Timing of HAART defines the integrity of memory B cells and the longevity of humoral responses in HIV-1 vertically-infected children

Pensieroso, Simone; Cagigi, Alberto; Palma, Paolo; Nilsson, Anna; Capponi, Claudia; Freda, Elio; Bernardi, Stefania; Thorstensson, Rigmor; Chiodi, Francesca; Rossi, Paolo

doi:10.1073/pnas.0901702106

Cited by 155 publications

(146 citation statements)

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“…This further points out the impaired recall/maintenance of antigen-specific memory B cells in patients with CGD, which, in the case of measles, should confer serologic memory for the entire lifespan in healthy subjects. 20 A similar scenario occurs in other diseases characterized by chronic immune activation, 16,30,31 in which the capacity to confer durable protection after vaccination is reduced and related to low memory B-cell frequencies. 32,33 Thus a possible explanation for the loss of long-term memory in patients with CGD can be an ineffective polyclonal activation of memory B cells, which usually maintain serologic memory.…”

Section: Discussionmentioning

confidence: 73%

“…ELISpot 96-well filtration plates (MSIPS4510; Millipore, Temecula, Calif) were precoated with either 0.5 mg of anti-IgG (109-006-088; Novakemi, Handen, Sweden) or 2 mg per well of measles antigen and subsequently loaded with 3 3 10 5 cells per well. Plates were then processed, as previously described, 16 and analyzed with an ELISpot reader. The frequency of memory B cells was calculated as related to total PBMCs.…”

Section: Elispot Assaymentioning

confidence: 99%

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Defective B-cell proliferation and maintenance of long-term memory in patients with chronic granulomatous disease

Cotugno

Finocchi

Cagigi

et al. 2015

Journal of Allergy and Clinical Immunology

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Background: Chronic granulomatous disease (CGD) is a primary immune deficiency characterized by a defect in reactive oxygen species production. Although the effect of CGD mainly reflects on the phagocytic compartment, B-cell responses are also impaired in patients with CGD. Objective: We sought to investigate how defective gp91 phox expression in patients with CGD and CGD carriers might affect the B-cell compartment and maintenance of long-term memory. Methods: We studied the B-cell compartment of patients with CGD in terms of phenotype and ability to produce reactive oxygen species and proliferate on stimuli differently directed to the B-cell receptor and Toll-like receptor 9. We further studied their capacity to maintain long-term memory by measuring cellular and serologic responses to measles. Results: We show that the memory B-cell compartment is impaired among patients with CGD, as indicated by reduced total (CD19 1 CD27 1 ) and resting (CD19 1 CD27 1 CD21 1 ) memory B cells in parallel to increased naive (CD19 1 CD27 2 IgD 1 ) B-cell frequencies. Data on CGD carriers reveal that such alterations are related to gp91 phox expression. Moreover, proliferative capabilities of B cells on selective in vitro stimulation of B-cell receptor or Toll-like receptor 9 pathways were reduced in patients with CGD compared with those seen in age-matched healthy control subjects. Significantly lower measles-specific antibody levels and antibody-secreting

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Section: Discussionmentioning

confidence: 73%

Section: Elispot Assaymentioning

confidence: 99%

Defective B-cell proliferation and maintenance of long-term memory in patients with chronic granulomatous disease

Cotugno

Finocchi

Cagigi

et al. 2015

Journal of Allergy and Clinical Immunology

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“…39,43 In HIV infection, both components of humoral immunity become perturbed soon after infection, 9,14,15,17 likely as a result of both aberrant polyclonal activation and deficiencies in mounting an antigen-specific response. Both the percentage and absolute numbers of unswitched (IgM ϩ ) and/or IgG ϩ switched memory B cells are decreased in the peripheral blood of HIV-infected individuals and this deficiency is not readily corrected by the initiation of ART in chronically infected individuals.…”

Section: Discussionmentioning

confidence: 99%

“…The few reports that have been published on early HIV infection have revealed a more complex picture, with most studies reporting that percentages of memory B cells before the initiation of ART are not decreased compared with those of healthy individuals whereas memory B-cell function is decreased. 9,14,35 Several factors may account for the apparent contradictions between phenotype and function of B cells, including high variability in the percentage and phenotype of memory B cells among healthy donors. In this regard, several subpopulations of B cells express CD27, especially in HIV-viremic individuals, which can lead to conflicting results.…”

Section: Discussionmentioning

confidence: 99%

“…[8][9][10][11][12][13] Most of these studies, whether longitudinal or cross-sectional, have been conducted on chronically HIV-infected individuals, whereas only a few studies, generally with small sample sizes, have addressed the effect of duration of infection and initiation of antiretroviral therapy (ART) on perturbations of B-cell subpopulations in HIVinfected individuals. 9,14,15 Functional perturbations of B cells in HIV-infected individuals include hypergammaglobulinemia associated with polyclonal and HIV-specific activation of B cells induced by ongoing HIV replication, 15,16 as well as decreased B-cell responses to specific immunogens and non-HIV pathogens. 11,17,18 The latter is likely a reflection of both CD4 ϩ T-cell dependent and independent defects in B cells that arise in HIV-infected individuals, and especially in individuals with ongoing viral replication.…”

Section: Introductionmentioning

confidence: 99%

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B cells in early and chronic HIV infection: evidence for preservation of immune function associated with early initiation of antiretroviral therapy

