Search anything and hit enter
  • Teams
  • Members
  • Projects
  • Events
  • Calls
  • Jobs
  • publications
  • Software
  • Tools
  • Network
  • Equipment

A little guide for advanced search:

  • Tip 1. You can use quotes "" to search for an exact expression.
    Example: "cell division"
  • Tip 2. You can use + symbol to restrict results containing all words.
    Example: +cell +stem
  • Tip 3. You can use + and - symbols to force inclusion or exclusion of specific words.
    Example: +cell -stem
e.g. searching for members in projects tagged cancer
Search for
Count
IN
OUT
Content 1
  • member
  • team
  • department
  • center
  • program_project
  • nrc
  • whocc
  • project
  • software
  • tool
  • patent
  • Administrative Staff
  • Assistant Professor
  • Associate Professor
  • Clinical Research Assistant
  • Full Professor
  • Graduate Student
  • Lab assistant
  • Non-permanent Researcher
  • Permanent Researcher
  • Pharmacist
  • PhD Student
  • Physician
  • Post-doc
  • Project Manager
  • Research Associate
  • Research Engineer
  • Retired scientist
  • Technician
  • Undergraduate Student
  • Veterinary
  • Visiting Scientist
  • Deputy Director of Center
  • Deputy Director of Department
  • Deputy Director of National Reference Center
  • Deputy Head of Facility
  • Director of Center
  • Director of Department
  • Director of Institute
  • Director of National Reference Center
  • Group Leader
  • Head of Facility
  • Head of Operations
  • Head of Structure
  • Honorary President of the Departement
  • Labex Coordinator
Content 2
  • member
  • team
  • department
  • center
  • program_project
  • nrc
  • whocc
  • project
  • software
  • tool
  • patent
  • Administrative Staff
  • Assistant Professor
  • Associate Professor
  • Clinical Research Assistant
  • Full Professor
  • Graduate Student
  • Lab assistant
  • Non-permanent Researcher
  • Permanent Researcher
  • Pharmacist
  • PhD Student
  • Physician
  • Post-doc
  • Project Manager
  • Research Associate
  • Research Engineer
  • Retired scientist
  • Technician
  • Undergraduate Student
  • Veterinary
  • Visiting Scientist
  • Deputy Director of Center
  • Deputy Director of Department
  • Deputy Director of National Reference Center
  • Deputy Head of Facility
  • Director of Center
  • Director of Department
  • Director of Institute
  • Director of National Reference Center
  • Group Leader
  • Head of Facility
  • Head of Operations
  • Head of Structure
  • Honorary President of the Departement
  • Labex Coordinator
Search
Go back
Scroll to top
Share
Scientific Fields
Diseases
Organisms
Applications
Technique
Starting Date
29
Jul 2015
Status
Ongoing
Members
6
Structures
1
Publications
1

About

Human Antibody Responses to Viruses

Adaptive immune responses naturally occurring upon infection or induced by vaccination generate high affinity antibodies, and memory B-cell subsets to respond to further antigenic challenges, providing protection against (re-)infections. Our research aimed at understanding the human memory B-cell responses triggered by viral infections participating to viral clearance and infection control.

These studies were supported by the European Research Council (Grant: ERC-2013-StG HumAntiViruses).

IgA antibodies play a key protective function as immune effectors against invading pathogens but also as immunosuppressors of pro-inflammatory responses, and immunomodulators of the gut microbiota. Conversely, IgA-antigen complexes can promote inflammatory processes, and therefore be pathogenic mediators in certain auto-inflammatory and autoimmune disorders. In humans, besides their paramount presence in mucosal tissues, IgA class-switched (IgA+) memory B cells and IgA antibodies are abundant in the blood. Although circulating IgA+ memory B cells and their corresponding secreted immunoglobulins likely possess major protective and/or regulatory immune roles, little is known about their specificity and function. Hence, we were interested in characterizing blood IgA memory B-cell antibodies in normal conditions in healthy humans as a first step, prior to their study in infectious diseases. To this end, we cloned, produced and characterized the gene repertoire and reactivity of more than 330 IgA and IgG memory B-cell antibodies from healthy donors (Lorin et al, 2015; Prigent et al, 2016). We found that although IgA+ and IgG+ memory antibodies shared common immunoglobulin gene features, IgA+ memory B cells contained fewer polyreactive clones and importantly, only rare self-reactive clones compared to IgG+ memory B cells. We further showed that IgA self-reactivity was acquired following B-cell affinity maturation and not antibody class switching. Together, our data show that although blood class-switched CD27+IgG+ and CD27+IgA+ B cells derive from the GC-dependent pathway, and are often considered as a relatively homogenous memory B-cell population as key components of the “reactive” humoral immunity, they differ considerably regarding their level of poly- and self-reactivity. This suggests the existence of different maturation pathways and/or different regulatory mechanisms for removing autoreactive clones from the IgG+ and IgA+ memory B-cell repertoires (Prigent et al, 2016). Strikingly, the later may provide an attractive explanation for the rarity of IgA-mediated autoimmune diseases (i.e., coeliac disease and IgA blistering dermatoses), whereas pathogenic and non-pathogenic IgG autoantibodies are a hallmark for most autoimmune disorders.

