Impaired Phenotype and Function of T Follicular Helper Cells in HIV-1-Infected Children Receiving ART

Bekele, Yonas; Amu, Sylvie; Bobosha, Kidist; Lantto, Rebecka; Nilsson, Anna; Endale, Birtukan; Gebre, Meseret; Aseffa, Abraham; Réthi, Bence; Howe, Rawleigh; Chiodi, Francesca

doi:10.1097/md.0000000000001125

Cited by 12 publications

(26 citation statements)

References 33 publications

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“…Previous reports have shown a similar link between frequencies of circulating memory T FH cells and the quality of B-cell responses [17–19, 27]. T FH cells in lymphoid tissues are important for the formation of germinal centers, the histological sites where long-lived plasma cells and memory B cells are generated during immune reactions.…”

Section: Discussionmentioning

confidence: 64%

“…Similar to the previous reports, when compared with community controls, both high viremia and low viremia groups had lower proportions of total resting memory B cells (P<0.01 in both cases), IgD + (Unswitched) resting memory B cells (P<0.01 and P = 0.01, respectively) and IgD - (switched) resting memory B cells (P<0.01 and P = 0.01, respectively) (Fig 3A–3C) [9, 11, 13, 14, 27]. …”

Section: Resultsmentioning

confidence: 99%

“…The recent identification of memory circulating counterparts of T FH cells in blood has enabled studies that evaluate how HIV-induced defects on the T FH compartment affect B-cell responses [17–19, 27]. …”

Section: Discussionmentioning

confidence: 99%

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Proportions of circulating follicular helper T cells are reduced and correlate with memory B cells in HIV-infected children

et al. 2017

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IntroductionHIV causes defects in memory B cells in children, but the mechanisms of those defects have not been fully elucidated. One possible mechanism is the lack of T-cell help to B cells during immune reactions. However, few studies have assessed the effect of HIV on follicular helper T cells (TFH cells) in children.MethodsIn this study, follicular-homing CD4 T cells and memory B cells were assessed in HIV-infected children and compared with children from the community. CXCR5 and CD45RO were used as markers of follicular-homing T cells and memory T cells, respectively. Memory TFH cells were identified as CD3+CD8-CD4+CXCR5+CD45RO+PD1+. Central memory T cells were identified based on CCR7 expression. Relationship between the proportions of follicular-homing CD4 T cells and memory B cells were determined in multivariable regression models.ResultsHighly viremic HIV-infected children had lower proportions of memory TFH cells when compared with community control children. In multivariable analyses, high proportions of memory TFH cells were associated with increased percentages of resting memory B cells after adjusting for other covariates.ConclusionThe impact of HIV on follicular helper T cells could influence the accumulation of memory B cells in HIV-infected children.

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Section: Discussionmentioning

confidence: 64%

Section: Resultsmentioning

confidence: 99%

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Proportions of circulating follicular helper T cells are reduced and correlate with memory B cells in HIV-infected children

et al. 2017

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“…192,193,195 Human T FH cells express an RNA expression profile distinct from T H 1, T H 2, and T H 17 cells, 190,196 and this profile can be markedly altered by HIV/SIV infection. [197][198][199] This CD4 + T-cell subset serves as a major reservoir for HIV.…”

Section: Follicular Helper T Cells (T Fh )mentioning

confidence: 99%

Differentiating Immune Cell Targets in Gut-Associated Lymphoid Tissue for HIV Cure

Khan

Telwatte

Trapečar

et al. 2017

AIDS Research and Human Retroviruses

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The single greatest challenge to an HIV cure is the persistence of latently infected cells containing inducible, replication-competent proviral genomes, which constitute only a small fraction of total or infected cells in the body. Although resting CD4 T cells in the blood are a well-known source of viral rebound, more than 90% of the body's lymphocytes reside elsewhere. Many are in gut tissue, where HIV DNA levels per million CD4 T cells are considerably higher than in the blood. Despite the significant contribution of gut tissue to viral replication and persistence, little is known about the cell types that support persistence of HIV in the gut; importantly, T cells in the gut have phenotypic, functional, and survival properties that are distinct from T cells in other tissues. The mechanisms by which latency is established and maintained will likely depend on the location and cytokine milieu surrounding the latently infected cells in each compartment. Therefore, successful HIV cure strategies require identification and characterization of the exact cell types that support viral persistence, particularly in the gut. In this review, we describe the seeding of the latent HIV reservoir in the gut mucosa; highlight the evidence for compartmentalization and depletion of T cells; summarize the immunologic consequences of HIV infection within the gut milieu; propose how the damaged gut environment may promote the latent HIV reservoir; and explore several immune cell targets in the gut and their place on the path toward HIV cure.

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“…T FH frequency correlated strongly with bnAb development, thus indicating that T FH are important for generating bnAb. In HIV-infected children receiving ART, circulating memory T FH declined, expressed low levels of ICOS, and had a diminished capacity to produce IL-4 (75). Thus, impairments of T FH function can persist in the absence of viremia.…”

Section: Impact Of Altered Tfh Function On Anti-hiv Antibody Responsementioning

confidence: 99%

CD4 T Follicular Helper and Regulatory Cell Dynamics and Function in HIV Infection

2016

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T follicular helper cells (TFH) are a specialized subset of CD4 T cells that reside in B cell follicles and promote B cell maturation into plasma cells and long-lived memory B cells. During chronic infection prior to the development of AIDS, HIV-1 (HIV) replication is largely concentrated in TFH. Paradoxically, TFH numbers are increased in early and midstages of disease, thereby promoting HIV replication and disease progression. Despite increased TFH numbers, numerous defects in humoral immunity are detected in HIV-infected individuals, including dysregulation of B cell maturation, impaired somatic hypermutation, and low quality of antibody production despite hypergammaglobulinemia. Clinically, these defects are manifested by increased vulnerability to bacterial infections and impaired vaccine responses, neither of which is fully reversed by antiretroviral therapy (ART). Deficits in TFH function, including reduced HIV-specific IL-21 production and low levels of co-stimulatory receptor expression, have been linked to these immune impairments. Impairments in TFH likely contribute as well to the ability of HIV to persist and evade humoral immunity, particularly the inability to develop broadly neutralizing antibodies. In addition to direct infection of TFH, other mechanisms that have been linked to TFH deficits in HIV infection include upregulation of PD-L1 on germinal center B cells and augmented follicular regulatory T cell responses. Challenges to development of strategies to enhance TFH function in HIV infection include lack of an established phenotype for memory TFH as well as limited understanding of the relationship between peripheral TFH and lymphoid tissue TFH. Interventions to augment TFH function in HIV-infected individuals could enhance immune reconstitution during ART and potentially augment cure strategies.

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Impaired Phenotype and Function of T Follicular Helper Cells in HIV-1-Infected Children Receiving ART

Abstract: Supplemental digital content is available in the text

Cited by 12 publications

References 33 publications

Proportions of circulating follicular helper T cells are reduced and correlate with memory B cells in HIV-infected children

Proportions of circulating follicular helper T cells are reduced and correlate with memory B cells in HIV-infected children

Differentiating Immune Cell Targets in Gut-Associated Lymphoid Tissue for HIV Cure

CD4 T Follicular Helper and Regulatory Cell Dynamics and Function in HIV Infection

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