Blood was collected into heparinized tubes and used for analysis immediately after sampling. The study was approved by the Charité—University Medicine Berlin ethical review board, and all participants gave informed consent to study participation.
Flow Cytometric Analysis
Flow cytometric analysis of CD4+ T cells was performed with whole blood using antibodies against CD4 (clone SK3; BD Biosciences, Heidelberg, Germany), CD31 (WM59; BD), CD45RO (UCHL-1; BD), and CD62L (Dreg-56; BD). Absolute numbers of CD4+ T cells were determined by the use of TruCount tubes and CD3/CD4/CD8 TriTest (BD) according to the manufacturer's protocol. Antibodies were conjugated to fluorescin, phycoerythrin, peridin chlorophyll protein, or allophycocyanin. Data were acquired on the FACSCalibur (BD) and analyzed with CellQuest software (BD). Lymphocytes were gated on the basis of characteristic forward and side scatter properties.
Naive CD4+ T cells were identified by CD62L expression on CD45RO− CD4+ T cells and differentiated into CD31+ and CD31−. TCM were classified by co-expression of CD45RO and CD62L, and TEM were classified by lack of CD62L expression. TTD were identified by the lack of CD62L expression on CD45RO− CD4+ T cells. Gating strategies are shown in Figure S1 (see Supplemental Digital Content, http://links.lww.com/QAI/A501). Derived from absolute numbers of CD4+ T cells and the percentages of the distinct cells subsets, absolute numbers of CD31+ naive, CD31− naive, TEM, TCM, and TTD were calculated.
Analysis of cell proliferation was performed with isolated PBMC. Surface staining with antibodies against CD4, CD45RO, and CD62L was followed by intranuclear immunostaining with anti-Ki67 mononuclear antibody (MIB-1; DAKO, Hamburg, Germany). Cells were permeabilized and fixed using Fix/Perm buffers (eBioscience, Frankfurt, Garmeny) according to the manufacturer's instructions.
Analysis of CD4+ T-Cell Cytokine Production
To determine the capacity of CD4+ T cells to produce interferon (IFN)γ, IL-2, IL-4, and IL-17, PBMC were incubated without (negative control) or with phorbol myristate acetate (20 ng/mL; Sigma, Munich, Germany) and ionomycin (2 μg/mL; Sigma), HIV-peptides (PepMix HIV-1; 120 μg/mL; JPT Peptide Technologies, Berlin, Germany), or CMV-peptides (PepMix pp65; 100 μg/mL; JPT) for 6 hours at 37°C in a humidified 5% CO2 air atmosphere. Brefeldin A (10 μg/mL; Sigma) was added for the last 3 hours followed by flow cytometric analysis of cytokine producing CD4+ T cells with antibodies against CD3, CD4, and IFNγ (B27; BD), IL-2 (MQ1 17H12; BD), IL-4 (8D4-8, BD), or IL-17 (eBio6AP17; eBioscience). Values obtained in the negative control were subtracted from the respective test values.
Data are represented as medians with interquartile ranges and were analyzed using Mann–Whitney U test. Multiple independent tests were performed for comparisons between younger and older controls or patients and between patients and age-matched controls. Bivariate correlations and statistical significance were determined by the Spearman rank correlation test. All data were statistically analyzed with Prism software version 4.0 (Graph Pad Inc., La Jolla, CA).
Quantitative Effects of HIV and Aging: Preferential Loss of Naive CD4+ T Cells in HIV Infection Is More Pronounced in Older Than in Younger Patients
Absolute numbers of CD4+ T-cell subsets in younger and older HIV-infected patients were compared with those in age-matched control groups. Both older age and HIV infection were associated with reduced CD31+ naive CD4+ T-cell numbers demonstrating an additive effect of HIV on CD31+ naive CD4+ T cells to the effect of aging alone (Fig. 1B, upper left). In addition, there was an age-related loss of CD31− naive CD4+ T cells in HIV-infected patients but not in controls suggesting that the HIV-associated depletion of naive CD4+ T cells increases with age (Fig. 1B, upper right; Table 1). In both patient groups, CD31+ and CD31− naive CD4+ T-cell counts were not related to plasma viral loads (Table 1), which may indicate that other factors than viral replication alone contribute to the observed decline in naive CD4+ T cells.