Mucosal transmission of HIV-1 can induce a local production of IgG and IgA antibodies predominantly targeting the gp41 subunit of the viral envelope glycoprotein gp160. However, whether they limit viral dissemination upon HIV-1 exposure is unclear. Moreover, polyreactive antibodies naturally produced by intestinal B cells and coating commensals in situ have been proposed to compromise optimal humoral responses to HIV-1 by immune diversion5,6 but overall, very little is known about the antibody response to HIV-1 at mucosal sites and the properties of gut-resident B cells recognizing the virus. To interrogate the intestinal B cells “sensing” HIV-1, we probed 76 recombinant monoclonal antibodies expressed from gp160-binding IgA+ and IgG+ B cells from rectosigmoid colon tissues of HIV-1-infected individuals. We found that a large fraction of mucosal mAbs were polyreactive, and showed only low-affinity to HIV-1 envelope glycoproteins particularly, the gp41 moiety. A few high-affinity gp160 mAbs were isolated but lacked neutralizing, potent ADCC and transcytosis-blocking capacities. Instead, they displayed cross-reactivity with defined self-antigens. Specifically, certain intestinal HIV-1 gp41 mAbs cross-reacted with the p38α mitogen-activated protein kinase 14 (MAPK14) (Planchais et al, 2019). Altogether, our data suggest that the physiologic polyreactivity of intestinal B cells and molecular mimicry-based self-reactivity of HIV-1 antibodies are two phenomena likely diverting and/or impairing mucosal humoral immunity to HIV-1. Our data suggests an inability of the gut immune system to locally generate functional high-affinity antibodies in response to HIV-1 infection.

Human high affinity antibodies to pathogens often recognize unrelated ligands. The molecular origin and the role of this polyreactivity are largely unknown. Several unusual but essential immunoglobulin features characterize HIV-1 bNAbs, some of which are associated with antibody polyreactivity. To better appreciate whether polyreactivity contributes to HIV-1 neutralization or simply be a bystander effect of affinity maturation, we aimed at elucidating the molecular mechanisms linking acquisition of bNAbs activity with poly- / auto-reactivity. We found that HIV-1 bNAbs were frequently polyreactive, cross-reacting with non-HIV-1 molecules including self-antigens. Mutating bNAb genes to increase HIV-1 binding and neutralization also created de novo polyreactivity. Using binding affinity, thermodynamic and molecular dynamics analyses, we showed that unliganded paratopes of polyreactive bNAbs with improved HIV-1 neutralization exhibited a conformational flexibility. Hence, promiscuous reactivity of HIV-1 bNAbs can be inputted to the binding sites’ flexibility, triggered by somatic hypermutations, which aid in accommodating not only divergent HIV-1 Env glycoproteins but also topologically distinct non-HIV-1 molecules via plastic hydrophobic structural interfaces (Prigent et al, 2018). This suggests that affinity maturation of HIV-1-reactive B cells towards neutralizing breadth may be tightly regulated between the selection of clones with “adaptable” antibody binding sites for an expanded HIV-1 recognition and the counterselection by immune tolerance of highly polyreactive clones reacting with self-antigens. We speculate that this phenomenon may occur with other pathogens with diversifying antigens, making antibodies’ natural development or elicitation by vaccines particularly difficult.

Apart from neutralization, the Fc region of HIV-1 bNAbs is required for suppressing viremia, through mechanisms that remained poorly understood. In a collaborative work with the team led by Olivier Schwartz (Institut Pasteur), we aimed at identifying HIV-1 bNAbs that exert ADCC in cell culture and kill HIV-1-infected lymphocytes through NK engagement. We found that: (i) most bNAbs were potent ADCC-mediators; (ii) the landscape of gp160 epitope exposure at the surface and the sensitivity of infected cells to ADCC varied considerably between viral strains; (iii) efficient ADCC required sustained cell surface binding of bNAbs to gp160; (iv) reactivated infected cells from HIV-positive individuals exposed heterogeneous envelope protein levels that are often sufficient to trigger killing by bNAbs or bNAb mixtures. Thus, this study allowed delineating the parameters controlling ADCC activity of bNAbs, and supports the use of the most potent bNAbs to clear the viral reservoir (Bruel et al, 2016). In a follow-up work, non-neutralizing antibodies (nnAbs) and bNAbs’ potencies to bind and eliminate HIV-1-infected cells in culture were compared. Overall, data revealed important qualitative and quantitative differences between nnAbs and bNAbs in their ADCC capacity and strongly suggest that the breadth of recognition of HIV-1 by nnAbs is narrow (Bruel et al, 2017).

Immunoprophylaxis with potent bNAbs efficiently protects non-human primates from mucosal transmission even after repeated challenges. However, the precise mechanisms of bNAbs-mediated viral inhibition in mucosal tissues were still unexplored. Our work showed that bNAbs, produced as recombinant IgG but also IgA mAbs (Lorin et al, 2015), did not interfere with the endocytic transport of HIV-1 across epithelial cells, a process referred to as transcytosis. Instead, both free and antibody-opsonized virions were translocated to the basal pole of epithelial cells. Importantly, as opposed to free viruses, viral particles bound by bNAbs were no longer infectious after transepithelial transit. Post-transcytosis neutralization activity of bNAbs displayed comparable inhibitory concentrations as those measured in classical neutralization assays. Overall, our results show that bNAbs do not block the transport of incoming HIV-1 viruses across the mucosal epithelium but rather neutralize the transcytosed virions, highlighting their efficient prophylactic and protective activity in vivo (Lorin et al, 2017).

Fundings