CD4 + T Memory Stem Cells Correlate with Disease Progression in Chronically HIV-1-Infected Patients

Abstract

Recently identified T memory stem (Tscm) cells have stem-cell-like properties, including long lifespan, self-renewal capacity, and multipotency to differentiate into other memory T cell types. In the study of simian immunodeficiency virus (SIV) infection, selective depletion of CCR5⁺CD4⁺ Tscm cells and the high proliferation rate of these cells are believed to be responsible for the pathogenesis of SIV-infected rhesus macaques. Here, we conducted a cohort study to investigate the influence of chronic human immunodeficiency virus (HIV)-1 infection on CD4⁺ Tscm cell homeostasis, and the effect of antiretroviral therapy (ART) on CD4⁺ Tscm cells. Chronic HIV-1 infection resulted in a decrease of the CD4⁺ Tscm cell proportion in HIV-1 patients. The decreased number of CD4⁺ Tscm cells in HIV-1 patients correlated positively with that of circulating CD4⁺ T cells. Further, the depletion of CD4⁺ Tscm cells was inversely correlated with an increased level of T cell immune activation during chronic HIV-1 infection. Prolonged ART recovered the CD4⁺ Tscm cells, and the dynamic change of CD4⁺ Tscm cells was in parallel with CD4⁺ T cell restoration and a decrease in the level of T cell immune activation. We propose that the abnormity of CD4⁺ Tscm cells may contribute to the pathogenesis and disease progression in HIV-1-infected individuals.

Introduction

Memory T cells are usually divided into central memory T (Tcm) cells and effector memory T (Tem) cells according to the expression of lymph node-homing C-C motif receptor (CCR) 7 and isoforms of the protein tyrosine phosphatase CD45 (CD45RA or CD45RO) on the T cell surface (Tcm cells: CD45RA⁻CCR7⁺; Tem cells: CD45RA⁻CCR7⁻) (27). Recently, a relatively small-memory T cell subset, termed T memory stem (Tscm) cells, was identified in mice, non-human primates (NHPs), and humans (11,18,19). Tscm cells are found predominantly in peripheral blood and secondary lymphoid tissues (18). These cells can be generated from naive T (Tn) cells in vitro, and they have a similar phenotype (CD45RO⁻CD45RA⁺CCR7⁺CD62L⁺CD27⁺CD28⁺ IL-7Rα⁺) to that of Tn cells, but they also co-express the memory marker CD95 (11,19). Functionally, Tscm cells exhibit stem cell properties, including long lifespan and homeostatic self-renewal capacity (11). Tscm cells are believed to be the least differentiation memory T cells, and they undergo robust proliferation and differentiate into other memory T cell types after re-exposure to antigens (11,13). In addition, Tscm cells display a superior antitumor capacity and immune reconstitution potential compared with Tcm and Tem cells due to their properties of long lifespan, homeostatic self-renewal capacity, and robust proliferative ability (1,8,11 –13,26).

There is increasing evidence demonstrating that Tscm cells play a crucial role in human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) pathogenesis. CD4⁺ Tscm cells are susceptible to both CXCR4- and CCR5-tropism HIV-1 strains and can be a stable HIV-1 latent reservoir regardless of successful antiretroviral therapy (ART) (2,5,7,10,15,17,29). CD8⁺ Tscm cells correlate with HIV-1 disease progression (24). Maintenance of HIV-1-specific CD8⁺ Tscm cells during long-term ART raises the possibility that a combination of HIV-1-specific CD8⁺Tscm cells and latency-reversing agents may support the elimination of the HIV-1 residual reservoir (30). An SIV study showed that, in contrast to pathogenic SIV-infected rhesus macaques (RMs), the resistance of CCR5⁺CD4⁺ Tscm cells to SIV infection and the preservation of these cells are responsible for the nonpathogenic infection in SIV natural hosts such as sooty mangabeys (SMs) (3). ART induces restoration of CCR5⁺CD4⁺ Tscm cells in blood and lymphoid nodes of RMs (4). However, the proviral DNA in CD4⁺ Tscm cells does not decline in RMs after ART, supporting the contribution of Tscm cells to persistent SIV infection (4).

