HIV-infected late presenters have increased risk of opportunistic infections, AIDS defining events, and death.1,2 Despite increasing efforts to promote testing, late presentation continues to be a considerable problem in developed countries. Thus, approximately 50% of individuals diagnosed with HIV infection in developed countries are late presenters defined as presenting for care with a CD4 cell count below 350 cells per microliter or an AIDS-defining event.3 Individuals presenting with a CD4 cell count below 200 cells per microliter or an AIDS-defining event are further described as having advanced HIV disease which further increases the risk of morbidity and mortality.3 Low CD4 cell count is associated with reduced chance of optimal immune recovery after initiation of combination antiretroviral therapy (cART).4 Furthermore, T cell subset distribution before and after initiation of cART is altered in late presenters and seems to accompany suboptimal immune recovery.5 However, the immunological mechanisms and causes of suboptimal immune recovery after initiation of cART are incompletely understood.
Interleukin-7 (IL-7) and the corresponding IL-7 receptor (IL-7R) are crucial for T cell homeostasis. IL-7 induces both de novo production, proliferation, and survival of T cells.6 The IL-7R is a heterodimer consisting of the common γ-chain (CD132) and the IL-7R specific α-chain (CD127). Previously, both low percentage of CD127+CD4+ T cells and high percentage of CD127+CD8+ T cells have been associated with suboptimal immune recovery.7,8 Furthermore, low baseline plasma IL-7 has been associated with increased immune recovery.8,9 Finally, we and others have previously demonstrated that the single nucleotide polymorphism rs6897932 placed in the transmembrane region of CD127 predicts fast immune recovery in HIV-infected individuals.9,10 Thus, low plasma IL-7 and CD127 expression may contribute to suboptimal immune recovery in late presenters initiating cART. Knowledge regarding impact of plasma IL-7 and CD127 expression on immune recovery in late presenting HIV-infected individuals is sparse and the potential impact on T cell subset distribution is, to our knowledge, unknown.
We hypothesized lower plasma IL-7 and reduced CD127 expression in HIV-infected late presenters compared with HIV-infected individuals presenting with higher CD4 cell counts. Furthermore, we hypothesized that plasma IL-7 and CD127 expression before cART is predictive for immune recovery and T cell subset distribution after initiation of cART. To examine this, the plasma level of IL-7 and soluble CD127 (sCD127) and CD127 T cell expression were examined before initiation of cART and 6, 12, and 24 months after initiation of cART in HIV-infected individuals presenting with different CD4 cell counts, and were tested as predictors for immune recovery.
A total of 100 treatment naive HIV-infected individuals initiating cART were included in a prospective follow-up study. Decision about cART initiation was made by the patient's physician and the patient. All individuals were enrolled from Department of Infectious Diseases, Rigshospitalet, Copenhagen University Hospital or Department of Infectious Diseases, Hvidovre Hospital. Participants were consecutively included and divided into 4 groups according to baseline CD4 cell count: CD4 cell count below 200 cells per microliter “Late presenters, advanced disease,” CD4 cell count 200–350 cells per microliter “Late presenters, nonadvanced disease,” CD4 cell count 350–500 cells per microliter “Intermediate presenters,” and CD4 cell count above 500 cells per microliter “Early presenters.” Furthermore, a control group of 16 uninfected, healthy individuals were recruited among hospital staff. A total of 19 HIV-infected individuals also participated in a study regarding natural killer cells and antibody-dependent cellular toxicity.11
Informed consent was obtained in writing and verbally from all participants, and the study was performed in accordance with the ethical guidelines of the 1975 Declaration of Helsinki and approved by Local Ethical Committee (H-3-2011-089) and Danish Data Protection Agency. Blood samples were collected at baseline (day 0 of cART) and after 6, 12, and 24 months of cART. Individuals diagnosed with primary HIV infection were excluded from analyses. Furthermore, individuals with virological failure defined as viral load above 400 copies per milliliter more than 6 months after initiation of cART were excluded from follow-up analyses (see Fig. 1, Supplemental Digital Content, http://links.lww.com/QAI/A879).
