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Abstract
Understanding the B-cell response during chronic human immunodeficiency virus (HIV) infection is essential for eliciting broad and potent neutralizing antibodies (Abs). In this study, we analyzed the plasmablast repertoire of chronically HIV-infected individuals in combination with antiretroviral therapy (ART). Among the obtained 72 recombinant monoclonal antibodies (mAbs), 27.8% weakly bound to HIV gp140 and were non-neutralizing. Remarkably, 56.9% were polyreactive and 55.6% were autoreactive. The prominent feature of being polyreactive/autoreactive is not limited to anti-gp140 Abs. Furthermore, these polyreactive/autoreactive Abs displayed striking cross-reactivity with DWEYS in the N-methyl-d-aspartate receptor (NMDAR), and this binding induced SH-SY5Y cell apoptosis. We also found higher frequencies of VH4-34 utilization and VH replacement in the plasmablast repertoire of chronically HIV-infected individuals, which may contribute to the generation of poly/autoreactive Abs. Taken together, these data demonstrate that circulating plasmablasts in chronically HIV-infected individuals experienced with ART predominantly produce poly/autoreactive Abs with minimal anti-HIV neutralizing capacity and potential cross-reactivity with autoantigens. This may represent another dysfunction of B cells during chronic HIV infection.
Highlights
Human immunodeficiency virus (HIV) infection affects millions of people worldwide [1]
57.1% (4/7) of the Abs encoded by VH replacement products were polyreactive (Figure 7D) and 85.7% (6/7) were autoreactive (Figure 7E); 28.6% (2/7) reacted with gp140 (Figure 7F). These results indicate that the enriched VH replacement products in the plasmablast repertoires of chronically human immunodeficiency virus (HIV)-infected individuals may contribute to the generation of poly/autoreactive Abs
We demonstrated that plasmablast-derived Abs from chronically HIV-infected individuals with antiretroviral therapy (ART) experience have weak anti-gp140-binding affinity and are nonneutralizing
Summary
Human immunodeficiency virus (HIV) infection affects millions of people worldwide [1]. Designing effective vaccines to induce broad and potent neutralizing antibodies (bnAbs) remains the ultimate approach for preventing HIV transmission [2]. HIV-1 directly infects and depletes CD4+ T cells [3,4,5,6], which destroys T follicular helper cell function and impairs the T-dependent B-cell response [7,8,9,10]. Polyreactive Antibodies in HIV Infection that multiple B-cell dysfunctions directly or indirectly result from HIV replication [11, 12]. HIV infection induces polyclonal activation and depletion of follicular B cells [13,14,15]. A better understanding of the B-cell response is essential for inducing bnAbs to control HIV infection
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