Thus far, the abnormity of CD4⁺ Tscm cells in HIV-1 infection and the effect of ART on the dynamic change of CD4⁺ Tscm cells are not well documented. Therefore, we conducted longitudinal analysis of CD4⁺ Tscm cells in the circulating blood of HIV-1 patients by using an ART-treated cohort. We found that HIV-1 infection resulted in a significant decrease in the proportion of CD4⁺ Tscm cells. The reduction of CD4⁺ Tscm cells was correlated with the loss of circulating CD4⁺ T cells and the high level of T cell immune activation in HIV-1 patients. In addition, prolonged ART induced restoration of CD4⁺ Tscm cells. Increased CD4⁺ Tscm cells contributed to the recovery of circulating CD4⁺ T cells and the decline of T cell immune activation to a normal level. Overall, our study further implicates the important role of CD4⁺ Tscm cells in the pathogenesis and immune reconstitution of HIV-1 patients.

Materials and Methods

Patients and samples

Twenty-five chronic HIV-1 patients were recruited from the ART-treated chronic patient cohort in Beijing You'an Hospital. Thirty-six age-matched healthy controls (HCs) were also included in this study. No subject had hepatitis B or C virus co-infection.

After baseline evaluation, HIV-1 patients began treatment with antiretroviral drugs and were followed up every 3 months. The ART regimen included AZT (Zidovudine)/3TC (Lamivudine)/NVP (Nevirapine) (n = 12) or TDF (Tenofovir)/3TC/EFV (Efavirenz) (n = 13). Blood samples from the HIV-1 patients were collected at baseline and at each followed-up time point. Peripheral blood mononuclear cells (PBMCs) from whole blood were isolated by density gradient centrifugation and stored in liquid nitrogen. All participants in this study provided written informed consent. This study was approved by the Beijing You' an Hospital Research Ethics Committee.

Immunophenotyping

Cryopreserved PBMCs were thawed in RPMI 1640 medium (Invitrogen, Carlsbad, CA) and washed with phosphate-buffered saline (PBS) containing 1% bovine serum albumin. The cells were stained with the following anti-human antibodies purchased from Biolegend (San Diego, CA): CD3 APC-cy7 (SK7), CD4 FITC (SK3), CD8 Percp-cy5.5 (RPA-T8), CD45RA PE-cy7 (HI100), CCR7 APC (G043H7), CD27 PE (O323), CD95 BV421 (DX2), CD38 PE (HIT2), and HLA-DR APC (TU36). At least 50,000 live lymphocytes were analyzed with a BD FACSCanto II flow cytometer (BD Biosciences, San Diego, CA). The final analysis was performed by using Flowjo 7.6.1 software (Tree Star, Inc., Ashland, OR).

Measurements of CD4⁺ T cell numbers and plasma viral load

Routine CD4⁺ T TruCount (BD Biosciences) and plasma HIV-1 viral load (pVL, Versant440; Siemens Healthcare Diagnostics, Germany) were measured according to the manufacturers' instructions. The detecting limitation of pVL is 50 copies/mL.

Statistical analysis

All statistical analyses were performed by using GraphPad Prism software v5.0 (GraphPad Software, Inc., La Jolla, CA). Statistical significance between two groups was calculated by using the nonparametric Mann–Whitney U-test, whereas comparisons among ART periods (Fig. 3) were determined by the Kruskal–Wallis one-way analysis of variance (ANOVA) with Dunn's comparison test. Correlations were determined by the Spearman rank correlation test. A p-value of less than 0.05 represented significance.

Results

Loss of CD4⁺ Tscm cells in HIV-1 infection

Twenty-five chronic HIV-1 patients and 36 HCs were included in our study. The baseline characteristics of HIV-1 patients and HCs are presented in Table 1. Table 2 is the CD4⁺ T cells and pVL pre-ART or on ART in each individual. All subjects were male. The frequency of CD4⁺ T cells in HIV-1 patients was significantly lower than that in HCs (p < 0.0001). The total circulating CD4⁺ T cell count was not compared between HIV-1 patients and HCs because of a lack of CD4⁺ T cell data from HCs. ART resulted in the decrease of pVL to an undetectable level in all patients. To determine the influence of chronic HIV-1 infection on CD4⁺ Tscm cells, we compared the frequency of circulating CD4⁺ Tscm cells in HIV-1 patients and HCs. CD4⁺ Tscm cells were defined as CD3⁺CD4⁺CD45RA⁺CCR7⁺CD27⁺CD95⁺ (Fig. 1A). As shown in Figure 1B, the CD4⁺ Tscm cell proportion was decreased significantly by chronic HIV-1 infection compared with HCs (p < 0.0001).

