Suppression of viral replication with highly active antiretroviral therapy has no impact on the functional profile of HIV‐specific CD8<sup>+</sup> T cells

López, Mariola; Soriano, Vincent; Rallón, Norma; Cascajero, Almudena; González-Lahoz, Juan; Benito, José M.

doi:10.1002/eji.200738054

Cited by 13 publications

(17 citation statements)

References 30 publications

(29 reference statements)

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“…Our data reveal that ART is associated with a reduced total response magnitude in both blood and mucosa, as expected based on previous studies, but the complexity of the response is affected differentially in the two tissues (Fig 5A & B). In blood, the response complexity was not different relative to ART status, an observation which is consistent with a recent report [39]. In contrast, the drastic reduction in rectal response complexity associated with ART is a unique observation and suggests that ART exerts more complex effects on mucosal CTL functionality.…”

Section: Discussionsupporting

confidence: 89%

Magnitude and Complexity of Rectal Mucosa HIV-1-Specific CD8+ T-Cell Responses during Chronic Infection Reflect Clinical Status

et al. 2008

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BackgroundThe intestinal mucosa displays robust virus replication and pronounced CD4+ T-cell loss during acute human immunodeficiency virus type 1 (HIV-1) infection. The ability of HIV-specific CD8+ T-cells to modulate disease course has prompted intensive study, yet the significance of virus-specific CD8+ T-cells in mucosal sites remains unclear.Methods and FindingsWe evaluated five distinct effector functions of HIVgag-specific CD8+ T-cells in rectal mucosa and blood, individually and in combination, in relationship to clinical status and antiretroviral therapy (ART). In subjects not on ART, the percentage of rectal Gag-specific CD8+ T-cells capable of 3, 4 or 5 simultaneous effector functions was significantly related to blood CD4 count and inversely related to plasma viral load (PVL) (p<0.05). Polyfunctional rectal CD8+ T-cells expressed higher levels of MIP-1β and CD107a on a per cell basis than mono- or bifunctional cells. The production of TNFα, IFN-γ, and CD107a by Gag-specific rectal CD8+ T-cells each correlated inversely (p<0.05) with PVL, and MIP-1β expression revealed a similar trend. CD107a and IFN-γ production were positively related to blood CD4 count (p<0.05), with MIP-1β showing a similar trend. IL-2 production by rectal CD8+ T-cells was highly variable and generally low, and showed no relationship to viral load or blood CD4 count.ConclusionsThe polyfunctionality of rectal Gag-specific CD8+ T-cells appears to be related to blood CD4 count and inversely related to PVL. The extent to which these associations reflect causality remains to be determined; nevertheless, our data suggest a potentially important role for mucosal T-cells in limiting virus replication during chronic infection.

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Section: Discussionsupporting

confidence: 89%

Magnitude and Complexity of Rectal Mucosa HIV-1-Specific CD8+ T-Cell Responses during Chronic Infection Reflect Clinical Status

et al. 2008

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“…The same was observed when the relative contribution of T cell populations with different numbers of effecter functions to the total HIV-specific CD8 T cell responses was compared between arms and over time (Fig. 4D),in line with previous reports [26], [28].…”

Section: Resultssupporting

confidence: 91%

Effect of Maraviroc Intensification on HIV-1-Specific T Cell Immunity in Recently HIV-1-Infected Individuals

Kawana-Tachikawa

Llibre²,

Bravo³

et al. 2014

PLoS ONE

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BackgroundThe effect of maraviroc on the maintenance and the function of HIV-1-specific T cell responses remains unknown.MethodsSubjects recently infected with HIV-1 were randomized to receive anti-retroviral treatment with or without maraviroc intensification for 48 weeks, and were monitored up to week 60. PBMC and in vitro-expanded T cells were tested for responses to the entire HIV proteome by ELISpot analyses. Intracellular cytokine staining assays were conducted to monitor the (poly)-functionality of HIV-1-specific T cells. Analyses were performed at baseline and week 24 after treatment start, and at week 60 (3 months after maraviroc discontinuation).ResultsMaraviroc intensification was associated with a slower decay of virus-specific T cell responses over time compared to the non-intensified regimen in both direct ex-vivo as well as in in-vitro expanded cells. The effector function profiles of virus-specific CD8+ T cells were indistinguishable between the two arms and did not change over time between the groups.ConclusionsMaraviroc did not negatively impact any of the measured parameters, but was rather associated with a prolonged maintenance of HIV-1-specific T cell responses. Maraviroc, in addition to its original effect as viral entry inhibitor, may provide an additional benefit on the maintenance of virus-specific T cells which may be especially important for future viral eradication strategies.

