Intraepithelial Cell Neutralization of HIV-1 Replication by IgA

Abstract

HIV is transmitted sexually through mucosal surfaces where IgA Abs are the first line of immune defense. In this study, we used paired IgA and IgG mAbs against HIV gp160 to study intraepithelial cell neutralization and inhibition of HIV replication. African green monkey kidney cells, Vero C1008, polarizable epithelial cells transfected to express the polymeric Ig receptor (pIgR), were transfected with HIV proviral DNA, and intracellular neutralization mediated by the mAbs was assessed. D47A and D19A IgA, which neutralized HIV in a conventional assay, potently inhibited intracellular HIV replication as assessed by infecting HeLa-CD4-long terminal repeat/β-galactosidase cells (human cervical carcinoma cell line) and CEMx174 cells (human T cell line) with apical supernatant, basolateral medium, and cell lysate from transfected cells. D47A also inhibited the production of virus as assessed by direct assay of p24. In contrast, D47 and D19 IgG, sharing the same V regions, but which were not transcytosed by the pIgR, did not inhibit intracellular HIV replication, nor did D47A and D19A IgA in pIgR− cells, incapable of transcytosing IgA. Confocal immunofluorescence microscopy showed prominent colocalization of HIV protein and D47A, in agreement with the intracellular neutralization data. D10A, which did not neutralize HIV in the conventional assay, and irrelevant IgA did not show intracellular neutralization or colocalization. Control studies with two kinds of conditioned medium confirmed that HIV neutralization had indeed occurred inside the cells. Thus, during its transcytosis through epithelial cells, HIV-specific IgA can neutralize HIV replication.

The gp41 epitope, QARVLAVERY, is highly conserved and a potent inducer of IgA that neutralizes HIV-1 and inhibits viral transcytosis

“…27,28 In addition to the role of IgG, several studies have also reported the importance of IgA against HIV. IgA has proven to be functional in protecting against HIV infection by direct neutralization, 29 -34 by inhibiting transcytosis of HIV across the mucosa, 29,31,35 -40 by intracellular virus neutralization, 41,42 and by preventing HIV entry past the epithelial lumen. 37 Furthermore, virus-specific IgA has been independently identified in the serum and cervicovaginal lavage of exposed uninfected (EU) cohorts of European, African, and Asian origins.…”

Rotavirus Anti-VP6 Secretory Immunoglobulin A Contributes to Protection via Intracellular Neutralization but Not via Immune Exclusion

“…In most cases where intracellular neutralization by IgA has been described, for human immunodeficiency virus (HIV) (2,22), Sendai virus (18), and influenza virus (29), the active IgA molecule was directed at a viral protein known to be the target of extracellularly acting neutralizing antibodies. However, in the case of RV, such neutralizing antibodies directed to VP4 (44) did not exhibit intracellular neutralization activity.…”

FcαRI (CD89) Alleles Determine the Proinflammatory Potential of Serum IgA

“…The differential biologies of the Ser 248 -Fc␣RI and Gly 248 -Fc␣RI alleles could also play a role in other phenotypes involving IgA, including dermatitis herpetiformis, celiac disease, periodontal disease, and possibly IgA nephropathy. Even the uptake and inactivation of virus, demonstrated in epithelial cells with anti-HIV IgA, might be impacted by CD89 alleles (54). Because mice do not have FCAR, the gene encoding CD89, clues will not be forthcoming from studies of spontaneous mouse phenotypes but will need to be done in humans or, possibly, in mice reconstituted with human immune systems (55,56).…”