MicroRNA profiling in plasma of HIV-1 infected patients: potential markers of infection and immune status
Original Article

MicroRNA profiling in plasma of HIV-1 infected patients: potential markers of infection and immune status

Yuhua Qi1*, Haiyang Hu1*, Hongxiong Guo1, Peng Xu2, Zhiyang Shi1, Xiping Huan1, Zheng Zhu1, Minghao Zhou1, Lunbiao Cui1

1Key Laboratory of Enteric Pathogenic Microbiology, Ministry of Health, Institute of Pathogenic Microbiology, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing 210009, China; 2State Key Laboratory of Bioelectronics, School of Biological Science & Medical Engineering, Southeast University, Nanjing 210096, China

Contributions: (I) Conception and design: Y Qi, L Cui; (II) Administrative support: Z Shi, M Zhou; (III) Provision of study materials or patients: H Hu, X Huan; (IV) Collection and assembly of data: Z Zhu, H Guo; (V) Data analysis and interpretation: Y Qi, P Xu; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

*These authors contributed equally to this work.

Correspondence to: Lunbiao Cui. Key Laboratory of Enteric Pathogenic Microbiology, Ministry of Health, Institute of Pathogenic Microbiology, Jiangsu Provincial Center for Disease Control and Prevention, 172 Jiangsu Rd, Nanjing 210009, China. Email: lbcui@jscdc.cn.

Background: Circulating miRNAs are recently used as promising biomarkers for infectious diseases. The aim of this study was to identify plasma miRNAs for infection detection and monitoring the immune status of HIV infection.

Methods: A cohort of 128 plasma samples from HIV-1 infected subjects and 37 samples from healthy donors were analyzed by TaqMan Low-Density Array (TLDA) method to find the differentially expressed miRNAs, in the light of HIV-1infected patients with low (<200 cell/µL), medium (200–350 cell/µL), and high (>350 cell/µL) CD4+ T cell count.

Results: Seven miRNAs (miR-29a, miR-223, miR-27a, miR-19b, miR-151-3p, miR-28-5p, miR-766 and miR-30a-3p) were significantly associated with CD4+ T cell count (P<0.05) and thus have a great potential to serve as biomarkers for monitoring the HIV immune status. A combination of five miRNAs (miR-29a, miR-223, miR-27a, miR-19b, miR-151-3p) were found to distinguish the HIV-1 infected patients from healthy controls with sensitivity of 96.1% and specificity of 97.3% by RT-qPCR and receiver operational characteristic (ROC) curve analysis (AUC =0.99).

Conclusions: We have identified highly sensitive and specific signatures of circulating miRNAs enabling non invasive detection and immune status monitoring of HIV-1 infection.

Keywords: HIV; miRNA; infection diagnosis; immune status


Received: 10 May 2017; Accepted: 23 May 2017; Published: 03 July 2017.

doi: 10.21037/jphe.2017.05.11


Introduction

Over the past decade, acquired immunodeficiency syndrome (AIDS) caused by HIV-1 infection began to spread from the original drug use, commercial sex workers and other high-risk groups to the general population. By the end of 2014, nearly 501,000 HIV/AIDS people (including 59.1% HIV people and 40.9% AIDS patients) and 159,000 deaths had been reported in China (1). However, HIV-1 is continuing to spread, with an estimated rate of about 50,000 new infections annually (1). Rapid and accurate diagnostic tools were essential for early detection and monitoring the immune status of HIV-1 infection. Current laboratory tests can detect HIV-1 antibodies, viral nucleic acids, CD4+ T lymphocytes, and p24 antigens (2). HIV-1 antibody test is the gold standard, but sometimes the false negative results could be detected during the window period of infection. As the main target cells of HIV, the CD4+ T cell counts are useful to monitor how effective antiretroviral treatment (ART) is in suppressing the virus and determine the risk of progression of HIV disease.

