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Initiation of Antiretroviral Therapy (ART) at Different Stages of HIV-1 Disease Is Not Associated with the Proportion of Exhausted CD8+ T Cells.

Jensen SS, Fomsgaard A, Larsen TK, Tingstedt JL, Gerstoft J, Kronborg G, Pedersen C, Karlsson I - PLoS ONE (2015)

Bottom Line: Early initiation of antiretroviral treatment (ART) and the duration of ART have been associated with immune reconstitution.The frequency of CD8+ T cells expressing the inhibitory markers PD-1, 2B4 and CD160 was lower in ART-treated individuals compared with ART-naïve individuals and similar to the frequency in HIV-uninfected controls.The expression of the three markers was similarly independent of when therapy was initiated.

View Article: PubMed Central - PubMed

Affiliation: Virus Research & Development Laboratory, Department of Microbial Diagnostic and Virology, Statens Serum Institut, Copenhagen, Denmark; Department of Infectious Diseases, Odense University Hospital, Odense, Denmark; Infectious Disease Research Unit, Clinical Institute, University of Southern Denmark, Odense, Denmark.

ABSTRACT
CD8+ T cell-restricted immunity is important in the control of HIV-1 infection, but continued immune activation results in CD8+ T cell dysfunction. Early initiation of antiretroviral treatment (ART) and the duration of ART have been associated with immune reconstitution. Here, we evaluated whether restoration of CD8+ T cell function in HIV-1-infected individuals was dependent on early initiation of ART. HIV-specific CD107a, IFNγ, IL-2, TNFα and MIP-1β expression by CD8+ T cells and the frequency of CD8+ T cells expressing PD-1, 2B4 and CD160 were measured by flow cytometry. The frequency of CD8+ T cells expressing the inhibitory markers PD-1, 2B4 and CD160 was lower in ART-treated individuals compared with ART-naïve individuals and similar to the frequency in HIV-uninfected controls. The expression of the three markers was similarly independent of when therapy was initiated. Individuals treated before seroconversion displayed an HIV-specific CD8+ T cell response that included all five functional markers; this was not observed in individuals treated after seroconversion or in ART-naïve individuals. In summary, ART appears to restore the total CD8+ T cell population to a less exhausted phenotype, independent of the time point of initiation. However, to preserve multifunctional, HIV-1-specific CD8+ T cells, ART might have to be initiated before seroconversion.

No MeSH data available.


Related in: MedlinePlus

2B4 and PD-1 in individuals on ART normalizes to the levels observed for HIV-negative controls.Frequencies of total and memory CD8+ T cells expressing the inhibitory receptors 2B4, PD-1 and CD160. A) The frequency of CD8+ T cells expressing 2B4 was significantly higher in ART-naïve individuals compared with ART-treated individuals and the HIV-negative controls, independent of when ART was initiated. B) The frequency of CD8+ T cells expressing PD-1 was significantly higher in ART-naïve individuals compared with ART-treated individuals and the HIV-negative controls, independent of when ART was initiated. C) No differences were found in the frequency of CD8+ T cells expressing CD160 between ART-naïve, ART-treated and HIV-negative individuals. * means 0.01<p<0.05; ** means 0.001<p<0.01; *** means 0.0001<p<0.001.
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pone.0139573.g001: 2B4 and PD-1 in individuals on ART normalizes to the levels observed for HIV-negative controls.Frequencies of total and memory CD8+ T cells expressing the inhibitory receptors 2B4, PD-1 and CD160. A) The frequency of CD8+ T cells expressing 2B4 was significantly higher in ART-naïve individuals compared with ART-treated individuals and the HIV-negative controls, independent of when ART was initiated. B) The frequency of CD8+ T cells expressing PD-1 was significantly higher in ART-naïve individuals compared with ART-treated individuals and the HIV-negative controls, independent of when ART was initiated. C) No differences were found in the frequency of CD8+ T cells expressing CD160 between ART-naïve, ART-treated and HIV-negative individuals. * means 0.01<p<0.05; ** means 0.001<p<0.01; *** means 0.0001<p<0.001.