Collection of Blood Samples and Flow Cytometry
Blood collected in ethylenediamine tetraacetic acid (EDTA) tubes was used for flow cytometry. In brief, 100 μL of ethylenediamine tetraacetic acid blood was incubated with fluorescent dye-conjugated monoclonal antibodies, erythrocytes were lysed with Lysing Solution (Becton Dickinson (BD), Franklin Lakes, NJ), and samples were washed and resuspended in FACS flow (BD). CD3 was used in combination with CD4 or CD8 to identify recent thymic emigrants (RTE, CD45RA+CD31+), naive cells (CD45RA+CD27+CCR7+), central memory (CM, CD45RA−CD27+CCR7+), effector memory (EM, CD45RA−CD27+CCR7−), and IL-7R+ cells (CD127+, CD127+CD132+). Monoclonal antibodies used to determine lymphocyte subsets were CD8-peridinin chlorophyll proteins-cyanine (PerCP-Cy5.5), CD3-fluorescein isothiocyanate (FITC), CCR7−Phycoerythrin (PE), CD132-PE, CD31-FITC, CD45RA-FITC, CD127-FITC, CD27-PE-Cy7, and CD4-Allophycocyanin-H7, and appropriate isotype controls all purchased from BD. Acquisition was performed using a FACS Canto, and data were processed using FACS Diva software (BD). For each sample, a minimum of 100,000 cells were acquired and gated as described (Fig. 1).12 Lymphocyte subsets are given as the proportion (%) of the cell population concerned (CD4+ T cells or CD8+ T cells), and additionally, median fluorescence intensity (MFI) of CD127 was determined on CD127+CD4+ and CD127+CD8+ T cells.13–15
Enzyme-Linked Immunosorbent Assay
The concentration of IL-7 and sCD127 were determined in snap frozen plasma separated within 30 minutes after collection and immediately stored at −80°C. Enzyme-linked immunosorbent assay kits (NeoBiolab, Woburn, MA) were used according to manufacturer's instructions. Plasma concentration of IL-7 and sCD127 were only determined in HIV-infected individuals with available plasma samples at baseline (n = 91) and 6 months after initiation of cART (n = 57). Samples were not available from healthy controls.
DNA was extracted using QIAamp DNA Blood Midi Kit (Qiagen, Copenhagen, Denmark). Samples were available in 98 of the 100 HIV-infected individuals. Genotyping of rs6897932 was performed by competitive allele-specific PCR using the KASPar1 method (KBioscience, Hoddeston, United Kingdom) according to manufacturer's instruction.10 Hardy–Weinberg equilibrium was obeyed (P = 0.172). Success rate was 100%.
Results are given as medians and interquartile ranges (IQRs). Differences between groups of HIV-infected individuals were evaluated by Kruskal–Wallis test and if significant followed by Mann–Whitney U test. Likewise, differences between each group of HIV-infected individuals and healthy controls were evaluated by Mann–Whitney U test. Difference in gender distribution was evaluated by χ2 test. The effect of baseline plasma IL-7 and sCD127 and CD127 T cell expression on immune recovery and changes in T cell subset distribution after initiating cART were evaluated in a univariable general linear model. If significant, the effect was tested in multivariable models, including age, CD4 nadir, and baseline viral load as covariates. Log transformation of viral load, plasma concentration of IL-7, and sCD127 were performed to achieve normal distribution. Two-tailed P-values <0.05 were considered significant. All statistical analyses were performed using SAS (version 9.2; SAS Institute, Copenhagen, Denmark) and graphs were produced in GraphPad Prism 6.0 (GraphPad Software, La Jolla, CA).
The clinical characteristics of study population are presented in Table 1. A total of 14 individuals were with primary HIV infection and excluded. The 86 individuals with chronic HIV infection were allocated in 4 groups: “Late presenters, advanced disease” (<200 cells/μL at presentation, N = 20); “Late presenters, nonadvanced disease” (200–350 cells/μL, N = 19); “Intermediate presenters” (350–500 cells/μL, N = 25); “Early presenters” (>500 cells/μL, N = 22). The majority of study participants were male (90.7%) and median age was 39.1 years (interquartile range: 31.4–45.2). No differences in age and sex distribution were found between the groups, whereas CD4 nadir, baseline CD4 cell count, CD8 cell count, and HIV-RNA all differed among the HIV-infected groups (Table 1). Three individuals with virological failure (above 400 copies/mL) during the follow-up period were excluded from follow-up analyses. CD4 and CD8 cell counts were available in 80 individuals after 6 (4.9–6.6) months of cART, in 71 after 12 (11.2–13.7) months, and in 43 after 24 (22.2–25.5) months of cART (see Fig. 1, Supplemental Digital Content, http://links.lww.com/QAI/A879).
