Antibody-dependent Enhancement Of Infection Research Articles

Mechanisms and results of the antibody-dependent enhancement of viral infections and role in the pathogenesis of coxsackievirus B-induced diseases

The mechanisms of the antibody-dependent enhancement (ADE) of viral infection are presented, particularly within the Picornaviridae family. The ADE of infection has been described in both human and animal models, worsens viral infections and compromises vaccine safety. The ADE of coxsackievirus B infection can also be implied in the pathogenesis of diseases like chronic dilated cardiomyopathy or insulin-dependent type 1 diabetes.

Dramatic caspase-dependent apoptosis in antibody-enhanced dengue virus infection of human mast cells

Severe forms of dengue virus disease, known as dengue hemorrhagic fever and dengue shock syndrome, result from an aberrant immune response involving antibody-dependent enhancement of infection, thrombocytopenia, and a loss of vascular integrity, culminating in hemorrhage, shock, and in some cases, death. Several studies have indicated that dengue virus infection results in the induction of apoptosis of certain cells believed to be contributory players in dengue pathogenesis. However, none have specifically examined the role of antibody enhancement in the context of induction of apoptosis. Here, we show that antibody-enhanced dengue virus infection of the FcR-bearing mast cell/basophil KU812 cell line results in a massive induction of apoptosis. Confocal microscopy and flow cytometry indicate two distinct subpopulations consisting of productively infected cells and apoptotic-uninfected bystanders. Apoptosis was found to be caspase-dependent, involving global caspase activation and cleavage of poly-ADP-ribose polymerase (PARP) and D4-guanosine diphosphate dissociation inhibitor (D4-GDI). Additional FcR-bearing cells, including K562, U937, and human mast cell 1 (HMC-1), were analyzed for apoptosis induction following infection. Although all cells displayed high susceptibility to antibody-enhanced dengue virus infection, only cells of a mast cell phenotype (KU812 and HMC-1) were found to undergo apoptosis. Dengue-induced apoptosis of KU812 cells was shown to require antibody-enhanced dengue virus infection by blockade of FcgammaRII. Transfection of KU812 cells with L-SIGN/DC-SIGNR was able to overcome the requirement for antibody enhancement with regard to dengue virus infection and apoptosis.

Dengue in Vietnamese Infants—Results of Infection‐Enhancement Assays Correlate with Age‐Related Disease Epidemiology, and Cellular Immune Responses Correlate with Disease Severity

The pathogenesis of severe dengue is not well understood. Maternally derived subneutralizing levels of dengue virus-reactive IgG are postulated to be a critical risk factor for severe dengue during infancy. In this study, we found that, in healthy Vietnamese infants, there was a strong temporal association between the Fc-dependent, dengue virus infection-enhancing activity of neat plasma and the age-related epidemiology of severe dengue. We then postulated that disease severity in infants with primary infections would be associated with a robust immune response, possibly as a consequence of higher viral burdens in vivo. Accordingly, in infants hospitalized with acute dengue, the activation phenotype of peripheral-blood NK cells and CD8+ and CD4+ T cells correlated with overall disease severity, but HLA-A*1101-restricted NS3(133-142)-specific CD8+ T cells were not measurable until early convalescence. Plasma levels of cytokines/chemokines were generally higher in infants with dengue shock syndrome. Collectively, these data support a model of dengue pathogenesis in infants whereby antibody-dependent enhancement of infection explains the age-related case epidemiology and could account for antigen-driven immune activation and its association with disease severity. These results also highlight potential risks in the use of live attenuated dengue vaccines in infants in countries where dengue is endemic.