There was no difference in the decline of TCM or TEM between younger and older patients (Fig. 1B, middle), and neither aging nor HIV infection had an effect on TTD numbers (Fig. 1, bottom). Although TTD numbers in HIV-infected patients were not different to those in controls, there was an inverse correlation with viral loads (Table 1) indicating enhanced recruitment of CD4+ T cells into the terminal stage of differentiation rather than exclusion of TTD from viral infection. Taken together, these findings demonstrate that older age of HIV-infected persons is associated with increased depletion of naive CD4+ T cells.
Depletion of CD31− Naive CD4+ T Cells in Older HIV-Infected Persons Is Associated With an Enrichment of CD4+ T Cells by TEM
An important characteristic for aging of the CD4+ T-cell compartment is the distribution of T cells with distinct differentiation phenotypes.19,35 To define the effect of age on the CD4+ T-cell composition in HIV-infected patients, proportionate CD4+ T-cell subset representation was compared in the study groups.
In controls, we observed an age-correlated reduction of CD31+ naive cells within the CD4+ T-cell compartment (Fig. 1C, upper left; Table 1). Age-related depletion of CD31+ naive cells from the CD4+ T-cell pool was also observed in HIV infection, and both patient groups had an additional 50% reduced frequency of this subset compared to their healthy counterparts (Fig. 1C, upper left). In strong contrast to controls, there was no age-related increase in the relative frequency of CD31− naive CD4+ T cells in HIV-infected patients (Table 1; Fig. 1C, upper right). Instead, frequencies of CD31− naive CD4+ T cells were within the normal range of controls in younger patients but significantly reduced by 40% in older patients (Fig. 1C, upper right). Thus, HIV infection of older but not of younger patients was associated with age-inappropriate proportions of CD31− naive CD4+ T cells, although CD31− naive CD4+ T-cell numbers were reduced in both groups (Fig. 1B, upper right).
TCM levels weakly correlated with age in controls, whereas in HIV-infected patients there was an age-related increase in TEM frequencies (Fig. 1C, middle; Table 1). Thus, the strong reduction of naive CD4+ T cells in older patients coincided with a selective enrichment of CD4+ T cells by TEM (Fig. 1C, middle right). TTD frequencies were increased among CD4+ T cells of HIV-infected patients in comparison to controls, regardless of their ages (Fig. 1C, bottom).
Proliferation of CD4+ T-Cell Subsets
To determine whether proliferation of CD4+ T-cell subsets changes with the age of HIV-infected persons and thus contributes to the differences in the CD4+ T-cell composition observed between younger and older patients, we analyzed intranuclear Ki-67 expression, that is present during all active phases of the cell cycle and is closely related to cell proliferation.36 Fifteen individuals of each comparison group were analyzed (Figs. 2A–D). As expected, proliferation of the memory CD4+ T-cell subsets was strikingly higher in HIV-infected patients than in controls. However, no significant difference between younger and older HIV-infected patients was observed in terms of Ki-67 expression in any of the 3 memory CD4+ T-cell subsets (Figs. 2B–D).
Naive CD4+ T cells contained also a higher proliferating fraction in HIV-infected patients compared to controls (Fig. 2A). Older HIV-infected patients had a 3-fold higher proportion of proliferating naive CD4+ T cells than younger ones (Fig. 2A). In both patient groups, there was no correlation between cell numbers and proliferation of each of the CD4+ T-cell subsets. Also, Ki-67 expression in any CD4+ T-cell subset did not correlate with total CD4+ T-cell numbers. Together, these results demonstrate that neither increased proliferation of TEM nor impaired proliferation of naive CD4+ T cells is the driving force behind the enrichment of TEM or preferential depletion of naive CD4+ T cells in older patients.
Cytokine Secretion Properties of CD4+ T Cells Differ Between Younger and Older HIV-Infected Patients
As TEM are the main producers of effector cytokines, enrichment of CD4+ T cells by TEM in older HIV-infected patients indicates enhanced effector functions of the CD4+ T-cell compartment. We therefore analyzed cytokine secretion properties of CD4+ T cells in 10 subjects of each study group.