The differences in CD4 cell count between the 4 HIV groups remained after 6, 12, and 24 months of cART. Furthermore, although the CD4 cell count in “Early presenters” became comparable with that in healthy controls after 24 months of cART, the other groups continued to have lower CD4 cell counts than healthy controls (Fig. 2A). In contrast, the CD8 cell count only differed at baseline between the four HIV groups, as “Late presenters, advanced disease” presented with significantly lower CD8 cell count. “Intermediate presenters” had higher CD8 cell count at baseline compared with healthy controls (Fig. 2B).
IL-7R Expression Before and After Initiation of cART in the CD4+ T Cell Compartment
At baseline, lower proportions of CD127+CD4+ T cells in “Late presenters, advanced disease” compared with all other HIV groups were found. Furthermore, “Intermediate presenters” had lower proportions of CD127+CD4+ T cells compared with “Early presenters” (Fig. 2C). Although, the proportion of CD127+CD4+ T cells in “Late presenters, advanced disease” increased after initiation of cART, the proportion was lower compared with healthy controls until after 24 months of cART (Fig. 2C). Including CD132 in the CD127+ T cell phenotype showed a similar pattern (Fig. 2E). However, no significant inter-group differences in the proportion of CD127+CD132+CD4+ T cells after initiation of cART were found, and lower proportion of CD127+CD132+CD4+ T cells in “Late presenters, advanced disease” compared with healthy controls was only found at baseline (Fig. 2E). Likewise, lower density of CD127 (MFI) on CD4+ T cells in “Late presenters, advanced disease” was found at baseline compared with the other groups including healthy controls, but no differences between the groups after initiation of cART were found (Fig. 2G).
IL-7R Expression Before and After Initiation of cART in the CD8+ T Cell Compartment
“Late presenters, advanced disease” had lower proportion of CD127+CD8+ T cells compared with “Intermediate presenters” and “Early presenters” at baseline, but the proportions of CD127+CD8+ T cells increased after initiation of cART resulting in comparable proportions of CD127+CD8+ T cells in all HIV groups after 6 months of cART (Fig. 2D). However, all HIV groups had lower proportions of CD127+CD8+ T cells compared with healthy controls both before cART and after 6 months of cART, and only “Early presenters” increased to a comparable level with healthy controls after 12 months of cART (Fig. 2D). Including CD132 in the CD127+CD8+ phenotype resulted in a similar pattern (Fig. 2F). Finally, the CD127 MFI on CD8+ T cells in “Late presenters, advanced disease” was lower compared with the other groups and healthy controls at baseline (Fig. 2H).
IL-7 and sCD127 in Plasma
Plasma concentrations of IL-7 and sCD127 were determined at baseline and after 6 months of cART in the 4 HIV groups (Fig. 2I and J). Although, no differences were found in plasma IL-7, plasma sCD127 was higher in “Late presenters, advanced disease” compared with the 3 other HIV groups before initiation of cART, but no difference was found after 6 months of cART (Fig. 2J).
T Cell Subset Distribution Before and After Initiation of cART
T cell subset distribution at baseline and after initiation of cART was determined (Table 2). The proportion of CD4+ RTE did not differ between the HIV groups at baseline and only “Late presenters, advanced disease” was lower compared with healthy controls (Table 2). However, the proportion of CD4+ RTE decreased in “Late presenters, advanced disease” and was lower compared with the other HIV groups after 6 months (Table 2). In contrast, the proportion of naïve CD4+ T cells was lower in “Late presenters, advanced disease” both at baseline and after initiation of cART compared with the other groups including healthy controls. No differences in the proportion of CM CD4+ T cells were found, whereas the proportion of EM CD4+ T cells was higher in “Late presenters, advanced disease” and “Late presenters, nonadvanced disease” compared with “Early presenters” and healthy controls (Table 2). Differences in T cell subset distribution in the CD8+ T cell compartment between the HIV groups were comparable with the differences described in the CD4+ T cell compartment (Table 2). However, in the CD8+ T cell compartment all 4 HIV groups differed compared with healthy controls with regards to RTE, naïve, CM, and EM at baseline (Table 2).