Fc receptor-mediated, antibody-dependent enhancement of bacteriophage lambda-mediated gene transfer in mammalian cells

Lambda phage vectors mediate gene transfer in cultured mammalian cells and in live mice, and in vivo phage-mediated gene expression is increased when mice are pre-immunized with bacteriophage lambda. We now show that, like eukaryotic viruses, bacteriophage vectors are subject to Fc receptor-mediated, antibody-dependent enhancement of infection in mammalian cells. Antibody-dependent enhancement of phage gene transfer required FcγRI, but not its associated γ-chain, and was not supported by other FcγR family members (FcγRIIA, FcγRIIB, and FcγRIII). Studies using chlorpromazine and latrunculin A revealed an important role for clathrin-mediated endocytosis (chlorpromazine) and actin filaments (latrunculin A) in antibody-enhanced phage gene transfer. This was confirmed by experiments using inhibitors of endosomal acidification (bafilomycin A1, monensin) and by immunocytochemical colocalization of internalized phage particles with early endosome-associated protein-1 (EAA1). In contrast, microtubule-targeting agents (nocodazole, taxol) increased the efficiency of antibody-enhanced phage gene transfer. These results reveal an unexpected antibody-dependent, FcγRI-mediated enhancement of phage transduction in mammalian cells, and suggest new approaches to improve bacteriophage-mediated gene transfer.

Traitors of the immune system—Enhancing antibodies in HIV infection: Their possible implication in HIV vaccine development

Considering recent HIV vaccine failures, the authors believe that it would be most important to find new targets for vaccine-induced immunity, and to analyze the data from previous trials, using an innovative approach. In their review article, the authors briefly summarize the significance of the antibody-dependent enhancement of infection in different viral diseases and discuss role of these types of antibodies as the obstacles for vaccine development. Findings which indicate that complement-mediated antibody-dependent enhancement (C-ADE) is present also in HIV-infected patients, are summarized. Previous results of the authors, suggesting that C-ADE plays a very important role in the progression of HIV infection are described. Data reflecting that enhancing antibodies may develop even in vaccinated animals and human volunteers, and may be responsible for the paradoxical results obtained in some subgroups of vaccinees are discussed. Finally, based on their hypothesis, the authors offer some suggestions for the future development of vaccines.

Complement Protein C1q Inhibits Antibody-Dependent Enhancement of Flavivirus Infection in an IgG Subclass-Specific Manner

Severe dengue virus infection can occur in humans with pre-existing antibodies against the virus. This observation led to the hypothesis that a subneutralizing antibody level in vivo can increase viral burden and cause more severe disease. Indeed, antibody-dependent enhancement of infection (ADE) in vitro has been described for multiple viruses, including the flaviviruses dengue virus and West Nile virus. Here, we demonstrate that the complement component C1q restricts ADE by anti-flavivirus IgG antibodies in an IgG subclass-specific manner in cell culture and in mice. IgG subclasses that avidly bind C1q induced minimal ADE in the presence of C1q. These findings add a layer of complexity for the analysis of humoral immunity and flavivirus infection.

Dengue virus (DENV) antibody-dependent enhancement of infection upregulates the production of anti-inflammatory cytokines, but suppresses anti-DENV free radical and pro-inflammatory cytokine production, in THP-1 cells

The immunopathogenesis of dengue haemorrhagic fever and dengue shock syndrome is thought to be mediated by a variety of host factors. Enhancing antibodies are one of the key regulating molecules. These antibodies, via antibody-dependent enhancement (ADE) of infection, are able to facilitate dengue virus (DENV) growth in Fc-bearing host cells. The mechanism of ADE-enhanced DENV production is believed to be mediated through increasing the infected-cell mass. In the present work, the effect of ADE infection was explored further, focusing on the post-entry events of ADE infection. It was hypothesized that the higher virus production in ADE infection compared with DENV infection may be due to the ability of this infection pathway to suppress key antiviral molecules. Therefore, the influence of ADE infection on pro- and anti-inflammatory cytokines, including interleukin-12 (IL-12), gamma interferon (IFN-gamma), tumour necrosis factor alpha (TNF-alpha), IL-6 and IL-10, was investigated and it was found that DENV infection via the Fc receptor-mediated pathway was able to suppress the transcription and translation of IL-12, IFN-gamma and TNF-alpha. In contrast, infection via this route facilitated expression and synthesis of the anti-inflammatory cytokines IL-6 and IL-10. Moreover, this study demonstrates that the ADE infection pathway also suppresses an innate anti-DENV mediator, nitric oxide radicals, by disrupting the transcription of the iNOS gene transcription factor, IRF-1, and blocking the activation of STAT-1. In conclusion, ADE infection not only facilitates the entry process, but also modifies innate and adaptive intracellular antiviral mechanisms, resulting in unrestricted DENV replication in THP-1 cells.