Recently, several miRNAs are being used as biomarkers for the diagnosis of infectious diseases. MicroRNAs (miRNAs) are small (21–22 nt), non-coding RNAs which could play important roles in infectious diseases (3,4). Previous studies have found the different expression pattern of miRNAs in PBMCs, CD8+ T cells, monocytes and CD4+ T cells from HIV-1 infected subjects (5-9). Huang et al. has established that five miRNAs including miR-28 and miR-223 can directly target to the 3’ end of HIV mRNAs in order to inhibit viral mRNA expression in CD4+ T cells (5). Wang et al. has reported that miR-223 and miR-28 showed different expression level between monocytes and macrophages in HIV infection (6). Other studies have shown that miR-29a in the PBMC and CD4+ T cells can reduce viral replication (10). Furthermore, circulating miRNAs have been intensively studied in various cancers and infectious diseases (11-16). Serum/plasma miRNAs are stable, resistant to RNase digestion and consistent in the same species which could act as useful biomarkers for disease detection (17,18).

The goal of our study was set to identify differentially expressed miRNAs isolated from HIV-1 individuals that could be used to assist in HIV-1 detection and analyze the potential biological functions of these miRNAs. To further illustrate the correlation between miRNAs expression and HIV/AIDS immune progression, we have separated the HIV-1 infected individuals into three groups according to the CD4+ T cell level and have analyzed the expression level of the candidate miRNAs in these three groups.


Methods

Sample collection

A total of 165 participants (37 healthy subjects and 128 patients with HIV-1 infection) were enrolled in the Jiangsu Province in 2013. The 128 infected people were categorized into low (CD4 <200 cell/ µL) (n=41), medium (200< CD4 <350 cell/µL) (n=44) and high (CD4 >350 cell/ µL) (n=43) groups based on CD4+ T cell count. Among them, ten subjects (sex and age matched) from each group were used in the Taqman Low-Density Array (TLDA) study. All subjects taken by the RT-qPCR test were used for confirming the array data. Blood samples were obtained by venipuncture into BD Vacutainer tubes with EDTA-k2. The samples were centrifuged immediately at 2,000 ×g for 15 minutes at room temperature (RT). Aliquots of plasma were stored in −80 °C until use. Plasma samples were collected from confirmed HIV-1 infected patients without ART who had HIV-1 antibody positive results using HIV Western Blot Assay (MP Biomedicals Asia Pacific Pte Ltd, Singapore) at the time of enrollment. All people were not infected with hepatitis B and C viruses

Analysis of the plasma miRNA profile by TLDA

The plasma pools were created by combining ten samples (30 µL per sample) from four respective groups (control group; three HIV-1 infection groups with low, medium and high CD4+ T cells) for TLDA analysis. Total RNA was isolated from each pool of plasma samples using NucleoSpin miRNA Plasma kits (Macherey-Nagel GmbH & Co, Germany) following the manufacturer’s instructions. miRNA expression profiles were executed by the TLDA v3.0 (Applied Biosystems, USA) which can detect 754 miRNAs including 4 endogenous controls. The TLDA experiment was performed and analyzed as previously reported (19).

Confirmation Candidate miRNAs using RT-qPCR

Total RNA used for RT-qPCR assay was extracted from individual plasma sample following the instruction as above. Cel-miR-238 used as an internal control was added into each individual sample before starting the isolation procedure. To confirm the array results, candidate miRNAs were quantified for each individual plasma sample by RT-qPCR test. The RT-qPCR experiment was performed and analyzed as previously reported (19).

Statistical analysis

Log2 relative level was used to compare the difference between the target miRNA and cel-miR-238 (∆Cq). Student’s t-test was used to compare the differences in the miRNA expression between the two groups. 1-way ANOVA was used to compare between more than two groups and the differences between the groups were performed by the Fisher LSD test. A p value <0.05 shows the statistically significant. In addition, the area under curve (AUC) value and a receiver operating characteristic (ROC) curve were used to evaluate the diagnostic potential of each miRNA. 95% confidence intervals (CI) were used to detect the sensitivity and specificity of HIV-1 infection. In order to increase the accuracy of diagnostics, multiple logistic regression analysis was performed as previously reported (20).


