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HIV-1 viremia prevents the establishment of interleukin 2-producing HIV-specific memory CD4+ T cells endowed with proliferative capacity.

Younes SA, Yassine-Diab B, Dumont AR, Boulassel MR, Grossman Z, Routy JP, Sekaly RP - J. Exp. Med. (2003)

Bottom Line: Two subsets of HIV-specific memory CD4+ T cells were identified in aviremic patients, CD45RA- CCR7+ central memory cells (Tcm) producing exclusively interleukin (IL)-2, and CD45RA- CCR7- effector memory cells (Tem) that produced both IL-2 and interferon (IFN)-gamma.In contrast, in viremic, therapy-failing patients, we found significant frequencies of Tem that unexpectedly produced exclusively IFN-gamma.Our data favor a model whereby competent HIV-specific Tcm continuously arise in small numbers but under persistent antigenemia are rapidly induced to differentiate into IFN-gamma only-producing cells that lack self-renewal capacity.

View Article: PubMed Central - PubMed

Affiliation: Département de Microbiologie et Immunologie, Université de Montréal, 2900 Edouard-Montpetit Boulevard, Montréal H3T 1J4, Canada.

ABSTRACT
CD4+ T cell responses are associated with disease control in chronic viral infections. We analyzed human immunodeficiency virus (HIV)-specific responses in ten aviremic and eight viremic patients treated during primary HIV-1 infection and for up to 6 yr thereafter. Using a highly sensitive 5-(and-6)-carboxyfluorescein diacetate-succinimidyl ester-based proliferation assay, we observed that proliferative Gag and Nef peptide-specific CD4+ T cell responses were 30-fold higher in the aviremic patients. Two subsets of HIV-specific memory CD4+ T cells were identified in aviremic patients, CD45RA- CCR7+ central memory cells (Tcm) producing exclusively interleukin (IL)-2, and CD45RA- CCR7- effector memory cells (Tem) that produced both IL-2 and interferon (IFN)-gamma. In contrast, in viremic, therapy-failing patients, we found significant frequencies of Tem that unexpectedly produced exclusively IFN-gamma. Longitudinal analysis of HIV epitope-specific CD4+ T cells revealed that only cells that had the capacity to produce IL-2 persisted as long-term memory cells. In viremic patients the presence of IFN-gamma-producing cells was restricted to periods of elevated viremia. These findings suggest that long-term CD4+ T cell memory depends on IL-2-producing CD4+ T cells and that IFN-gamma only-producing cells are short lived. Our data favor a model whereby competent HIV-specific Tcm continuously arise in small numbers but under persistent antigenemia are rapidly induced to differentiate into IFN-gamma only-producing cells that lack self-renewal capacity.

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Alternative differentiation schemes describing the impact of HIV viremia on the size of memory/effector CD4+ T cell pools. (a) According to an extension of a general differentiation scheme proposed for CD8 T cells by Kaech et al. (reference 46), HIV-specific central memory CD4+ T cells (Tcm) are derived in aviremic patients from effectors (Tem1) elicited during the acute phase of the infection. Transient activation episodes and IL-2 production–dependent self-renewal would facilitate maintenance of a stable steady state of this memory pool, in equilibrium with the Tem1 pool, after viremia has been controlled. When viremia persists, naive CD4+ T cells are constantly recruited and differentiate into effectors (Tem1). Constant antigenic stimulation prevents the differentiation of these effectors into Tcm. Instead, they differentiate into more differentiated cells, Tem2, which lack the capacity to produce IL-2 and to self-renew, but are able to produce IFN-γ. (b) Alternatively, the order of differentiation is always from naive to Tcm to Tem, as proposed by Lanzavecchia and Sallusto (reference 45). In aviremic patients, Tcm and Tem1 are maintained, as in the other model, by self-renewal and occasional activation and differentiation events (limited ongoing division counters the slow rate of death in the population). In the viremic patients, activation of HIV-specific naive and resting memory cells is enhanced, but according to the “balance of growth and differentiation” model (see Discussion), accumulation of Tcm and Tem1 memory cells through self-renewal division is prohibited because these proliferating cells are preferentially induced to differentiate into the IFN-γ only–producing Tem2 cells. The relative rates of self-renewal and differentiation are crudely reflected in the figure by the thickness of the arrows representing cellular flow. The relative size of the different pools is indicated by the size of the circles representing these pools.
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fig6: Alternative differentiation schemes describing the impact of HIV viremia on the size of memory/effector CD4+ T cell pools. (a) According to an extension of a general differentiation scheme proposed for CD8 T cells by Kaech et al. (reference 46), HIV-specific central memory CD4+ T cells (Tcm) are derived in aviremic patients from effectors (Tem1) elicited during the acute phase of the infection. Transient activation episodes and IL-2 production–dependent self-renewal would facilitate maintenance of a stable steady state of this memory pool, in equilibrium with the Tem1 pool, after viremia has been controlled. When viremia persists, naive CD4+ T cells are constantly recruited and differentiate into effectors (Tem1). Constant antigenic stimulation prevents the differentiation of these effectors into Tcm. Instead, they differentiate into more differentiated cells, Tem2, which lack the capacity to produce IL-2 and to self-renew, but are able to produce IFN-γ. (b) Alternatively, the order of differentiation is always from naive to Tcm to Tem, as proposed by Lanzavecchia and Sallusto (reference 45). In aviremic patients, Tcm and Tem1 are maintained, as in the other model, by self-renewal and occasional activation and differentiation events (limited ongoing division counters the slow rate of death in the population). In the viremic patients, activation of HIV-specific naive and resting memory cells is enhanced, but according to the “balance of growth and differentiation” model (see Discussion), accumulation of Tcm and Tem1 memory cells through self-renewal division is prohibited because these proliferating cells are preferentially induced to differentiate into the IFN-γ only–producing Tem2 cells. The relative rates of self-renewal and differentiation are crudely reflected in the figure by the thickness of the arrows representing cellular flow. The relative size of the different pools is indicated by the size of the circles representing these pools.