Immunoglobulin G Antibody-Mediated Enhancement of Measles Virus Infection Can Bypass the Protective Antiviral Immune Response

Antibodies to viral surface glycoproteins play a crucial role in immunity to measles by blocking both virus attachment and subsequent fusion with the host cell membrane. Here, we demonstrate that certain immunoglobulin G (IgG) antibodies can also enhance the entry of measles virus (MV) into monocytes and macrophages. Antibody-dependent enhancement of infectivity was observed in mouse and human macrophages using virions opsonized by a murine monoclonal antibody against the MV hemagglutinin (H) glycoprotein, polyclonal mouse anti-MV IgG, or diluted measles-immune human sera. Neither H-specific Fab fragments nor H-specific IgM could enhance MV entry in monocytes or macrophages, indicating involvement of a Fc gamma receptor (FcgammaR)-mediated mechanism. Preincubation with an anti-fusion protein (anti-F) monoclonal antibody or a fusion-inhibitory peptide blocked infection, indicating that a functional F protein was required for viral internalization. Classical complement pathway activation did not promote infection through complement receptors and inhibited anti-H IgG-mediated enhancement. In vivo, antibody-enhanced infection allowed MV to overcome a highly protective systemic immune response in preimmunized IfnarKo-Ge46 transgenic mice. These data demonstrate a previously unidentified mechanism that may contribute to morbillivirus pathogenesis where H-specific IgG antibodies promote the spread of MV infection among FcgammaR-expressing host cells. The findings point to a new model for the pathogenesis of atypical MV infection observed after immunization with formalin-inactivated MV vaccine and underscore the importance of the anti-F response after vaccination.

Antibody-dependent enhancement of infection: bacteria do it too

Antibodies should defend us from microbial infection, however, new research suggests that bacteria can use antibodies against us. An ingenious strategy by pneumococcus uses specific antibacterial IgA antibodies to enhance colonisation on respiratory cells. After degradation by a bacterial protease, IgA–Fab fragments induce the selective unmasking of a bacterial ligand used in interactions with host cells, providing a means for enhanced attachment. This finding challenges conventional views on vaccine design for mucosal pathogens.

Antibody-dependent enhancement of virus infection and disease.

In general, virus-specific antibodies are considered antiviral and play an important role in the control of virus infections in a number of ways. However, in some instances, the presence of specific antibodies can be beneficial to the virus. This activity is known as antibody-dependent enhancement (ADE) of virus infection. The ADE of virus infection is a phenomenon in which virus-specific antibodies enhance the entry of virus, and in some cases the replication of virus, into monocytes/macrophages and granulocytic cells through interaction with Fc and/or complement receptors. This phenomenon has been reported in vitro and in vivo for viruses representing numerous families and genera of public health and veterinary importance. These viruses share some common features such as preferential replication in macrophages, ability to establish persistence, and antigenic diversity. For some viruses, ADE of infection has become a great concern to disease control by vaccination. Consequently, numerous approaches have been made to the development of vaccines with minimum or no risk for ADE. Identification of viral epitopes associated with ADE or neutralization is important for this purpose. In addition, clear understanding of the cellular events after virus entry through ADE has become crucial for developing efficient intervention. However, the mechanisms of ADE still remain to be better understood.

Suppression of lipopolysaccharide-induced antiviral transcription factor (STAT-1 and NF-kappa B) complexes by antibody-dependent enhancement of macrophage infection by Ross River virus.