Moir

Buckner

et al. 2010

Blood

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IntroductionNumerous perturbations of B-cell phenotype and function have been described in HIV-infected individuals (reviewed in Cagigi et al 1 and Moir and Fauci 2 ). Phenotypic perturbations of B cells circulating in the peripheral blood include over-representation of activated, exhausted, and terminally differentiated B cells associated with HIV viremia 3-5 ; over-representation of immature/ transitional B cells associated with HIV-induced CD4 ϩ T-cell lymphopenia 6,7 ; and reduced representation of CD27 ϩ memory B cells associated with most stages of HIV infection. [8][9][10][11][12][13] Most of these studies, whether longitudinal or cross-sectional, have been conducted on chronically HIV-infected individuals, whereas only a few studies, generally with small sample sizes, have addressed the effect of duration of infection and initiation of antiretroviral therapy (ART) on perturbations of B-cell subpopulations in HIVinfected individuals. 9,14,15 Functional perturbations of B cells in HIV-infected individuals include hypergammaglobulinemia associated with polyclonal and HIV-specific activation of B cells induced by ongoing HIV replication, 15,16 as well as decreased B-cell responses to specific immunogens and non-HIV pathogens. 11,17,18 The latter is likely a reflection of both CD4 ϩ T-cell dependent and independent defects in B cells that arise in HIV-infected individuals, and especially in individuals with ongoing viral replication. Many of the functional B-cell defects described in HIV-viremic individuals can be improved with ART, although there is 1 important exception that has received relatively little attention. While B-cell responses against non-HIV antigens are either stabilized or increased after initiation of ART, 19-22 the reverse is often observed for B-cell responses against HIV antigens,15,23,24 suggesting that the humoral response against HIV is dependent on continuous HIV replication. In the most comprehensive study on B-cell responses after ART, Morris and colleagues described a rapid loss of HIV-specific B cells (actively secreting plasmablasts) during therapy, followed by a more gradual decrease in antibody titers against HIV in chronically infected individuals; the loss was even more rapid in early-treated individuals. 15 In a previous study of chronically HIV-infected individuals, we reported a reduction in B-cell numbers and the presence of perturbed B-cell subpopulations before initiation of ART followed by partial normalization 1 year after successful reduction in viremia by ART. 25 In a more recent study, 5 we identified a subpopulation of CD27 Ϫ tissue-like memory B cells within an abnormal CD21 lo B-cell compartment of the peripheral blood of chronically HIVviremic individuals; this subpopulation had been included within the activated B-cell compartment that we had previously described. 25 These CD27 Ϫ tissue-like memory B cells bore many features of exhausted cells, arising in the context of chronic immune activation, and with features that include expression of multiple inhibitory...

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Early ART initiation during infancy preserves natural killer cells in young European adolescents living with HIV (CARMA cohort)

et al. 2021

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Introduction: HIV infection causes pathological changes in the natural killer (NK) cell compartment that can be only partially restored by antiretroviral therapy (ART). We investigated NK cells phenotype and function in children with perinatally acquired HIV (PHIV) and long-term viral control (five years) due to effective ART in a multicentre cross-sectional European study (CARMA, EPIICAL consortium). The impact of age at ART start and viral reservoir was also evaluated. Methods: Peripheral blood mononuclear cells (PBMCs) from 40 PHIV who started ART within two years of life (early treated patients (ET), ≤6 months; late treated patients (LT), > 6 months), with at least five years of HIV-1 suppression (<40 HIV copies/mL), were collected between November 2017 and August 2018. NK phenotype and function were analysed by flow cytometry and transcriptional profile of PBMCs by RNA-Seq. HIV-1 DNA was measured by real-time polymerase chain reaction (Data were analysed by Spearman correlation plots and multivariable Poisson regression model (adjusted for baseline % CD4 and RNA HIV viral load and for age at ART start as an interaction term, either ET or LT) to explore the association between NK cell parameters and HIV reservoir modulated by age at ART start. Results: A significantly higher frequency of CD56 neg NK cells was found in LT compared with ET. We further found in LT a positive correlation of CD56 neg NK cells with HIV-1 DNA. LT also displayed increased expression of the NKG2D and NKp46 activating receptors and perforin compared with ET. Moreover, CD107a + and IFN-c + frequencies in non-stimulated NK were associated with HIV-1 DNA in LT patients. Finally, RNA-Seq analysis showed in LT an up-regulation of genes related to NKactivating pathways and susceptibility to apoptosis compared with ET. Conclusions: We show that early initiation of ART during infancy preserves the NK compartment and is associated with lower HIV-1 reservoir. Such condition persists over adolescence due to long-term viral control achieved through effective ART.

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Timing of HAART defines the integrity of memory B cells and the longevity of humoral responses in HIV-1 vertically-infected children

Cited by 155 publications

References 42 publications

Defective B-cell proliferation and maintenance of long-term memory in patients with chronic granulomatous disease

Defective B-cell proliferation and maintenance of long-term memory in patients with chronic granulomatous disease

B cells in early and chronic HIV infection: evidence for preservation of immune function associated with early initiation of antiretroviral therapy

Early ART initiation during infancy preserves natural killer cells in young European adolescents living with HIV (CARMA cohort)

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