No significant differences in mitogen-induced cytokine responses were observed between younger and older controls (Fig. 3). In CD4+ T cells of younger HIV-infected patients, cytokine secretion did not significantly differ from those of age-matched controls (Fig. 3). CD4+ T cells of older patients, in contrast, showed a lower production of IL-2 and a higher secretion of IFNγ, IL-4, and IL-17 than those of age-matched controls. In addition, both IFNγ and IL-4 responses in CD4+ T cells of older HIV-infected patients were increased in comparison to younger patients (Fig. 3). Cytokine production on HIV- or CMV-specific CD4+ T-cell stimulation did not differ significantly between our younger and older patients (data not shown). These results demonstrate that aging of HIV-infected patients is associated with functional changes of the CD4+ T-cell compartment that are not observed during natural immune aging.
CD4+ T-Cell Reconstitution Under cART
Since we found age-related differences in the effect of HIV infection on CD4+ T cells, we evaluated whether cART enables to restore the subsets to age-appropriate levels. According to several previous publications, cART initiated earlier than at 350 CD4+ T cells per microliter may improve the immunological response to cART and decrease mortality.37–39 In this study, the observed associations between total CD4+ T-cell counts and CD31+ and CD31− naive CD4+ T-cell levels indicate that restoration of the naive CD4+ T-cell compartment might depend on the stage of CD4+ T-cell depletion at initiation of cART. For these reasons, we divided each of our patient age groups into a subgroup with <350 CD4+ T cells per microliter blood and a subgroup with 350 or more CD4+ T cells per microliter at initation of cART (referred to as standard cART and early cART, respectively). At baseline in both subgroups, younger and older patients were not different for CD4+ T-cell counts or plasma viral loads. No significant difference in the duration of cART did exist between the groups.
Under standard cART, in both younger and older patients, proportions of CD31+ naive CD4+ T cells remained reduced, whereas TTD remained increased in comparison to age-matched controls (Figs. 4A, E). In older patients, in addition, the depletion of CD31− naive cells from the CD4+ T-cell compartment and the enrichment of TEM persisted despite viral suppression, indicating an irreversible homeostatic impairment of CD4+ T cells (Figs. 4B, D). In contrast, under early cART, frequencies of all CD4+ T-cell subsets were within the normal range of age-matched healthy individuals in both the younger and the older patient groups (Figs. 4A–E). In total CD4+ T-cell counts, no differences were observed in patients under on early cART in comparison to age-matched controls, whereas under standard cART younger and older patients showed significantly reduced CD4+ T-cell counts (Fig. 4F).
In this study, we investigated alterations of the CD4+ T-cell compartment in HIV-infected patients older than 50 years and younger than 40 years in comparison to age-matched healthy controls. In both age groups of HIV-infected persons, we found a preferential decline in naive CD4+ T cells, which is consistent with previous studies about the dynamics of CD4+ T-cell depletion in untreated HIV infection.40 Naive cells were further differentiated into CD31+ and CD31− naive CD4+ T cells, as the homeostatic change of these 2 cell subsets is a characteristic immunological alteration observed during normal aging: While CD31+ naive CD4+ T cells, which include a significant proportion of recent thymic emigrants, decline continuously, CD31− naive CD4+ T cells remain rather constant over time.11,13,14,41 Our results confirmed an age-related decline of CD31+ naive CD4+ T cells in controls and in HIV-infected patients. In both younger and older HIV-infected patients, we found reduced CD31+ naive CD4+ T cells in comparison to age-matched controls, consistent with a previous report.32 Thereby, the additional loss of CD31+ naive cells from the CD4+ T-cell compartment beyond that of natural aging did not differ between younger and older HIV-infected patients indicating that the detrimental effect of HIV on CD31+ naive CD4+ T cells does not change with age. However, because CD31+ naive CD4+ T cells are characterized by a highly diverse TCR repertoire,14 these findings suggest that HIV infection accelerates the age-related loss of antigen specificities. Such a defect in the T cellular immune system leads to increased sensitivity to clinically relevant conditions including infections, autoimmunity, and possibly cancer,42,43 which all are common among HIV-infected persons.