Subneutralizing concentrations of antibody may enhance virus infection by bringing the virus-antibody complex into contact with the cell surface Fc receptors; this interaction facilitates entry of virus into the cell and is referred to as antibody-dependent enhancement (ADE) of infection. Northern analysis of macrophage RNA demonstrated that ADE infection by the indigenous Australian alphavirus Ross River (RRV-ADE) ablated or diminished message for tumor necrosis factor alpha (TNF-alpha), nitric-oxide synthase 2 (NOS2), and IFN regulatory factor 1 (IRF-1), as well as for IFN-inducible protein 10 (IP-10) and IFN-beta; the transcription of a control gene was unaffected. Additionally, electrophoretic mobility-shift assay (EMSA) studies showed that transcription factor IFN-alpha-activated factor (AAF), IFN-stimulated gene factor 3 (ISGF3), and nuclear factor-kappaB (NF-kappaB) complex formation in macrophage nuclear extracts were specifically suppressed post-RRV-ADE infection, emphasizing the capacity for ADE infections to compromise antiviral responses at the transcriptional level. The suppression of antiviral transcription factor complexes was shown to depend on replicating virus and was not simply a result of general antibody-Fc-receptor interaction. Although only a minority of cells ( approximately 15%) were shown to be positive for RRV by immunostaining techniques post ADE, molecular (RT-PCR) analysis showed that unstained cells carried RRV-RNA, indicating a higher level of viral infectivity than previously suspected. Electron microscopy studies confirmed this observation. Furthermore, levels of cellular IL-10 protein were dramatically elevated in RRV-ADE cultures. This evidence demonstrates that RRV can potently disrupt the activation of specific antiviral pathways via ADE infection pathways, and may suggest a significant mechanism in the infection and pathogenesis of other ADE viruses.

Identification of aleutian mink disease parvovirus capsid sequences mediating antibody-dependent enhancement of infection, virus neutralization, and immune complex formation.

Aleutian mink disease parvovirus (ADV) causes a persistent infection associated with circulating immune complexes, immune complex disease, hypergammaglobulinemia, and high levels of antiviral antibody. Although antibody can neutralize ADV infectivity in Crandell feline kidney cells in vitro, virus is not cleared in vivo, and capsid-based vaccines have proven uniformly ineffective. Antiviral antibody also enables ADV to infect macrophages, the target cells for persistent infection, by Fc-receptor-mediated antibody-dependent enhancement (ADE). The antibodies involved in these unique aspects of ADV pathogenesis may have specific targets on the ADV capsid. Prominent differences exist between the structure of ADV and other, more-typical parvoviruses, which can be accounted for by short peptide sequences in the flexible loop regions of the capsid proteins. In order to determine whether these short sequences are targets for antibodies involved in ADV pathogenesis, we studied heterologous antibodies against several peptides present in the major capsid protein, VP2. Of these antibodies, a polyclonal rabbit antibody to peptide VP2:428-446 was the most interesting. The anti-VP2:428-446 antibody aggregated virus particles into immune complexes, mediated ADE, and neutralized virus infectivity in vitro. Thus, antibody against this short peptide can be implicated in key facets of ADV pathogenesis. Structural modeling suggested that surface-exposed residues of VP2:428-446 are readily accessible for antibody binding. The observation that antibodies against a single target peptide in the ADV capsid can mediate both neutralization and ADE may explain the failure of capsid-based vaccines.

Infectivity-enhancing antibodies to Ebola virus glycoprotein.

