ ( 127 ). Surprisingly, the higher molecular weight of Fcα-Fcγ or Fcγ-Fcγ tandem chimeras compared to parental Abs was not taken into account in these studies, probably introducing a bias.…”

Section: Chimeric Antibodies Containing Fcγ-fcα Enhance Fc-mediated F...mentioning

confidence: 97%

Antibody Fc-chimerism and effector functions: When IgG takes advantage of IgA

Cottignies-Calamarte

Tudor²,

Bomsel³

2023

Front. Immunol.

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Recent advances in the development of therapeutic antibodies (Abs) have greatly improved the treatment of otherwise drug-resistant cancers and autoimmune diseases. Antibody activities are mediated by both their Fab and the Fc. However, therapeutic Abs base their protective mechanisms on Fc-mediated effector functions resulting in the activation of innate immune cells by FcRs. Therefore, Fc-bioengineering has been widely used to maximise the efficacy and convenience of therapeutic antibodies. Today, IgG remains the only commercially available therapeutic Abs, at the expense of other isotypes. Indeed, production, sampling, analysis and related in vivo studies are easier to perform with IgG than with IgA due to well-developed tools. However, interest in IgA is growing, despite a shorter serum half-life and a more difficult sampling and purification methods than IgG. Indeed, the paradigm that the effector functions of IgG surpass those of IgA has been experimentally challenged. Firstly, IgA has been shown to bind to its Fc receptor (FcR) on effector cells of innate immunity with greater efficiency than IgG, resulting in more robust IgA-mediated effector functions in vitro and better survival of treated animals. In addition, the two isotypes have been shown to act synergistically. From these results, new therapeutic formats of Abs are currently emerging, in particular chimeric Abs containing two tandemly expressed Fc, one from IgG (Fcγ) and one from IgA (Fcα). By binding both FcγR and FcαR on effector cells, these new chimeras showed improved effector functions in vitro that were translated in vivo. Furthermore, these chimeras retain an IgG-like half-life in the blood, which could improve Ab-based therapies, including in AIDS. This review provides the rationale, based on the biology of IgA and IgG, for the development of Fcγ and Fcα chimeras as therapeutic Abs, offering promising opportunities for HIV-1 infected patients. We will first describe the main features of the IgA- and IgG-specific Fc-mediated signalling pathways and their respective functional differences. We will then summarise the very promising results on Fcγ and Fcα containing chimeras in cancer treatment. Finally, we will discuss the impact of Fcα-Fcγ chimerism in prevention/treatment strategies against infectious diseases such as HIV-1.

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The CH1α domain of mucosal gp41 IgA contributes to antibody specificity and antiviral functions in HIV-1 highly exposed Sero-Negative individuals

Cited by 13 publications

References 63 publications

HIV-Exposed Seronegative Sex Workers Express Low T-Cell Activation and an Intact Ectocervical Tissue Microenvironment

HIV-Exposed Seronegative Sex Workers Express Low T-Cell Activation and an Intact Ectocervical Tissue Microenvironment

Persistent but dysfunctional mucosal SARS-CoV-2-specific IgA and low lung IL-1β associate with COVID-19 fatal outcome: A cross-sectional analysis

Antibody Fc-chimerism and effector functions: When IgG takes advantage of IgA

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