title: Abnormal B cell memory subsets dominate HIV-specific responses in infected individuals.
abstract: Recently, several neutralizing anti-HIV antibodies have been isolated from memory B cells of HIV-infected individuals. Despite extensive evidence of B cell dysfunction in HIV disease, little is known about the cells from which these rare HIV-specific antibodies originate. Accordingly, we used HIV envelope gp140 and CD4 or coreceptor (CoR) binding site (bs) mutant probes to evaluate HIV-specific responses in peripheral blood B cells of HIV-infected individuals at various stages of infection. In contrast to non-HIV responses, HIV-specific responses against gp140 were enriched within abnormal B cells, namely activated and exhausted memory subsets, which are largely absent in the blood of uninfected individuals. Responses against the CoRbs, which is a poorly neutralizing epitope, arose early, whereas those against the well-characterized neutralizing epitope CD4bs were delayed and infrequent. Enrichment of the HIV-specific response within resting memory B cells, the predominant subset in uninfected individuals, did occur in certain infected individuals who maintained low levels of plasma viremia and immune activation with or without antiretroviral therapy. The distribution of HIV-specific responses among memory B cell subsets was corroborated by transcriptional analyses. Taken together, our findings provide valuable insight into virus-specific B cell responses in HIV infection and demonstrate that memory B cell abnormalities may contribute to the ineffectiveness of the antibody response in infected individuals.
authors.forename: Lela
authors.initials: L
authors.lastname: Kardava
authors.forename: Susan
authors.initials: S
authors.lastname: Moir
authors.forename: Naisha
authors.initials: N
authors.lastname: Shah
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Richard
authors.initials: R
authors.lastname: Wilson
authors.forename: Clarisa M
authors.initials: CM
authors.lastname: Buckner
authors.forename: Brian H
authors.initials: BH
authors.lastname: Santich
authors.forename: Leo J Y
authors.initials: LJ
authors.lastname: Kim
authors.forename: Emily E
authors.initials: EE
authors.lastname: Spurlin
authors.forename: Amy K
authors.initials: AK
authors.lastname: Nelson
authors.forename: Adam K
authors.initials: AK
authors.lastname: Wheatley
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Harvey
authors.forename: Adrian B
authors.initials: AB
authors.lastname: McDermott
authors.forename: Kai W
authors.initials: KW
authors.lastname: Wucherpfennig
authors.forename: Tae-Wook
authors.initials: TW
authors.lastname: Chun
authors.forename: John S
authors.initials: JS
authors.lastname: Tsang
authors.forename: Yuxing
authors.initials: Y
authors.lastname: Li
authors.forename: Anthony S
authors.initials: AS
authors.lastname: Fauci
mesh_terms: D000208:Acute Disease; D019380:Anti-HIV Agents / Q000627:therapeutic use; D057134:Antibodies, Neutralizing / Q000097:blood; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002908:Chronic Disease; D015483:HIV Antibodies / Q000097:blood; D015699:HIV Envelope Protein gp120 / Q000276:immunology; D015658:HIV Infections / Q000235:genetics / Q000276:immunology* / Q000821:virology; D006801:Humans; D007156:Immunologic Memory; D059467:Transcriptome; D019562:Viral Load; D054299:env Gene Products, Human Immunodeficiency Virus / Q000276:immunology
chemical_list: D019380:Anti-HIV Agents; D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D054299:env Gene Products, Human Immunodeficiency Virus; C097729:gp140 envelope protein, Human immunodeficiency virus 1