Ebola virus causes severe hemorrhagic fever in primates, resulting in mortality rates of up to 100%, yet there are no satisfactory biologic explanations for this extreme virulence. Here we show that antisera produced by DNA immunization with a plasmid encoding the surface glycoprotein (GP) of the Zaire strain of Ebola virus enhances the infectivity of vesicular stomatitis virus pseudotyped with the GP. Substantially weaker enhancement was observed with antiserum to the GP of the Reston strain, which is much less pathogenic in humans than the Ebola Zaire and Sudan viruses. The enhancing activity was abolished by heat but was increased in the presence of complement system inhibitors, suggesting that heat-labile factors other than the complement system are required for this effect. We also generated an anti-Zaire GP monoclonal antibody that enhanced viral infectivity and another that neutralized it, indicating the presence of distinct epitopes for these properties. Our findings suggest that antibody-dependent enhancement of infectivity may account for the extreme virulence of the virus. They also raise issues about the development of Ebola virus vaccines and the use of passive prophylaxis or therapy with Ebola virus GP antibodies.

Specific ablation of antiviral gene expression in macrophages by antibody-dependent enhancement of Ross River virus infection.

Ross River virus (RRV) is an indigenous Australian arthropod-borne alphavirus responsible for epidemic polyarthritis (EPA), myalgia, and lethargy in humans. Macrophages and monocytes have been associated with human RRV disease, and previous studies have shown that RRV is capable of infecting macrophages via both a natural virus receptor and by Fc receptor-mediated antibody-dependent enhancement (ADE). Similar to other viruses, such as human immunodeficiency virus and dengue virus, ADE infection results in dramatic RRV growth increases for in vitro macrophage cultures. This study demonstrates that RRV could resist lipopolysaccharide (LPS)-induced antiviral activity in macrophage cultures when infection was via the ADE pathway. Investigation of this infection pathway found that RRV was able to suppress the transcription and translation of key antiviral genes (tumor necrosis factor and inducible nitric oxide synthase) in LPS-stimulated macrophages by disrupting the transcription into mRNA of the genes coding for the associated transcription factors IRF-1 and NF-kappaB. The transcription of non-antiviral control genes was not perturbed by RRV-ADE infection, and de novo protein synthesis also was not significantly affected in RRV-ADE infected cells. The ADE pathway of infection allowed RRV to specifically target antiviral genes in macrophages, resulting in unrestricted virus replication. As ADE has been observed for several virus families and associated with disease and adverse vaccination outcomes, these findings may have broad relevance to viral disease formation and antiviral vaccination strategies.

Antibody-dependent enhancement of feline infectious peritonitis virus infection in feline alveolar macrophages and human monocyte cell line U937 by serum of cats experimentally or naturally infected with feline coronavirus.

Infection of the type II feline infectious peritonitis virus (FIPV) strain 79-1146 to primary feline alveolar macrophages and human monocyte cell line U937 was enhanced by the sera of cats experimentally infected with the 79-1146 strain, but not those of cats infected with KU-2 or UCD-1 strain of type I FIPV. The experiments using sera of cats with feline infectious peritonitis (FIP) and of cats naturally infected with feline coronavirus (FCoV) revealed that infection of the FIPV 79-1146 strain to the U937 cells was enhanced only by the sera of cats infected with type II FIPV or feline enteric coronavirus. The samples positive for antibody-dependent enhancement (ADE) activity had high neutralizing antibody titers against the FIPV 79-1146 strain and the samples negative for ADE activity had low neutralizing antibody titers. These findings support the previous results where a monoclonal antibody with neutralizing activity had high ADE activity, suggesting that there was a close relationship between the neutralization and enhancement sites. And then it is also suggested that ADE of infection is likely to be induced by re-infection with the same serotype of virus in type II FIPV infection. Furthermore, U937 cells are considered useful and can be substituted for the feline macrophages for determining ADE of FIPV-infection.

