Abnormal B cell memory subsets dominate HIV-specific responses in infected individuals

Kardava, Lela; Moir, Susan; Shah, Naisha; Wang, Wei; Wilson, Richard F.; Buckner, Clarisa M.; Santich, Brian H.; Kim, Leo J.Y.; Spurlin, Emily; Nelson, Amy; Wheatley, Adam K.; Harvey, Christopher J.; McDermott, Adrian B.; Wucherpfennig, Kai W.; Chun, Tae‐Wook; Tsang, John S.; Li, Yuxing; Fauci, Anthony S.

doi:10.1172/jci74351

Cited by 125 publications

(207 citation statements)

References 59 publications

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“…However, they only found a relationship between development of bNAbs and viral load, and not Env-specific ASC, CD4 ϩ T cell count, or years since diagnosis (2). Thus, the present findings builds upon those of Kardava et al, who reported no significant associations between CD4 T cells (frequency or count) and percent RM Env-specific B cells (17).…”

Section: Discussionsupporting

confidence: 79%

“…Unlike the case with AM and TLM cells, the depletion of the RM subset is not corrected by ART treatment. Moreover, using various distinct HIV Env probes, Kardava et al showed that the majority of Env-specific B cells lie in abnormal memory subsets and that control of viremia results in enrichment of these responses in the RM cell compartment (17). We similarly found that Envspecific B cells in controllers are enriched in the RM B cell subset, whereas in progressors, Env-specific B cells are significantly contained in the TLM and, to a lesser extent, AM subsets.…”

Section: Discussionsupporting

confidence: 62%

“…As Tfh cell expansion has been associated with a concurrent expansion of B cells and plasma cells in lymphoid germinal centers, we next studied bulk and HIV-specific B cell phenotypes in the peripheral blood of the cohorts to determine how the observed To analyze the effects of antigenemia on memory B cell subsets, bulk B cells were separated into the four following memory subsets based on expression of CD21 and CD27 as previously described (14,15,17): CD27 ϩ CD21 Ϫ activated memory (AM), CD27 ϩ CD21 ϩ resting memory (RM), CD27 Ϫ CD21 Ϫ tissue-like memory (TLM), and CD27 Ϫ CD21 ϩ intermediate memory (IM). We found that peripheral blood mononuclear cells (PBMCs) from HIV-infected individuals have altered profiles of B cell memory subtypes compared to those from uninfected individuals.…”

Section: Bulk B Cells Are Expanded In Uncontrolled Hiv Infection But mentioning

confidence: 99%

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Preservation of Peripheral T Follicular Helper Cell Function in HIV Controllers

Buranapraditkun

Pissani

Teigler

et al. 2017

J Virol

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The maturation process of high-affinity antibodies is a result of intricate interactions between B cells and follicular helper T (Tfh) cells occurring in lymphoid germinal centers. HIV infection induces significant chronic immune activation, phenotypic skewing, and inflammation driven by years of continuous viral replication. High levels of viremia as well as immune activation and dysfunction have been demonstrated to have a perturbing impact on the B cell memory compartment and contribute to B cell exhaustion. Counterintuitively, the factors associated with perturbation of the B cell compartment seem to be favorable for the generation of highly affinity-matured Env-specific antibodies in a minority of HIV-infected individuals. Thus, the impact of HIV antigenemia on B cells and Tfh cell interactions warrants further exploration. We therefore studied immunophenotypes of HIV-specific B cells in individuals with differing levels of viral control using HIV Env gp120 probes and characterized the functionality of matched T cells in peripheral blood. While CXCR5 ϩ CD4 ϩ T cells were significantly diminished in HIV progressors, we found that a small subset of gp120-specific interleukin-21 (IL-21)-secreting CXCR5 ϩ CD4 ϩ T cells were significantly associated with gp120-specific B cell frequencies. In contrast, neither bulk CXCR5 ϩ CD4 ϩ T cells nor other HIV antigen specificities were associated with gp120-specific B cell levels. HIV-specific B cells derived from elite controllers displayed greater amounts of gp120-specific B cells in the resting memory subset, whereas HIV-specific B cells in progressors accumulated in tissue-like and activated memory subsets. Furthermore, CXCR5 ϩ CD4 ϩ T cells from elite controllers showed a stronger ex vivo capacity to induce B cell maturation and immunoglobulin class switching than cells from HIV progressors.IMPORTANCE Dissecting the factors that are involved in B cell maturation and antibody development is important for HIV vaccine design. In this study, we found that HIV Env-specific CXCR5 ϩ CD4 ϩ T cells that secrete interleukin-21 are strongly associated with B cell memory phenotypes and function. Moreover, we found that the immune responses of HIV controllers showed intrinsically better helper activity than those of HIV progressors.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionsupporting

confidence: 62%

Section: Bulk B Cells Are Expanded In Uncontrolled Hiv Infection But mentioning

confidence: 99%

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Preservation of Peripheral T Follicular Helper Cell Function in HIV Controllers

Buranapraditkun

Pissani

Teigler

et al. 2017

J Virol

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“…B‐cell dysregulation is evidenced by the delayed antibody response in acute HIV‐1 infection,41 an increase in the proportion of activated memory B cells and exhausted B cells, non‐specific plasmablast activation (leading to polyclonal immunoglobulin production), and a decline in the frequency of long‐lived plasma cells 42, 60, 61, 62, 63. In addition, Env‐specific B cells are found in the activated and exhausted B‐cell subsets in viremic individuals 64. However, the B‐cell dysfunction in HIV‐1 infection does not prevent the generation of bnAbs, and the extent of dysregulation of circulating B‐cell subsets during chronic infection shows no correlation with neutralization breadth 65, 66.…”

Section: Development Of Broadly Neutralizing Antibodies In Hiv‐1 Infementioning

confidence: 99%

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

Borrow

Moody

2017

Immunological Reviews

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SummaryInduction of broadly neutralizing antibodies (bnAbs) capable of inhibiting infection with diverse variants of human immunodeficiency virus type 1 (HIV‐1) is a key, as‐yet‐unachieved goal of prophylactic HIV‐1 vaccine strategies. However, some HIV‐infected individuals develop bnAbs after approximately 2‐4 years of infection, enabling analysis of features of these antibodies and the immunological environment that enables their induction. Distinct subsets of CD4+ T cells play opposing roles in the regulation of humoral responses: T follicular helper (Tfh) cells support germinal center formation and provide help for affinity maturation and the development of memory B cells and plasma cells, while regulatory CD4+ (Treg) cells including T follicular regulatory (Tfr) cells inhibit the germinal center reaction to limit autoantibody production. BnAbs exhibit high somatic mutation frequencies, long third heavy‐chain complementarity determining regions, and/or autoreactivity, suggesting that bnAb generation is likely to be highly dependent on the activity of CD4+ Tfh cells, and may be constrained by host tolerance controls. This review discusses what is known about the immunological environment during HIV‐1 infection, in particular alterations in CD4+ Tfh, Treg, and Tfr populations and autoantibody generation, and how this is related to bnAb development, and considers the implications for HIV‐1 vaccine design.

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“…Heterogeneity has been demonstrated within the origins, development, and functional capacity of human memory B cell populations differentiated by a variety of cell surface markers (12). Recent studies have begun to assess the contributions of B cell subsets during active immune responses using antigen-specific probes (13,14), but the identity and regulation of virus-specific memory B cells during HIV and other viral infections remain poorly understood.…”

Section: Introductionmentioning

confidence: 99%