title: B-lymphocyte dysfunction in chronic HIV-1 infection does not prevent cross-clade neutralization breadth.
abstract: Aberrant expression of regulatory receptors programmed death-1 (PD-1) and B- and T-lymphocyte attenuator (BTLA) is linked with dysregulation and exhaustion of T lymphocytes during chronic human immunodeficiency virus type 1 (HIV-1) infection; however, less is known about whether a similar process impacts B-lymphocyte function during HIV-1 infection. We reasoned that disruption of the peripheral B cell compartment might be associated with decreased neutralizing antibody activity. Expression of markers that indicate dysregulation (BTLA and PD-1), immune activation (CD95), and proliferation (Ki-67) was evaluated in B cells from HIV-1-infected viremic and aviremic subjects and healthy subjects, in conjunction with immunoglobulin production and CD4 T cell count. Viral load and cross-clade neutralizing activity in plasma from viremic subjects were also assessed. Dysregulation of B lymphocytes was indicated by a marked disruption of peripheral B cell subsets, increased levels of PD-1 expression, and decreased levels of BTLA expression in viremic subjects compared to aviremic subjects and healthy controls. PD-1 and BTLA were correlated in a divergent fashion with immune activation, CD4 T cell count, and the total plasma IgG level, a functional correlate of B cell dysfunction. Within viremic subjects, the total IgG level correlated directly with cross-clade neutralizing activity in plasma. The findings demonstrate that even in chronically infected subjects in which B lymphocytes display multiple indications of dysfunction, antibodies that mediate cross-clade neutralization breadth continue to circulate in plasma.
authors.affiliation: Emory Vaccine Center at Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA.
authors.forename: Saikat
authors.initials: S
authors.lastname: Boliar
authors.forename: Megan K
authors.initials: MK
authors.lastname: Murphy
authors.forename: T Cameron
authors.initials: TC
authors.lastname: Tran
authors.forename: Diane G
authors.initials: DG
authors.lastname: Carnathan
authors.forename: Wendy S
authors.initials: WS
authors.lastname: Armstrong
authors.forename: Guido
authors.initials: G
authors.lastname: Silvestri
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Derdeyn
mesh_terms: D000328:Adult; D000368:Aged; D057134:Antibodies, Neutralizing / Q000097:blood / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018791:CD4 Lymphocyte Count; D002908:Chronic Disease; D005260:Female; D015483:HIV Antibodies / Q000097:blood / Q000276:immunology*; D015658:HIV Infections / Q000097:blood / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology*; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology / Q000378:metabolism; D011971:Receptors, Immunologic / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019562:Viral Load / Q000276:immunology; D014766:Viremia / Q000276:immunology
chemical_list: D057134:Antibodies, Neutralizing; C482586:BTLA protein, human; D015483:HIV Antibodies; D007074:Immunoglobulin G; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D011971:Receptors, Immunologic