Mentions: A major finding of our study is that HIV-specific CD4+ T cells having a central memory phenotype (CD45RA− CCR7+) and secreting IL-2 are found in aviremic but not viremic patients. A current model of memory T cell differentiation predicts that persistent antigenic stimulation prevents the establishment of a stable pool of functional long-term memory cells (46). The proposed mechanism was blocking, by persistent antigenic stimulation, of the differentiation of effectors into long-lived memory cells of the Tcm phenotype (46). An interpretation of our results according to this model is illustrated in Fig. 6 a. Alternatively, the “balance of growth and differentiation” model (47) would suggest that activation of HIV-specific naive cells, or of a small number of competent memory cells that are sustained by self-renewal, frequently occurs, but that HIV antigenemia in the therapy-failing patients rapidly induces differentiation of the activated cells into short-lived effector cells (Fig. 6 b) after a burst of proliferation (48). It is even possible that significant numbers of IL-2–producing memory cells (Tcm and Tem) exist in viremic patients but are rendered unresponsive through chronic stimulation-mediated tuning of activation thresholds (48). According to the results of our longitudinal study (Fig. 5), only viral loads that exceed a certain threshold might break this unresponsiveness, inducing proliferation/differentiation bursts that end up in IFN-γ only–producing cells. Similarly, some of the IFN-γ only–producing cells may regain capacity for IL-2 production after the viral load is sufficiently reduced.


HIV-1 viremia prevents the establishment of interleukin 2-producing HIV-specific memory CD4+ T cells endowed with proliferative capacity.

Younes SA, Yassine-Diab B, Dumont AR, Boulassel MR, Grossman Z, Routy JP, Sekaly RP - J. Exp. Med. (2003)

Alternative differentiation schemes describing the impact of HIV viremia on the size of memory/effector CD4+ T cell pools. (a) According to an extension of a general differentiation scheme proposed for CD8 T cells by Kaech et al. (reference 46), HIV-specific central memory CD4+ T cells (Tcm) are derived in aviremic patients from effectors (Tem1) elicited during the acute phase of the infection. Transient activation episodes and IL-2 production–dependent self-renewal would facilitate maintenance of a stable steady state of this memory pool, in equilibrium with the Tem1 pool, after viremia has been controlled. When viremia persists, naive CD4+ T cells are constantly recruited and differentiate into effectors (Tem1). Constant antigenic stimulation prevents the differentiation of these effectors into Tcm. Instead, they differentiate into more differentiated cells, Tem2, which lack the capacity to produce IL-2 and to self-renew, but are able to produce IFN-γ. (b) Alternatively, the order of differentiation is always from naive to Tcm to Tem, as proposed by Lanzavecchia and Sallusto (reference 45). In aviremic patients, Tcm and Tem1 are maintained, as in the other model, by self-renewal and occasional activation and differentiation events (limited ongoing division counters the slow rate of death in the population). In the viremic patients, activation of HIV-specific naive and resting memory cells is enhanced, but according to the “balance of growth and differentiation” model (see Discussion), accumulation of Tcm and Tem1 memory cells through self-renewal division is prohibited because these proliferating cells are preferentially induced to differentiate into the IFN-γ only–producing Tem2 cells. The relative rates of self-renewal and differentiation are crudely reflected in the figure by the thickness of the arrows representing cellular flow. The relative size of the different pools is indicated by the size of the circles representing these pools.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2194146&req=5