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“…However, cytotoxic effector capacity remains low even after years of successful antiretroviral therapy. The failure to recover cytolytic effector function in CD8 T cells [3], [32], [33], [34], [35] is a critical defect that partly explains the inability to eliminate the reservoir of infected cells. If we can learn to reconstitute cytotoxic effector function, we may come closer to replicating the elite controller status for a greater proportion of patients with HIV disease.…”

Section: Discussionmentioning

confidence: 99%

Levels of CD56+TIM-3- Effector CD8 T Cells Distinguish HIV Natural Virus Suppressors from Patients Receiving Antiretroviral Therapy

Poonia

Pauza

2014

PLoS ONE

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Prolonged antiretroviral therapy (ART) with effective HIV suppression and reconstitution of CD4 T cells, fails to restore CD8 T cell lytic effector function that is needed to eradicate the viral reservoir. Better understanding of the phenotype and function of circulating CD8 cells in HIV patients will contribute to new targeted therapies directed at increasing CD8 T cell lytic effector function and destruction of the viral reservoir. We show that CD8 T cells from ART treated patients had sharply reduced expression of CD56 (neural cell adhesion molecule-1), a marker associated with cytolytic function whereas elite patients who control HIV in the absence of ART had CD56+ CD8 T cell levels similar to uninfected controls. The CD56+ CD8 T cells had higher perforin upregulation as well as degranulation following stimulation with HIV gag peptides compared with CD56 negative CD8 T cells. Elite patients had the highest frequencies of perforin producing CD56+ CD8 T cells among all HIV+ groups. In patients receiving ART we noted high levels of the exhaustion marker TIM-3 on CD56+ CD8 T cells, implying that defective effector function was related to immune exhaustion. CD56+ CD8 T cells from elite or treated HIV patients responded to PMA plus ionomycin stimulation, and expressed transcription factors T-bet and EOMES at levels similar to uninfected controls. Consequently, the lytic effector defect in chronic HIV disease is due to immune exhaustion and quantitative loss of CD56+ CD8 T cells and this defect is not repaired in patients where viremia is suppressed and CD4 T cells are recovered after ART.Reconstituting the cytotoxic CD56+ subset of CD8+ T cells through new interventions might improve the lytic effector capacity and contribute to reducing the viral reservoir. Our initial studies indicate that IL-15 treatment partly reverses the CD56 defect, implying that myeloid cell defects could be targeted for immune therapy during chronic HIV disease.

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Suppression of viral replication with highly active antiretroviral therapy has no impact on the functional profile of HIV‐specific CD8⁺ T cells

Cited by 13 publications

References 30 publications

Magnitude and Complexity of Rectal Mucosa HIV-1-Specific CD8+ T-Cell Responses during Chronic Infection Reflect Clinical Status

Magnitude and Complexity of Rectal Mucosa HIV-1-Specific CD8+ T-Cell Responses during Chronic Infection Reflect Clinical Status

Effect of Maraviroc Intensification on HIV-1-Specific T Cell Immunity in Recently HIV-1-Infected Individuals

Levels of CD56+TIM-3- Effector CD8 T Cells Distinguish HIV Natural Virus Suppressors from Patients Receiving Antiretroviral Therapy

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Suppression of viral replication with highly active antiretroviral therapy has no impact on the functional profile of HIV‐specific CD8+ T cells

Cited by 13 publications

References 30 publications

Magnitude and Complexity of Rectal Mucosa HIV-1-Specific CD8+ T-Cell Responses during Chronic Infection Reflect Clinical Status

Magnitude and Complexity of Rectal Mucosa HIV-1-Specific CD8+ T-Cell Responses during Chronic Infection Reflect Clinical Status

Effect of Maraviroc Intensification on HIV-1-Specific T Cell Immunity in Recently HIV-1-Infected Individuals

Levels of CD56+TIM-3- Effector CD8 T Cells Distinguish HIV Natural Virus Suppressors from Patients Receiving Antiretroviral Therapy

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Suppression of viral replication with highly active antiretroviral therapy has no impact on the functional profile of HIV‐specific CD8⁺ T cells