Results and Discussion

Demographic characteristics of HIV-1 infected patient

Table 1 showed the demographic characteristics of HIV-1 infected patients. A total of 165 subjects were taken part in this study including 128 HIV-1 infected patients (87 males and 41 females; median age, 42.70±14.34 years) and 37 healthy people (18 males and 19 females; median age, 39.92±11.59 years). There was a significant difference (P<0.05, chi-square test) on the gender distribution between the HIV-1 infection and healthy people, but there was no significant difference in age between the two groups (P>0.05, t-test). The HIV-1 infected people were categorized into low (CD4 <200 cell/ µL), medium (200< CD4 <350 cell/ µL) and high (CD4 >350 cell/ µL) groups based on CD4+ T cell count. The first two groups showed significant differences (P<0.01 and P<0.05, chi-square test) in gender distribution between the HIV-1 infection and healthy people. There was no significant difference (P>0.05, chi-square test) in gender distribution in high CD4+ T cell count group. Although we found gender differences between the HIV-1 infection and healthy people, we and other study have shown that gender differences have no effect on miRNAs expression (15-17).

Table 1
Table 1 Demographic characteristics of HIV-1 infected patients and healthy controls
Full table

miRNA profiling analysis in control and HIV-1 Infected groups

TLDA analysis was executed to identify the differentially expressed level in HIV-1 subjects with low, medium, high CD4+ T cell count (LTC, MTC, and HTC), and control subjects. Results from LTC, MTC, and HTC groups were compared with the control group. Of the 754 host miRNAs (including endogenous controls) incorporated in the array, 231, 345, 315, and 257 miRNAs (Cq values <40) were detected in plasma of healthy controls, LTC, MTC, and HTC groups, respectively. In order to screen out HIV-specific candidate miRNAs, we set up two criteria: (I) Cq values <35 in both of two groups; and (II) Fold change ≥2 between the two groups. Total of 150 miRNAs met the two criteria in LTC subjects, of which 147 were up-regulated and 3 were down-regulated compared to controls (Table S1). Similarly, in the MTC group, a total of 150 miRNAs (148 up-regulated and 2 down-regulated) were differentially regulated compared to healthy controls (Table S2). However, in the HTC group, only 117 miRNAs (115 up-regulated and 2 down-regulated) were differentially regulated compared to healthy controls (Table S3). Figure 1 displays the number and overlap of significantly dysregulated miRNAs which are specific to each group. A total of 112 miRNAs (LTC and HTC combined) showed different expression in HIV-1 infection compared with healthy controls (CT). Similarly, 145 miRNAs (LTC and MTC combined) and 113 miRNAs (MTC and HTC combined) were significantly dysregulated in the infection. Among the 150 miRNAs that were dysregulated between the controls and LTC groups, 4 were unique to the LTC group. When the control was compared with MTC and HTC separately, 3 of the 150 and 3 of the 117 miRNAs were specific to the MTC and HTC groups. While comparing all the three groups, there were 111 different expressed miRNAs in all of them. Based on the HIV infection literatures and the results of target gene analysis, 12 miRNAs (miR-29a, miR-223, miR-27a, miR-19b, miR-766, miR-28-5p, miR-151-3p, miR-30a-3p, miR125b, miR-18a, miR-1197 and miR-518b) were selected for further analysis. Among these, 9 miRNAs (miR-223, miR-19b, miR-27a, miR-30a-3p, miR-151-3p, miR-766, miR-28-5p, miR-125b, and miR-18a) were commonly up-regulated in all three groups. Mir-29a was up-regulated expression in LTC and MTC groups but not in HTC group. MiR-1197 and miR-518b were unique in LTC and HTC groups, separately.