Expression and Characterization of CD4-IgG2, a Novel Heterotetramer That Neutralizes Primary HIV Type 1 Isolates

CD4-IgG2 is a novel fusion protein comprising human IgG2 in which the Fv portions of both heavy and light chains have been replaced by the V1 and V2 domains of human CD4. This tetrameric protein is being developed as an immunoprophylactic agent to reduce the probability of infection following HIV-1 exposure, in settings such as occupational or perinatal exposure to the virus. CD4-IgG2 has been expressed in Chinese hamster ovary cells and is secreted as a fully assembled heterotetramer. The protein binds with nanomolar affinity to purified gp120 from both a laboratory-adapted strain and a primary isolate of HIV-1. Pharmacokinetic studies in rabbits demonstrated that CD4-IgG2 has a plasma terminal half-life greater than 1 day, compared with 15 min for soluble CD4 (sCD4). CD4-IgG2 does not bind to Fc receptors on the surface of U937 monocyte/macrophage cells. Compared to molecules that incorporate the Fc portion of IgG1, CD4-IgG2 has less potential to mediate functions such as antibody-dependent enhancement of infection or transplacental transmission of HIV-1. When tested in a virus-free HIV-1 envelope glycoprotein-mediated cell fusion assay, the tetrameric CD4-IgG2 molecule inhibited syncytium formation more effectively than monomeric sCD4 or a dimeric CD4-gamma 2 fusion protein. This suggests the protein will block cell-to-cell transmission of HIV-1. Moreover, CD4-IgG2 effectively neutralized a panel of laboratory-adapted strains and primary isolates of HIV-1, including strains with different tropisms and isolated from different stages of the disease, at concentrations that should be readily achieved in vivo.

Antibody-Dependent Enhancement of Infection and the Pathogenesis of Viral Disease

Antibody-dependent enhancement of infection (ADE) is an in vitro serological phenomenon--or a group of phenomena--in which viral infection of susceptible cells is modified by the addition of virus-reactive antibody. Evidence suggests that ADE reflects immunologic processes that occur in vivo. Various severe and even fatal viral conditions of humans and animals, including dengue shock syndrome, the "early-death phenomenon" in experimental infections of immune animals, and other vaccine- and immunoglobulin-modified conditions, have been attributed to ADE by some researchers. ADE has caused great concern in relation to the development of vaccines against dengue virus and human immunodeficiency virus. More data are urgently needed on the mechanisms and determinants of ADE and on its alleged role in disease pathogenesis and in vaccine-associated phenomena.

Assessment of the antibody response to the immunosuppressive/immunodominant region of HIV gp41 in a 5‐year longitudinal study

The antibody response of HIV-infected individuals to the 581-609 amino acid (aa) region of HIV-1 gp41 containing the putative immunosuppressive and immunodominant sequences was examined. Sera collected every 5 to 6 months over a period of 5 years from 50 HIV-1-infected homosexual and bisexual men, 25 of whom progressed to AIDS during the collection period, were monitored for changes in ELISA reactivity against synthetic peptides encompassing aa581-609 of gp41. The data obtained in this blinded, historical prospective study were analyzed with respect to changes in mean ELISA absorbance over time and differences in absorbance between patient groups (those who progressed to AIDS and those who did not). No correlation was found between time or disease state and the presence of antibodies to the aa581-597 immunosuppressive sequence. In contrast, ELISA absorbance against the aa598-609 immunodominant sequence continued to increase over time in both the AIDS and non-AIDS groups. The rate of increase in absorbance was similar for both groups; however, the AIDS group had a significantly higher mean absorbance level at the outset of the study and maintained this difference throughout the study. This region of gp41 has been proposed to play a role in complement-mediated antibody-dependent enhancement of infection.

Neutralization of animal viruses.