Associations Between IL-7 and IL-7R and Immune Recovery and T Cell Subset Distribution
Plasma IL-7 and sCD127 and CD127 T cell expression at baseline were tested as predictors of CD4 cell increase after 6, 12, and 24 months of cART, as well as predictors for changes in thymic output in the form of RTE and naïve T cells, and on changes in already differentiated T cells in the form of both CM and EM T cells. Plasma level of IL-7 and sCD127 and CD127 expression were not associated with increase in total CD4 cell count after initiation of cART (Table 3). In contrast, positive associations were found between CD127 density on CD4+ T cells and increase in CD4+ RTE cell counts and naïve CD4+ T cell counts after initiation of cART (Table 3). After including baseline CD4 cell count, viral load, and age in the model the association remained statistically significant after 24 months of cART (Δ RTE T cells: r2 = 0.36; P = 0.044; Δ naïve T cells: r2 = 0.37; P = 0.018, Table 3).
The allele frequencies of rs6897932 are shown in Table 1.
Reduced proportion of IL-7R+ CD4+ T cells, reduced IL-7R density, and higher plasma sCD127 as well as altered T cell subset distribution were found in HIV-infected late presenters compared with HIV-infected individuals with higher pre-cART CD4 cell count and healthy controls. IL-7R expression in the CD4+ T cell compartment was partly normalized after initiation of cART, whereas an altered T cell subset distribution and IL-7R expression in the CD8+ T cell compartment in all groups of HIV-infected individuals continued after initiation of cART compared with healthy controls. Interestingly, reduced IL-7R expression and increased plasma sCD127 were virtually exclusively found in late presenters with advanced disease and baseline CD4+ T cell count below 200 cells per microliter. Despite these significant alterations of IL-7R expression in late presenters plasma IL-7 and sCD127 and IL-7R expression at baseline did not predict total CD4 immune recovery. However, positive associations between pre-cART expression of CD127 on CD4+ T cells and changes in RTE and naïve CD4+ cell counts were found indicating the IL-7 response to impact thymic output even after 24 months of cART.
Expression of CD127 on CD4+ and CD8+ T cells has previously been demonstrated to be lower in HIV-infected individuals, especially in individuals with untreated HIV infection.16–21 Furthermore, CD127 downregulation on CD4+ T cells has been suggested to be a marker for late presentation.22 This is in accordance with findings in the present study of lower proportions of CD127+ T cells and lower receptor density pre-cART in “Late presenters, advanced disease.” This study further elaborates these findings showing that the reduced IL-7R expression and increased plasma sCD127 were exclusively a problem in “Late presenters, advanced disease,” whereas “Late presenter, nonadvanced disease” was comparable with “Early presenters.” Additionally, the present study supplements these findings by including the common γ-chain of the IL-7R, CD132, in the phenotype, as CD127+CD132− T cells may not respond to IL-7. No difference in IL-7 concentration between “Late presenters, advanced disease” and “Late presenter, nonadvanced disease” was found. Thus, based on the difference in CD4 cell counts, this may be suggestive of a reduced responsiveness to IL-7 and/or a reduced capacity to gain a sufficient IL-7 level in “Late presenters, advanced disease.” Interestingly, we found “Late presenters, advanced disease” had both lower proportion of CD127+CD132+ T cells and lower receptor density indicating fewer cells susceptible for the anti-apoptotic effect of IL-7 and increased risk for the single IL-7R+ T cell not to respond to IL-7. Additionally, the higher plasma levels of sCD127 may limit the availability of IL-7 further reducing the response to IL-7.23 However, 2 studies have found a promoting effect of sCD127 on the responsiveness of IL-7.24,25 Thus, the low proportion of CD127+ T cells and the high level of sCD127 may illustrate shedding of CD127 on T cells as a mechanism to increase activity and availability of IL-7 in “Late presenters, advanced disease,” and studies are warranted to investigate this further.
