T-Cell Activation Independently Associates With Immune Senescence in HIV-Infected Recipients of Long-term Antiretroviral Treatment

Abstract

Background: Aging-associated noncommunicable comorbidities are more prevalent among human immunodeficiency virus type 1 (HIV)-infected individuals than among HIV-uninfected individuals. Residual HIV-related chronic immune activation and senescence may increase the risk of developing comorbidities.

Methods: Immune phenotyping, thymic output, and telomere length were assessed in 94 HIV-infected individuals who were aged >45 years and receiving antiretroviral therapy (ART; cases) and 95 age-matched uninfected controls.

Results: Cases had lower CD4(+) T-cell counts, higher CD8(+) T-cell counts, and increased levels of immune activation (ie, increased soluble CD14 [sCD14] level and increased percentages of CD38(+)HLA-DR(+) cells among both CD4(+) and CD8(+) T cells), regulatory T cells, and percentage of programmed cell death 1 (PD-1)-expressing cells among CD4(+) T cells. Immune senescence levels (ie, percentages of CD27(-)CD28(-) cells or CD57(+) cells) were comparable between cases and controls. Peripheral blood mononuclear cells from cases had shorter telomeres but increased single-joint T-cell receptor excision circle content and CD31(+) naive CD4(+) T cells. Although cytomegalovirus (CMV) antibody titers were higher in cases, CMV-specific T-cell responses were comparable between cases and controls. T-cell senescence in cases was independently associated with T-cell activation but not with CMV-specific immune responses.

Conclusions: Despite long-term receipt of ART, HIV-infected adults had higher levels of immune activation, regulatory T cells, and PD-1-expressing CD4(+) cells and shorter telomeres. The increased soluble CD14 levels and percentage of CD38(+)HLA-DR(+) cells among CD4(+) T cells correlated with shorter telomeres and increased regulatory T-cell levels. This suggests that HIV influences immune function irreversibly, with several pathways that are persistently abnormal during effective ART. Therapies aimed at improving immune health during ART are needed.

Keywords: ART; HIV; immune activation; senescence; telomeres; thymic output.

Figure 1.

T-cell phenotyping and immune activation in human immunodeficiency virus type 1 (HIV)–infected antiretroviral therapy (ART) recipients and uninfected controls. A, Absolute CD4⁺ T-cell counts, absolute CD8⁺ T-cell counts, and ratios of CD4⁺ to CD8⁺ T cells are shown for HIV-infected ART recipients and uninfected controls. B, T-cell activation was determined by the percentage of HLA-DR⁺CD38⁺ cells within the total CD4⁺ and CD8⁺ T-cell population, and the percentage of regulatory T cells (Tregs) was determined by the analysis of the proportion of CD4⁺CD25⁺CD127^low cells among the CD4⁺ T cells. C, Monocyte activation and microbial translocation were determined by measuring soluble CD14 (sCD14) and soluble CD163 (sCD163) levels in plasma. D, Thymic output was determined by the proportion of CD31⁺ naive CD4⁺ T cells and single-joint T-cell receptor excision circle (sjTREC) content in peripheral blood mononuclear cells (PBMCs).

Figure 2.

Shorter telomeres but normalization of immune senescence in human immunodeficiency virus type 1 (HIV)–infected individuals receiving long-term antiretroviral therapy. A, Telomere length in peripheral blood mononuclear cells was analyzed as a measure of historical cell proliferation. B and C, The percentage of late-differentiated and immune-senescent T cells was determined by the lack of CD27 and CD28 expression on CD4⁺ and CD8⁺ T cells (B) and the expression of CD57 on CD4⁺ and CD8⁺ T cells (C). Additionally, the percentage of CD57⁺ cells in the CD8⁺CD28⁻ cell population is given (C). D, The level of T-cell exhaustion is expressed as the percentage PD-1⁺ cells within the CD4⁺ and CD8⁺ T-cell population.

Figure 3.

Higher cytomegalovirus (CMV) antibody titers but normal frequencies of functional CMV-reactive T cells in human immunodeficiency virus type 1 (HIV)–infected antiretroviral therapy (ART) recipients. A, Total anti-CMV immunoglobulin G (IgG) titers and high-avidity antibody titers were determined in CMV-positive HIV–infected ART recipients and uninfected controls. T-cell responses to CMV-specific peptides (pp65) were characterized by the analysis of cytokine production (interferon γ, tumor necrosis factor α, interleukin 2, and macrophage inflammatory protein 1β) and the degranulation marker CD107a in 22 HIV-infected ART recipients and 24 uninfected controls. Polyfunctionality of the CMV-specific cells was determined by the ability of the cells to produce different cytokines and the expression of the degranulation marker (CD107a). B and C, The proportion of cells that displayed ≥1 function of the total number of CMV-pp65 reactive CD4⁺ (B) and CD8⁺ (C) T cells is given. Open circles denote HIV-infected ART recipients, and closed circles denote uninfected controls.