1 Introduction.- 2 Immunoglobulin G Neutralization by Inhibition of Attachment of Virus to the Cell.- 3 Immunoglobulin G Neutralization Which Does Not Inhibit Attachment of Virus to the Cell.- 4 Immunoglobulin G Neutralization by Aggregation of Virions . ..- 5 Immunoglobulin G Neutralization Mechanisms which Operate After Attachment of the Virus-Antibody Complex to a Cell Receptor Unit.- 5.1 Inhibition of Fusion at the Plasma Membrane.- 5.2 Inhibition of Endocytosis.- 5.3 Inhibition of Fusion of Viral and Cellular Membranes.- 5.4 Inhibition of Non-fusion Uncoating.- 5.5 Inhibition of Events which Occur After Primary Uncoating.- 6 Neutralization which Occurs by Virus Binding Antibody After It Has Attached to a Cell.- 7 Role of the Cell in Neutralization.- 8 Antibody-Dependent Enhancement of Infectivity by Neutralizing Antibody: Fc and Complement Receptors.- 9 Neutralization by Polymeric Immunoglobulin A.- 10 Neutralization by Immunoglobulin M.- 11 The Relevance of Immunoglobulin Isotype to Neutralization.- 12 Viral Carbohydrates, Proteins and Neutralization.- 12.1 Carbohydrates and Neutralization.- 12.2 Proteinsand Neutralization.- 13 Properties of Protein and Peptide Antigens Which Elicit Neutralizing Antibody.- 14 Neutralization In Vivo.- 15 Complement and Neutralization.- 16 Neutralization by Inhibition of Release of Progeny Virus from the Infected Cell.- 17 Changes in Virus Proteins and Virion Structure on Binding Antibody, Including Synergistic Neutralization.- 18 Reversibility of Neutralization.- 19 Neutralization by Fragments of Antibody.- 20 Quantitative Aspects of Neutralization.- 21 Unconventional Neutralization.- 21.1 Genetic Engineering of Antibodies and Viruses.- 21.2 Anti-idiotype Antibodies and Neutralization.- 22 The Evolutionary Significance of Neutralization Sites.- 22.1 Why Do Viruses Have Neutralization Sites?.- 22.2 Strategies which Avoid or Minimize Expression of, or Response, to Neutralization Sites.- 22.2.1 Relating to the Virus Particle.- 22.2.2 Relating to the Immune System.- 23 Neutralization of Poliovirus and Rhinovirus: A Summary.- 23.1 Introduction.- 23.2 Attachment.- 23.3 Internalization.- 23.4 Post-internalization.- 23.5 Aggregation.- 23.6 Conformational Changes on Binding Antibody.- 24 Neutralization of Type a Influenza Virus by Immunoglobulins M, A and G: A Summary.- 24.1 Introduction.- 24.2 IgM Neutralization.- 24.3 IgA Neutralization.- 24.4 IgG Neutralization.- 24.5 Discussion.- 25 Neutralization of HIV-1: A Summary.- 26 Conclusions.- References.

Monoclonal antibodies to the spike protein of feline infectious peritonitis virus mediate antibody-dependent enhancement of infection of feline macrophages.

Antibody-dependent enhancement of virus infection is a process whereby virus-antibody complexes initiate infection of cells via Fc receptor-mediated endocytosis. We sought to investigate antibody-dependent enhancement of feline infectious peritonitis virus infection of primary feline peritoneal macrophages in vitro. Enhancement of infection was assessed, after indirect immunofluorescent-antibody labelling of infected cells, by determining the ratio between the number of cells infected in the presence and absence of virus-specific antibody. Infection enhancement was initially demonstrated by using heat-inactivated, virus-specific feline antiserum. Functional compatibility between murine immunoglobulin molecules and feline Fc receptors was demonstrated by using murine anti-sheep erythrocyte serum and an antibody-coated sheep erythrocyte phagocytosis assay. Thirty-seven murine monoclonal antibodies specific for the nucleocapsid, membrane, or spike proteins of feline infectious peritonitis virus or transmissible gastroenteritis virus were assayed for their ability to enhance the infectivity of feline infectious peritonitis virus. Infection enhancement was mediated by a subset of spike protein-specific monoclonal antibodies. A distinct correlation was seen between the ability of a monoclonal antibody to cause virus neutralization in a routine cell culture neutralization assay and its ability to mediate infection enhancement of macrophages. Infection enhancement was shown to be Fc receptor mediated by blockade of antibody-Fc receptor interaction using staphylococcal protein A. Our results are consistent with the hypothesis that antibody-dependent enhancement of feline infectious peritonitis virus infectivity is mediated by antibody directed against specific sites on the spike protein.