Abstract
Both healthy aging and human immunodeficiency virus (HIV) infection lead to a progressive decline in naive CD8+ T-cell numbers and expansion of the CD8+ T-cell memory and effector compartments. HIV infection is therefore often considered a condition of premature aging. Total CD8+ T-cell numbers of HIV-infected individuals typically stay increased even after long-term (LT) combination antiretroviral treatment (cART), which is associated with an increased risk of non-AIDS morbidity and mortality. The causes of these persistent changes in the CD8+ T-cell pool remain debated. Here, we studied the impact of age, CMV infection, and LT successful cART on absolute cell numbers in different CD8+ T-cell subsets. While naïve CD8+ T-cell numbers in cART-treated individuals (N = 38) increased to healthy levels, central memory (CM), effector memory (EM), and effector CD8+ T-cell numbers remained higher than in (unselected) age-matched healthy controls (N = 107). Longitudinal analysis in a subset of patients showed that cART did result in a loss of memory CD8+ T-cells, mainly during the first year of cART, after which memory cell numbers remained relatively stable. As CMV infection is known to increase CD8+ T-cell numbers in healthy individuals, we studied whether any of the persistent changes in the CD8+ T-cell pools of cART-treated patients could be a direct reflection of the high CMV prevalence among HIV-infected individuals. We found that EM and effector CD8+ T-cell numbers in CMV+ healthy individuals (N = 87) were significantly higher than in CMV− (N = 170) healthy individuals. As a result, EM and effector CD8+ T-cell numbers in successfully cART-treated HIV-infected individuals did not deviate significantly from those of age-matched CMV+ healthy controls (N = 39). By contrast, CM T-cell numbers were quite similar in CMV+ and CMV− healthy individuals across all ages. The LT expansion of the CM CD8+ T-cell pool in cART-treated individuals could thus not be attributed directly to CMV and was also not related to residual HIV RNA or to the presence of HIV-specific CM T-cells. It remains to be investigated why the CM CD8+ T-cell subset shows seemingly irreversible changes despite years of effective treatment.
Highlights
Infection with human immunodeficiency virus (HIV) leads to substantial changes in the T-cell compartment
Changes in the CD8+ T-cell compartment of HIV-infected individuals are often compared to changes that occur during chronological aging, and HIV infection has been described as a condition of accelerated immunological aging
In line with previous findings, we found that CD8+ T-cell numbers in LT-treated HIV patients remained significantly increased compared to healthy age-matched controls, despite years of successful treatment
Summary
Infection with human immunodeficiency virus (HIV) leads to substantial changes in the T-cell compartment. There is a relative abundance of highly differentiated T-cells, characterized by a reduced capacity to proliferate, short telomere lengths [1] and changes in cytokine secretion capacity [2, 3]. A progressive decline in naïve CD8+ T-cell numbers occurs concomitant with an increase in memory CD8+ T-cell numbers [4]. Since these changes are reminiscent of the changes in the T-cell compartment observed during healthy aging [5, 6], HIV infection is often regarded a condition of premature immunological aging [7]. While immune senescence during healthy aging is thought to result from the multiple rounds of activation of the immune system throughout life, the chronic immune activation induced by HIV may accelerate this aging process [8, 9]
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