HIV-1-Specific IgA Monoclonal Antibodies from an HIV-1 Vaccinee Mediate Galactosylceramide Blocking and Phagocytosis

Abstract

Vaccine-elicited humoral immune responses comprise an array of antibody forms and specificities, with only a fraction contributing to protective host immunity. Elucidation of antibody effector functions responsible for protective immunity against human immunodeficiency virus type 1 (HIV-1) acquisition is a major goal for the HIV-1 vaccine field. Immunoglobulin A (IgA) is an important part of the host defense against pathogens; however, little is known about the role of vaccine-elicited IgA and its capacity to mediate antiviral functions. To identify the antiviral functions of HIV-1-specific IgA elicited by vaccination, we cloned HIV-1 envelope-specific IgA monoclonal antibodies (MAbs) by memory B cell cultures from peripheral blood mononuclear cells from an RV144 vaccinee and produced two IgA clonal cell lines (HG129 and HG130) producing native, nonrecombinant IgA MAbs. The HG129 and HG130 MAbs mediated phagocytosis by monocytes, and HG129 blocked HIV-1 Env glycoprotein binding to galactosylceramide, an alternative HIV-1 receptor. These findings elucidate potential antiviral functions of vaccine-elicited HIV-1 envelope-specific IgA that may act to block HIV-1 acquisition at the portal of entry by preventing HIV-1 binding to galactosylceramide and mediating antibody Fc receptor-mediated virion phagocytosis. Furthermore, these findings highlight the complex and diverse interactions of vaccine-elicited IgA with pathogens that depend on IgA fine specificity and form (e.g., multimeric or monomeric) in the systemic circulation and mucosal compartments.IMPORTANCE Host-pathogen interactions in vivo involve numerous immune mechanisms that can lead to pathogen clearance. Understanding the nature of antiviral immune mechanisms can inform the design of efficacious HIV-1 vaccine strategies. Evidence suggests that both neutralizing and nonneutralizing antibodies can mediate some protection against HIV in animal models. Although numerous studies have characterized the functional properties of HIV-1-specific IgG, more studies are needed on the functional attributes of HIV-1-specific IgA, specifically for vaccine-elicited IgA. Characterization of the functional properties of HIV-1 Env-specific IgA monoclonal antibodies from human vaccine clinical trials are critical toward understanding the capacity of the host immune response to block HIV-1 acquisition.

Serum IgA Fc effector functions in infectious disease and cancer

“…The protective potential of serum IgA has been suggested in elite controllers (individuals that spontaneously control HIV‐1 viremia) in whom higher titers of HIV‐1‐specific serum IgA have been observed compared with HIV‐1 progressors . In vitro studies have demonstrated that monoclonal IgA has the capacity to activate antibody functions against HIV‐1 antigens (ADCC and phagocytosis) . Furthermore, mucosal IgA (sIgA) may prevent HIV‐1 infection via immune exclusion/opsonization as observed in highly exposed seronegative individuals and various nonhuman primate vaccine trials (Figure ) …”

Human IgA Monoclonal Antibodies That Neutralize Poliovirus, Produced by Hybridomas and Recombinant Expression

“…Human IgA mAbs have been isolated from memory B cell populations using recombinant methods [13,[21][22][23], and IgAs have been produced in plants [26,29,47,48] and mammalian cells [25,28,30,49]. In this study, we produced PV-neutralizing IgA mAbs using two strategies: (1) de novo IgA cloning from primary human B cells using an updated hybridoma method; and (2) isotype switching of existing IgG mAbs, with recombinant expression in transiently transfected HEK293F cells.…”

The Multifaceted Nature of Immunoglobulin A and Its Complex Role in HIV

“…The notion for a potential role for IgA receptors is supported by a study that found serum IgA antibodies from HIV-infected individuals, but not seronegative HIV controls, enhanced HIV infection of monocytes and intestinal mononuclear cells. 114 Serum Anti-HIV IgA: Evidence for a Protective Role Despite the studies discussed above, which cast a cloud over the protective effect of serum IgAs in HIV, a number of potentially protective qualities, such as ADCC, 115 neutralization, 116 and phagocytosis, 117,118 have been attributed to serum anti-HIV IgA. 73,117 In one such recent study, two HIV envelope IgA mAbs were isolated and characterized from peripheral blood memory B cells from an RV144-vaccinated individual and were found to induce viral phagocytosis and block gp140 binding to the alternative HIV receptor galactosylceramide.…”

“…114 Serum Anti-HIV IgA: Evidence for a Protective Role Despite the studies discussed above, which cast a cloud over the protective effect of serum IgAs in HIV, a number of potentially protective qualities, such as ADCC, 115 neutralization, 116 and phagocytosis, 117,118 have been attributed to serum anti-HIV IgA. 73,117 In one such recent study, two HIV envelope IgA mAbs were isolated and characterized from peripheral blood memory B cells from an RV144-vaccinated individual and were found to induce viral phagocytosis and block gp140 binding to the alternative HIV receptor galactosylceramide. 117 In another recent study, targeting of HIV with envelope-specific gp41 IgA mAbs engaged CD89 on HIV-infected monocytes to trigger cell lysis by ADCC.…”

“…73,117 In one such recent study, two HIV envelope IgA mAbs were isolated and characterized from peripheral blood memory B cells from an RV144-vaccinated individual and were found to induce viral phagocytosis and block gp140 binding to the alternative HIV receptor galactosylceramide. 117 In another recent study, targeting of HIV with envelope-specific gp41 IgA mAbs engaged CD89 on HIV-infected monocytes to trigger cell lysis by ADCC. 85 The ability of dimeric and polymeric serum IgA, but not mIgA, to efficiently aggregate HIV into discreet complexes has also been demonstrated with the polyvalency provided by these isoforms associated with superior functionality.…”