FIG. 1.

Decreased proportion of CD4⁺ Tscm cells in chronically HIV-1-infected patients. (A) Flow cytometry gating strategy for CD4⁺ Tscm cells. The cells were gated as follows: (i) CD3 for lymphocytes, (ii) CD4⁺ T cells, (iii) CCR7 and CD45RA for Tcm and Tem cells, and (iv) CD27 and CD95 for Tscm and Tn cells. Tcm: CD45RA⁻CCR7⁺; Tem: CD45RA⁻CCR7⁻; Tscm: CD45RA⁺CCR7⁺CD27⁺CD95⁺; Tn: CD45RA⁺CCR7⁺CD27⁺ CD95⁻. Representative data of one HC and two HIV patients are shown. The percentage of CD4⁺ Tscm cells is shown among HCs and HIV patients. (B) The frequencies of CD4⁺ Tscm between HCs and HIV-1 patients are shown, with statistical significance indicated by ***p < 0.0001. The Mann–Whitney U-test was used for group comparisons. Error bars represent the mean ± SEM, n = 36 for HCs and n = 25 for HIV-1 patients.

Table 1.

Summary of Study Subjects' Characteristics

Baseline characteristic	Healthy controls	HIV-1 patients
Subjects(n)	36	25
Age, median (range), year	36(26–52)	33(27–58)
%CD4⁺ T, median (range)	42.05(18.6–60.6)	17.1(8.35–29.6)^***
CD4⁺ T, median (range), cells/μL	NA	269(120–350)
Plasma HIV RNA, median (range), log₁₀ copies/mL	NA	4.4(1.7–6.1)

HIV, human immunodeficiency virus; NA, not applicable.

***

p < 0.0001 compared with healthy controls.

Table 2.

Patients' Characteristics Pre- or On Antiretroviral Therapy

	0 W		12 W		24 W		36 W		48 W		72 W		96 W		120 W		144 W
ID	CD4	VL	CD4	VL	CD4	VL	CD4	VL	CD4	VL	CD4	VL	CD4	VL	CD4	VL	CD4	VL
1	235	72,000	341	N/A	325	TND	256	N/A	228	TND	288	N/A	426	TND	684	TND	367	TND
2	345	3,30,000	498	N/A	333	TND	239	N/A	503	TND	565	N/A	601	TND	611	TND	475	TND
3	328	15,00,000	181	N/A	384	TND	329	N/A	457	TND	479	N/A	686	TND	576	TND	542	TND
4	309	18,000	801	N/A	538	TND	619	N/A	754	TND	513	N/A	1319	TND	759	TND	751	TND
5	342	2,400	569	N/A	412	TND	426	N/A	487	TND	474	N/A	585	TND	464	TND	295	TND
6	223	1,60,000	322	N/A	313	150	508	N/A	315	TND	556	N/A	818	TND	613	TND	474	TND
7	151	74,000	245	N/A	252	TND	337	N/A	264	TND	272	N/A	296	TND	536	TND	337	TND
8	328	54	359	N/A	331	300	357	N/A	421	TND	425	N/A	729	TND	669	TND	603	TND
9	240	24,000	277	N/A	334	50	476	N/A	359	TND	435	N/A	472	TND	245	TND	364	TND
10	258	6,600	394	N/A	563	50	396	N/A	502	TND	909	N/A	575	TND	554	TND	475	TND
11	126	1,30,000	213	N/A	172	90	195	N/A	332	TND	334	N/A	423	TND	374	TND	289	TND
12	244	1,90,000	242	N/A	460	TND	425	N/A	387	TND	406	N/A	971	TND	509	TND	345	TND
13	254	200	457	N/A	303	TND	414	N/A	356	TND	458	N/A	411	TND	341	TND	418	TND
14	350	1,50,000	275	N/A	233	TND	360	N/A	395	TND	473	N/A	327	TND	357	TND	336	TND
15	248	1,70,000	209	N/A	244	TND	341	N/A	439	TND	319	N/A	324	TND	476	TND	492	TND
16	313	1,50,000	263	N/A	346	TND	300	N/A	359	TND	415	N/A	526	TND	393	TND	435	TND
17	301	4,500	408	N/A	452	TND	429	N/A	336	TND	308	N/A	458	TND	445	TND	364	TND
18	276	77,000	319	N/A	487	TND	598	N/A	537	TND	694	N/A	596	TND	801	TND	712	TND
19	191	1,50,000	258	N/A	377	TND	507	N/A	432	TND	366	N/A	563	TND	656	TND	1052	TND
20	279	67,000	374	N/A	338	TND	431	N/A	362	TND	346	N/A	466	TND	322	TND	491	TND
21	283	1,400	326	N/A	337	TND	497	N/A	562	TND	517	N/A	519	TND	539	TND	1202	TND
22	246	1,400	408	N/A	324	TND	492	N/A	767	TND	847	N/A	664	TND	613	TND	542	TND
23	295	1,189	540	N/A	318	TND	610	N/A	527	TND	665	N/A	649	TND	599	TND	599	TND
24	267	2,457	406	N/A	498	TND	622	N/A	468	TND	580	N/A	481	TND	442	TND	408	TND
25	269	9,951	714	N/A	598	TND	573	N/A	794	TND	798	N/A	629	TND	483	TND	398	TND