In HIV-infected individuals, immune recovery after initiation of cART follows a biphasic course.26–28 In the first phase, proliferation of memory T cells is the primary cause of CD4+ T cell increase, whereas de novo production of naïve T cells contributes to the slower CD4+ T cell increase after 6 months of cART (second phase). However, the biphasic model has been challenged by studies showing an impact of thymic size and high thymic output as well as high naïve CD4 cell count on the initial immune recovery role after initiation of cART.29–34 In addition to alterations in IL-7R expression, alterations of the T cell subset distribution was found, as “Late presenters, advanced disease” presented with lower proportions of naïve T cells and higher memory T cells compared with the other HIV groups. This is in line with previous studies,5,22,35,36 showing that the T cell subset distribution kinetic during immune recovery in HIV-infected individuals is greatly dependent on the baseline CD4 cell count, especially in those individuals with CD4+ T cell count below 200 cells per microliter.5,22 However, significant differences in T cell subset distribution between early presenters and individuals with CD4+ T cell count below 350 cells per microliter have been described as well.5,22 We could only partially confirm these findings possibly due to differences in study size, age of study participants, and choice of statistical analyses.5,22 Interestingly, increased baseline receptor density in the form of CD127 MFI on CD4+ T cells was found to be predictive for increases in thymic output after initiation of cART. This correlates with the previously described impact of IL-7 on de novo production of T cells.6 Furthermore, the association between CD127 MFI and increased thymic output was only significant in the second phase of immune recovery which is in line with the contribution of thymic output in the second phase of the biphasic model. Importantly, no association between either IL-7R expression or sCD127 and changes in total CD4 cell count was found. This finding contrasts 2 other studies showing associations between IL-7R expression and CD4+ T cell recovery.7,8 However, these 2 studies differed from the present study as one was cross-sectional and the other used proportion of CD8+ CM expressing CD127 and did not show data on proportion of CD127+CD4+ T cells. Thus, it seems questionable if IL-7R expression is a predictor of CD4+ T cell recovery. Furthermore, our finding of no association between baseline plasma IL-7 and CD4+ T cell recovery is in agreement with one study,13 whereas other studies have shown a positive and a negative association8,9,37 questioning a direct role of baseline plasma IL-7 for the rate CD4+ T cell recovery. Thus, reported association between IL-7R expression and CD4+ T cell recovery may be a consequence of associations between low IL-7R expression and immune exhaustion and low CD4 nadir. Accordingly, the reduced CD4+ T cell recovery may be a result of other mechanisms such as fibrosis in lymphatic tissue, decreased hematopoiesis, and increased immune activation and apoptosis.38
Previously, an association between carrying 2 T-alleles in rs6897932 and fast immune recovery in the initial phase in HIV-infected individuals has been described.10 This finding could not be tested in the current study population due to lack of individuals carrying 2 T-alleles.
To our knowledge this is the first prospective study to thoroughly investigate plasma IL-7, plasma sCD127 and IL-7R T cell expression and T cell subset distribution in groups of HIV-infected individuals based on a clinical relevant CD4 cell count. The study is limited by the number of individuals, and the present data are not adjusted for multiple comparisons. Furthermore, future studies investigating the CD127 expression on T cell subsets and the IL-7 response of these cells in late presenters initiation cART would be valuable. Subcutaneous administration of recombinant human IL-7 in HIV-infected individuals have been showed to be well tolerated in phase I/II studies and resulted in a dose dependent, long lasting increase in CD4 cell count.39,40 The present study adds significant knowledge of IL-7 and IL-7R in late presenters with reduced chance of optimal immune recovery and may be taken in mind considering future investigations of IL-7 administration as a supplement to cART to improve immune recovery.
In conclusion, reduced IL-7R T cell expression and increased plasma sCD127 before initiating cART in late presenters was found. Interestingly, this was only found in late presenters with advanced disease and was largely normalized after cART initiation. These findings may be explained by a deeply compromised immune system, including the IL-7/IL-7R system in HIV-infected presenting with CD4 cell count below 200 cells per microliter. Associations between baseline IL-7 and IL-7 expression and total CD4 T cell recovery were not evident. However, an association between high pre-cART IL-7Rα density on CD4+ T cells and increases in thymic output after 24 months of cART was found indicating the importance of the IL-7 response for the long-term immune recovering after initiation of cART.
The authors gratefully acknowledge the participants who made this study possible.
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