fig6: Alternative differentiation schemes describing the impact of HIV viremia on the size of memory/effector CD4+ T cell pools. (a) According to an extension of a general differentiation scheme proposed for CD8 T cells by Kaech et al. (reference 46), HIV-specific central memory CD4+ T cells (Tcm) are derived in aviremic patients from effectors (Tem1) elicited during the acute phase of the infection. Transient activation episodes and IL-2 production–dependent self-renewal would facilitate maintenance of a stable steady state of this memory pool, in equilibrium with the Tem1 pool, after viremia has been controlled. When viremia persists, naive CD4+ T cells are constantly recruited and differentiate into effectors (Tem1). Constant antigenic stimulation prevents the differentiation of these effectors into Tcm. Instead, they differentiate into more differentiated cells, Tem2, which lack the capacity to produce IL-2 and to self-renew, but are able to produce IFN-γ. (b) Alternatively, the order of differentiation is always from naive to Tcm to Tem, as proposed by Lanzavecchia and Sallusto (reference 45). In aviremic patients, Tcm and Tem1 are maintained, as in the other model, by self-renewal and occasional activation and differentiation events (limited ongoing division counters the slow rate of death in the population). In the viremic patients, activation of HIV-specific naive and resting memory cells is enhanced, but according to the “balance of growth and differentiation” model (see Discussion), accumulation of Tcm and Tem1 memory cells through self-renewal division is prohibited because these proliferating cells are preferentially induced to differentiate into the IFN-γ only–producing Tem2 cells. The relative rates of self-renewal and differentiation are crudely reflected in the figure by the thickness of the arrows representing cellular flow. The relative size of the different pools is indicated by the size of the circles representing these pools.
Mentions: A major finding of our study is that HIV-specific CD4+ T cells having a central memory phenotype (CD45RA− CCR7+) and secreting IL-2 are found in aviremic but not viremic patients. A current model of memory T cell differentiation predicts that persistent antigenic stimulation prevents the establishment of a stable pool of functional long-term memory cells (46). The proposed mechanism was blocking, by persistent antigenic stimulation, of the differentiation of effectors into long-lived memory cells of the Tcm phenotype (46). An interpretation of our results according to this model is illustrated in Fig. 6 a. Alternatively, the “balance of growth and differentiation” model (47) would suggest that activation of HIV-specific naive cells, or of a small number of competent memory cells that are sustained by self-renewal, frequently occurs, but that HIV antigenemia in the therapy-failing patients rapidly induces differentiation of the activated cells into short-lived effector cells (Fig. 6 b) after a burst of proliferation (48). It is even possible that significant numbers of IL-2–producing memory cells (Tcm and Tem) exist in viremic patients but are rendered unresponsive through chronic stimulation-mediated tuning of activation thresholds (48). According to the results of our longitudinal study (Fig. 5), only viral loads that exceed a certain threshold might break this unresponsiveness, inducing proliferation/differentiation bursts that end up in IFN-γ only–producing cells. Similarly, some of the IFN-γ only–producing cells may regain capacity for IL-2 production after the viral load is sufficiently reduced.

Bottom Line: Two subsets of HIV-specific memory CD4+ T cells were identified in aviremic patients, CD45RA- CCR7+ central memory cells (Tcm) producing exclusively interleukin (IL)-2, and CD45RA- CCR7- effector memory cells (Tem) that produced both IL-2 and interferon (IFN)-gamma.In contrast, in viremic, therapy-failing patients, we found significant frequencies of Tem that unexpectedly produced exclusively IFN-gamma.Our data favor a model whereby competent HIV-specific Tcm continuously arise in small numbers but under persistent antigenemia are rapidly induced to differentiate into IFN-gamma only-producing cells that lack self-renewal capacity.

View Article: PubMed Central - PubMed

Affiliation: Département de Microbiologie et Immunologie, Université de Montréal, 2900 Edouard-Montpetit Boulevard, Montréal H3T 1J4, Canada.

ABSTRACT
CD4+ T cell responses are associated with disease control in chronic viral infections. We analyzed human immunodeficiency virus (HIV)-specific responses in ten aviremic and eight viremic patients treated during primary HIV-1 infection and for up to 6 yr thereafter. Using a highly sensitive 5-(and-6)-carboxyfluorescein diacetate-succinimidyl ester-based proliferation assay, we observed that proliferative Gag and Nef peptide-specific CD4+ T cell responses were 30-fold higher in the aviremic patients. Two subsets of HIV-specific memory CD4+ T cells were identified in aviremic patients, CD45RA- CCR7+ central memory cells (Tcm) producing exclusively interleukin (IL)-2, and CD45RA- CCR7- effector memory cells (Tem) that produced both IL-2 and interferon (IFN)-gamma. In contrast, in viremic, therapy-failing patients, we found significant frequencies of Tem that unexpectedly produced exclusively IFN-gamma. Longitudinal analysis of HIV epitope-specific CD4+ T cells revealed that only cells that had the capacity to produce IL-2 persisted as long-term memory cells. In viremic patients the presence of IFN-gamma-producing cells was restricted to periods of elevated viremia. These findings suggest that long-term CD4+ T cell memory depends on IL-2-producing CD4+ T cells and that IFN-gamma only-producing cells are short lived. Our data favor a model whereby competent HIV-specific Tcm continuously arise in small numbers but under persistent antigenemia are rapidly induced to differentiate into IFN-gamma only-producing cells that lack self-renewal capacity.

Show MeSH
Related in: MedlinePlus