NA, not applicable.

TND, pVL <50 copies/mL.

Baseline CD4⁺ Tscm correlate with disease progression markers

To investigate the significance of CD4⁺ Tscm cells in HIV-1 pathogenesis, we next evaluated the correlation between baseline CD4⁺ Tscm cells in HIV-1 patients and HIV-1 disease progression markers, including the total circulating CD4⁺ T cell count, pVL, CD4/CD8 ratio, and the level of T cell immune activation. We found that both the frequency and count of baseline CD4⁺ Tscm cells in HIV-1 patients were positively correlated with the total circulating CD4⁺ T cell count (r = 0.36, p = 0.04, r = 0.67, p = 0.0002, respectively, Fig. 2A, B). In addition, baseline CD4⁺ Tscm cell count was also positively correlated with CD4/CD8 ratio (Fig. 2C, D). However, there was no correlation between baseline CD4⁺ Tscm cells and pVL in HIV-1 patients (data not shown). In addition, the level of T cell immune activation is an important disease marker in HIV-1 pathogenesis. Here, co-expression of CD38 and HLA-DR on the surface of CD8⁺ T cells was used as the T cell immune activation marker. The number of CD38⁺HLA-DR⁺CD8⁺ T cells in HIV-1 patients was much higher than that in HCs (p < 0.0001, Fig. 2E). A significantly negative correlation between CD38⁺HLA-DR⁺CD8⁺ T cells and the CD4⁺ Tscm cell count was observed at baseline in HIV-1 patients (r = −0.45, p = 0.03, Fig. 2F, G).

FIG. 2.

CD4⁺ Tscm cell counts are correlated with disease progression markers. Correlation between baseline CD4⁺ Tscm cells and CD4⁺ T cells (A, B) or CD4/CD8 ratio (C, D) in chronic HIV-1 patients was shown. (E) Comparison of the baseline level of T cell immune activation between HCs and chronic HIV-1 patients. Correlation between the baseline level of T cell immune activation and the CD4⁺ Tscm cell proportion (F) or the CD4⁺ Tscm cell count (G) in HIV-1 patients. The Mann–Whitney U-test was used for group comparisons. Error bars represent the mean ± SEM. The Spearman rank test was used for correlation analysis. ***p < 0.0001.