Mentions: The objective was to evaluate whether the time point when ART was initiated had an impact on the restoration of CD8+ T cell function during chronic HIV-1 infection. To pursue this aim, the frequencies of total and memory CD8+ T cells expressing the inhibitory markers 2B4, PD-1 and CD160 were examined in four groups of individuals: ART-naïve individuals, individuals with ART initiated early (at a CD4+ T cell count >350 cells/μl blood, including 4 individuals treated before seroconversion), individuals with ART initiated late (at a CD4+ T cell count <350 cells/μl blood) and HIV-negative controls (Fig 1). The frequency of CD8+ T cells expressing 2B4 was lower in individuals receiving ART compared with ART-naïve individuals (Fig 1A). No difference was observed depending on when ART was initiated, and the level in ART-treated individuals was similar to that in HIV-uninfected individuals (Fig 1A). The CD8+ T cells expressing 2B4 were mainly found within the TM, EM and effector subsets. In the CM CD8+ T cells, the 2B4 expression deviated between ART-naïve individuals and individuals treated at a CD4+ T cell count >350 cells/μl (Fig 1A). The frequencies of TM and EM CD8+ T cells expressing 2B4 were significantly higher in ART-naïve individuals compared with both HIV-1-positive individuals treated with ART and HIV-negative individuals. For the effector CD8+ T cells, the 2B4 expression was significantly higher in ART-naïve individuals compared with individuals treated at a CD4+ T cell count <350 cells/μl and with HIV-negative controls (Fig 1A). The expression of PD-1 was primarily found on TM and EM CD8+ T cells. The frequencies of CM, TM and EM CD8+ T cells expressing PD-1 were significantly higher in ART-naïve individuals compared with individuals treated at a CD4+ T cell count >350 cells/μl (Fig 1B). The frequency of TM CD8+ T cells expressing PD-1 also deviated between ART-naïve individuals and HIV-negative controls (Fig 1B). As for 2B4 expression, PD-1 expression during ART appeared to normalize to the levels observed for HIV-negative individuals, independent of the time of therapy initiation (Fig 1B).


Initiation of Antiretroviral Therapy (ART) at Different Stages of HIV-1 Disease Is Not Associated with the Proportion of Exhausted CD8+ T Cells.

Jensen SS, Fomsgaard A, Larsen TK, Tingstedt JL, Gerstoft J, Kronborg G, Pedersen C, Karlsson I - PLoS ONE (2015)

2B4 and PD-1 in individuals on ART normalizes to the levels observed for HIV-negative controls.Frequencies of total and memory CD8+ T cells expressing the inhibitory receptors 2B4, PD-1 and CD160. A) The frequency of CD8+ T cells expressing 2B4 was significantly higher in ART-naïve individuals compared with ART-treated individuals and the HIV-negative controls, independent of when ART was initiated. B) The frequency of CD8+ T cells expressing PD-1 was significantly higher in ART-naïve individuals compared with ART-treated individuals and the HIV-negative controls, independent of when ART was initiated. C) No differences were found in the frequency of CD8+ T cells expressing CD160 between ART-naïve, ART-treated and HIV-negative individuals. * means 0.01<p<0.05; ** means 0.001<p<0.01; *** means 0.0001<p<0.001.
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Related In: Results  -  Collection

