Impact of aging, cytomegalovirus infection, and long-term treatment for human immunodeficiency virus on CD8⁺ T-Cell subsets

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.