Dynamic change in CD4⁺ Tscm cells during long-term ART

A recent study showed that ART induces partial restoration of the proportion of CCR5⁺CD4⁺ Tscm cells but not total CD4⁺ Tscm cells in both PBMCs and lymph nodes during SIV infection (4). Therefore, we investigated the effect of ART on CD4⁺ Tscm cells in HIV-1 patients and the correlation between the change of CD4⁺ Tscm cells and disease markers. As expected, compared with the baseline, the circulating CD4⁺ T cell count increased gradually (p < 0.0001, Fig. 3A). Long-term ART resulted in the decrease of pVL to an undetectable level in all patients (p < 0.0001, Fig. 3B), and the level of CD38⁺HLA-DR⁺CD8⁺T cells was also reduced significantly (p < 0.0001, Fig. 3C). The CD4⁺ Tscm cell count was also increased at 144 weeks post-ART compared with at baseline (p < 0.01, Fig. 3D). Overall, the dynamic change in the CD4⁺ Tscm cell count in response to ART was similar to the change in circulating CD4⁺ T cells, and it was opposite to the change in the CD38⁺HLA-DR⁺CD8⁺ T cell level. Analysis of individual patients also demonstrated this close relationship between CD4⁺ Tscm cells and the circulating CD4⁺ T cell count or the level of T cell immune activation during prolonged ART (Fig. 3E, F).

FIG. 3.

Response of CD4⁺ Tscm cells to ART in chronically HIV-1-infected patients. A total of 25 HIV-1 patients accepted stable ART for at least 2 years. Blood samples were collected at each followed-up time point. Changes in the CD4⁺ T cell count (A), HIV-1 viral load (B), the level of T cell immune activation (C), and CD4⁺ Tscm cell count (D) in all patients during ART are shown. Kruskal–Wallis one-way ANOVA was used for multiple comparisons. Error bars represent the mean ± SEM. **p < 0.01, ***p < 0.0001. Dotted line in (B), the detecting limitation of pVL (50copies/mL). Dynamic changes in CD4⁺ Tscm and CD4⁺ T cell counts (E) and the level of T cell immune activation (F) in three representative patients are shown. ART, antiretroviral therapy.

Discussion

CD4 depletion is a hallmark of HIV/SIV infection. The pathogenic mechanisms of CD4⁺ T cell depletion have been extensively studied in the past 3 decades. A better preserved CD4⁺ Tcm cell compartment is a key mechanism that is responsible for HIV/SIV pathogenesis (6,20,22), and CD4⁺ Tcm cell restoration is a critical parameter for immune reconstitution after ART (14,21,23). A novel memory T cell subset, termed as Tscm cells, has been recently identified. These Tscm cells have superior proliferation and self-renewal capacity, and they are precursors of other T memory cell types (11). The dynamics of CD4⁺ Tscm cells have been well investigated in pathogenic and nonpathogenic SIV infection of NHP models in the past 2 years (3,4). Therefore, in this study, we focused on how CD4⁺ Tscm cells are affected by HIV-1 infection and the contribution of CD4⁺ Tscm cells to HIV-1 disease progression.

The main findings of our study are that chronic HIV-1 infection results in a reduction of CD4⁺ Tscm cells, and the loss of these cells positively correlates with a CD4⁺ T cell decrease and inversely correlates with the level of T cell immune activation. In addition, ART restores CD4⁺ Tscm cells, and the dynamic change in CD4⁺ Tscm cells is closely related to that of CD4⁺ T cells and T cell immune activation in ART-treated HIV-1 patients.

CD4⁺ Tscm cells are more susceptible to R5-tropsim HIV strains than other memory T cell subsets (5). Compared with healthy SIV nonpathogenic SMs, RMs have a higher level of CCR5 expression, and selective infection and depletion of CCR5⁺CD4⁺ Tscm cells are observed in SMs, although SMs exhibit preservation of total CD4⁺ Tscm cells (3). In this study, a decrease of CD4⁺ Tscm cell was also found in HIV-1 patients (Fig. 1B). Therefore, the infection and loss of CD4⁺ Tscm cells could be a novel mechanism of HIV/SIV pathogenesis. In addition to the loss of CD4⁺ Tscm cells by direct virus infection, whether bystander apoptosis leads to CD4⁺ Tscm cell exhaustion should be investigated further.