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pone.0139573.g001: 2B4 and PD-1 in individuals on ART normalizes to the levels observed for HIV-negative controls.Frequencies of total and memory CD8+ T cells expressing the inhibitory receptors 2B4, PD-1 and CD160. A) The frequency of CD8+ T cells expressing 2B4 was significantly higher in ART-naïve individuals compared with ART-treated individuals and the HIV-negative controls, independent of when ART was initiated. B) The frequency of CD8+ T cells expressing PD-1 was significantly higher in ART-naïve individuals compared with ART-treated individuals and the HIV-negative controls, independent of when ART was initiated. C) No differences were found in the frequency of CD8+ T cells expressing CD160 between ART-naïve, ART-treated and HIV-negative individuals. * means 0.01<p<0.05; ** means 0.001<p<0.01; *** means 0.0001<p<0.001.
Mentions: The objective was to evaluate whether the time point when ART was initiated had an impact on the restoration of CD8+ T cell function during chronic HIV-1 infection. To pursue this aim, the frequencies of total and memory CD8+ T cells expressing the inhibitory markers 2B4, PD-1 and CD160 were examined in four groups of individuals: ART-naïve individuals, individuals with ART initiated early (at a CD4+ T cell count >350 cells/μl blood, including 4 individuals treated before seroconversion), individuals with ART initiated late (at a CD4+ T cell count <350 cells/μl blood) and HIV-negative controls (Fig 1). The frequency of CD8+ T cells expressing 2B4 was lower in individuals receiving ART compared with ART-naïve individuals (Fig 1A). No difference was observed depending on when ART was initiated, and the level in ART-treated individuals was similar to that in HIV-uninfected individuals (Fig 1A). The CD8+ T cells expressing 2B4 were mainly found within the TM, EM and effector subsets. In the CM CD8+ T cells, the 2B4 expression deviated between ART-naïve individuals and individuals treated at a CD4+ T cell count >350 cells/μl (Fig 1A). The frequencies of TM and EM CD8+ T cells expressing 2B4 were significantly higher in ART-naïve individuals compared with both HIV-1-positive individuals treated with ART and HIV-negative individuals. For the effector CD8+ T cells, the 2B4 expression was significantly higher in ART-naïve individuals compared with individuals treated at a CD4+ T cell count <350 cells/μl and with HIV-negative controls (Fig 1A). The expression of PD-1 was primarily found on TM and EM CD8+ T cells. The frequencies of CM, TM and EM CD8+ T cells expressing PD-1 were significantly higher in ART-naïve individuals compared with individuals treated at a CD4+ T cell count >350 cells/μl (Fig 1B). The frequency of TM CD8+ T cells expressing PD-1 also deviated between ART-naïve individuals and HIV-negative controls (Fig 1B). As for 2B4 expression, PD-1 expression during ART appeared to normalize to the levels observed for HIV-negative individuals, independent of the time of therapy initiation (Fig 1B).

Bottom Line: Early initiation of antiretroviral treatment (ART) and the duration of ART have been associated with immune reconstitution.The frequency of CD8+ T cells expressing the inhibitory markers PD-1, 2B4 and CD160 was lower in ART-treated individuals compared with ART-naïve individuals and similar to the frequency in HIV-uninfected controls.The expression of the three markers was similarly independent of when therapy was initiated.

View Article: PubMed Central - PubMed

Affiliation: Virus Research & Development Laboratory, Department of Microbial Diagnostic and Virology, Statens Serum Institut, Copenhagen, Denmark; Department of Infectious Diseases, Odense University Hospital, Odense, Denmark; Infectious Disease Research Unit, Clinical Institute, University of Southern Denmark, Odense, Denmark.

ABSTRACT
CD8+ T cell-restricted immunity is important in the control of HIV-1 infection, but continued immune activation results in CD8+ T cell dysfunction. Early initiation of antiretroviral treatment (ART) and the duration of ART have been associated with immune reconstitution. Here, we evaluated whether restoration of CD8+ T cell function in HIV-1-infected individuals was dependent on early initiation of ART. HIV-specific CD107a, IFNγ, IL-2, TNFα and MIP-1β expression by CD8+ T cells and the frequency of CD8+ T cells expressing PD-1, 2B4 and CD160 were measured by flow cytometry. The frequency of CD8+ T cells expressing the inhibitory markers PD-1, 2B4 and CD160 was lower in ART-treated individuals compared with ART-naïve individuals and similar to the frequency in HIV-uninfected controls. The expression of the three markers was similarly independent of when therapy was initiated. Individuals treated before seroconversion displayed an HIV-specific CD8+ T cell response that included all five functional markers; this was not observed in individuals treated after seroconversion or in ART-naïve individuals. In summary, ART appears to restore the total CD8+ T cell population to a less exhausted phenotype, independent of the time point of initiation. However, to preserve multifunctional, HIV-1-specific CD8+ T cells, ART might have to be initiated before seroconversion.

No MeSH data available.


Related in: MedlinePlus