During natural aging, the naive TCR repertoire is partially maintained by the expansion of CD31− naive CD4+ T cells,11 but this seems not to be the case in HIV-infected persons. Instead, older patients exhibited a stronger depletion of CD31− naive CD4+ T cells than their younger counterparts, and age-inappropriate low levels of CD31− naive cells within the CD4+ T-cell population were observed only in older patients. This CD31− naive CD4+ T-cell depletion enhances TCR repertoire restrictions14 and thus may play an important role in the well-documented reduced immune responses to neoantigens and vaccines and the more rapid progression to AIDS in persons aged 50 years or older.44,45
Possible explanations for the decline in CD31− naive CD4+ T cells during HIV infection are an increased susceptibility of this cell subset to HIV-mediated cell death or/and an increased recruitment to the memory pool together with an insufficient renewal.46–48 Because in this study there was no difference in the plasma viral loads between our younger and older patients, and no correlation between viral loads and naive CD4+ T-cell subsets was observed, the difference in CD31− naive CD4+ T-cell depletion between both patient groups appears not to be an effect of viral replication alone. Our finding of a larger proliferating fraction within naive CD4+ T cells of older patients compared to younger patients rather suggests an increased tendency for naive CD4+ T-cell division and subsequent differentiation into effector cells. Consistent with this, older age of HIV-infected patients was associated with an enrichment of TEM in the CD4+ T-cell compartment that was not caused by an altered proliferation rate of TEM or one of the other memory cell subset. Enhanced naive CD4+ T-cell proliferation and differentiation has been described under lymphopenic conditions49,50 and might be induced in older patients in response to the viral CD4+ T-cell depletion to balance the age-related lessened naive CD4+ T-cell de novo generation.
Age-related increase in the CD4+ T-cell differentiation toward a TEM phenotype in our study patients was associated with enhanced CD4+ T-cell effector functions. In contrast to CD4+ T cells of younger patients, those of older patients showed an increased propensity to secrete the pro-inflammatory cytokines IFNγ and IL-17, whereas anti-inflammatory IL-4 secretion was only slightly higher than in age-matched healthy subjects. This shift in the balance of Th1, Th2, and Th17 responses may drive pro-inflammatory forces in older patients.
Given this influence of patient's age on the CD4+ T-cell compartment in untreated HIV infection, the immunological outcome of cART may differ between younger and older patients. We found that CD4+ T-cell subset distribution changes observed in untreated HIV infection largely persist under cART when initiated at CD4+ T-cell counts of <350 per microliter. Thus, both younger and older patients had decreased CD31+ naive and increased TTD levels despite viral suppression and increase in total CD4+ T-cell counts. Older age was additionally associated with persisting age-inappropriate low levels of CD31− naive cells and high levels of TEM within the CD4+ T-cell compartment. Whether this deficit in the differentiation profile of CD4+ T cells can be reversed with longer time on cART would be interesting to address in future studies. However, this strong failure of the naive CD4+ T-cell subsets to reconstitute is likely to have deleterious effects on the immune response to neoantigens. In the long-term, insufficient restoration of the CD4+ T-cell compartment may contribute to the well-documented increased risk of AIDS-related and non–HIV-related illnesses that have been described especially for older patients under cART.7,35 Importantly, when cART was started earlier, that is, at CD4+ T-cell counts ≥350 per microliter, relative frequencies of all CD4+ T-cell subsets and total CD4+ T-cell counts were within the normal range of healthy controls in both younger and older patients. This was mainly caused by the fact that pretreatment alterations of the CD4+ T-cell compartment are only less pronounced at this stage of infection.
Taken together, these results demonstrate detrimental effects of natural aging on CD4+ T cells in HIV-infected persons that can be prevented by an early onset of cART.
The authors are grateful to the patients and healthy subjects for their participation in this project. They thank Kristina Conrad, Martina Seipel, and Nadine Gehrmann for excellent technical assistance.
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HIV; aging; CD4+ T-cell impairment; T-cell subsets; CD4+ T-cell reconstitution; cART
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