Previous studies have demonstrated that stability of the CD4⁺ Tcm cell compartment is a key determinant in the timing of disease progression in HIV/SIV infection (20,22). Because of the ability to differentiate into other T memory cell types, CD4⁺ Tscm cells may also contribute to the maintenance of T cell homeostasis and disease progression of HIV/SIV infection. A comparative study between viremic non-progressors (VNPs) and putative progressors (PPs) revealed that VNPs preserve CD4⁺ Tscm cells with a higher proliferative potential compared with PPs (17). In addition, the limited infection of CD4⁺ Tcm and CD4⁺ Tscm cells is associated with the lack of progression in VNPs (17). In SIV-infected pathogenic RMs, increased CD4⁺ Tscm proliferation is the key feature distinguishing them from nonpathogenic SMs (3). The higher level of CD4⁺ Tscm cell proliferation inversely correlates with the proportion of CD4⁺ Tcm cells (3). In our study, a positive correlation was found between CD4⁺ Tscm count and CD4⁺ T cells pre-ART. Exhaustion of CD4⁺ Tscm cells may disturb the T cell homeostasis in HIV-1 or pathogenic SIV infections, and the CD4⁺ Tscm cell proliferation, at least in part, maintains T cell homeostasis and compensates for the loss of other memory T cells. Therefore, we proposed that the reduction of CD4⁺ Tscm cells may be responsible for the loss of CD4⁺ T cells during chronic HIV-1 infection. Further, CD4⁺ Tscm cells have a robust interleukin-2 secretion ability compared with other T memory cell types, which can help CD4⁺ Tscm cells to maintain their own homeostasis through proliferation (9,11).

Correction of the abnormity in CD4⁺ Tscm cells by ART administration was observed in our study and an SIV study, thus improving T cell homeostasis and immunological responses to HIV/SIV infection (Fig. 3) (4). However, ART cannot decrease SIV DNA in CD4⁺ Tscm cells in RMs, indicating persistent infection in CD4⁺ Tscm cells under ART (4). Consistent with RMs, the level of HIV-1 DNA in CD4⁺ Tscm cells does not decrease in HIV-1 patients (2). Therefore, a novel approach to reduce the CD4⁺ Tscm cell contribution to viral persistence should be developed to improve the outcome of HIV-1 treatment.

Decrease of T cell activation after ART has been well documented in many publications (16,25,28). Here, we observed a negative correlation between CD4⁺ Tscm cells and T cell activation at baseline, and an opposite dynamic change of them during long-term ART (Fig. 3). A study showed that the high frequency of CD4⁺ Tscm cells in the circulation expresses gut-homing marker α4β7 (24). Therefore, a potential mechanism of protective effect on T cell immune activation by CD4⁺ Tscm cells might be the maintenance of gut barrier function and the reduction of microbial translocation by the migration of α4β7⁺CD4⁺ Tscm cells from blood to gut mucosa.

In conclusion, this study provides evidence that HIV-1 infection induces the reduction of CD4⁺ Tscm cells, and CD4⁺ Tscm cells play an important role in both HIV-1 pathogenesis and disease progression.

Footnotes

Acknowledgments

The authors thank Wei Feng, Wei Xia, and Yuefang Zhou for the study cohort maintenance.

This study was supported by the National Natural Science Foundation of China (81501732 to XL), Beijing Municipal of Science and Technology Major Project (D161100000416003 to HW), the Funding for Chinese overseas talents returning to China in 2016 (to BS), and the Beijing Key Laboratory for HIV/AIDS Research (BZ0089).

Author Disclosure Statement

The authors of this article report no conflicts of interest.

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CD4 + T Memory Stem Cells Correlate with Disease Progression in Chronically HIV-1-Infected Patients

Abstract

Introduction

Materials and Methods

Patients and samples

Immunophenotyping

Measurements of CD4+ T cell numbers and plasma viral load

Statistical analysis

Results

Loss of CD4+ Tscm cells in HIV-1 infection

Baseline CD4+ Tscm correlate with disease progression markers

Dynamic change in CD4+ Tscm cells during long-term ART

Discussion

Footnotes

Acknowledgments

Author Disclosure Statement

References

Measurements of CD4⁺ T cell numbers and plasma viral load

Loss of CD4⁺ Tscm cells in HIV-1 infection

Baseline CD4⁺ Tscm correlate with disease progression markers

Dynamic change in CD4⁺ Tscm cells during long-term ART