Table S1
Table S1 Differential expressed miRNAs in HIV- infected subjects with CD4 <200 T+ cell count (LTC) compared with controls
Full table
Table S2
Table S2 Differential expressed miRNAs in HIV-infected subjects with 200< CD4 <350 T+ cell count (MTC) compared with controls
Full table
Table S3
Table S3 Differential expressed miRNAs in HIV- infected subjects with CD4 >350 T+ cell count (HTC) compared with controls
Full table
Figure 1 Expression profile of differentially regulated miRNAs in HIV-1 infected and controls. The Venn diagram displays the number and overlap of significantly differentially expressed miRNAs among the LTC, MTC, and HTC groups relative to the controls (CT) and within the infected groups.

RT-qPCR confirmation of miRNA expression in HIV-1 infected subjects

RT-qPCR (TaqMan miRNA assays) was used to confirm the expression levels of 12 candidate miRNAs which were identified by TLDA. Eight miRNAs (miR-29a, miR-19b, miR-223, miR-27a, miR-151-3p, miR-766, miR-28-5p, and miR-30a-3p) were significant up-regulation in HIV-1 infected plasma (P<0.05, student’s t-test) (Figure 2) compared to healthy control. However, there was no significant difference in other four miRNAs (miR-1197, miR-125b, miR18a, and miR-518b) in HIV-1 subjects compared to healthy controls (data not shown).

Figure 2 Eight miRNAs expression levels were analyzed in the plasma of HIV-1 infected subjects and healthy controls using RT-qPCR. Plasma levels of miR-29a, miR-223, miR-27a, miR-19b, miR-151-3p, miR-28-5p, miR-766, and miR-30a-3p were significantly higher in HIV infected subjects compared with those in the control group (**, P<0.01). Expression levels of the miRNAs were normalized to cel-miR-238 (Log2 relative level).

Diagnostic potential of plasma miRNAs

ROC curve analysis was performed to evaluate the diagnostic potential of candidate miRNAs. The ROC curves of miR-29a, miR-223, miR-27a, miR-19b and miR-151-3p showed a high discrimination with AUC value of 0.949 (95% CI: 0.915-0.983), 0.905 (95% CI: 0.860–0.949), 0.897 (95% CI: 0.848–0.946), 0.989(95% CI: 0.974–1.003), 0.967(95% CI: 0.941–0.992), respectively (Figure 3). MiR-28-5p (95% CI: 0.703–0.859), miR-766 (95% CI: 0.694–0.842), and miR-30a-3p (95% CI: 0.680–0.834) showed a moderate discrimination with AUC value less than 0.8 (Figure 3). In order to increase the diagnostic efficiency of these markers, a combination of five miRNAs were used to show strong discrimination between the HIV-1 and control samples with high AUC value of 0.990 (Figure 4). Table 2 exhibits the specificity and sensitivity of each candidate miRNA with an optimal cutoff value. A cutoff value set at −6.00, the combined miRNAs showed a specificity of 97.3% and a sensitivity of 96.1% (Table 2).

Figure 3 Receive operating characteristic (ROC) curves of differentially expressed miRNAs between HIV-1 infected subjects and healthy controls. ROC curves of miR-29a, miR-223, miR-27a, miR-19b, miR-151-3p, miR-28-5p, miR-766, and miR-30a-3p showed a different distinguishing efficiency.
Figure 4 Receive operating characteristic (ROC) curves of differentially expressed miRNAs between HIV-1 infected subjects and healthy controls. The combination of the five miRNAs showed a higher AUC value of 0.990.
Table 2
Table 2 The sensitivity and specificity of candidate miRNAs and the combination of five miRNAs to diagnose HIV-1 infection with an optimal cutoff value
Full table

Different expression levels of eight miRNAs in LTC, MTC, and HTC groups

To monitor HIV/AIDS immune status, we further distinguished the expression levels of eight candidate miRNAs in LTC, MTC and HTC groups. The expression levels of miR-29a, miR-223, miR-27a, miR-19b, miR-151-3p, miR-766 and miR-30a-3p showed a significant difference among the LTC, MTC and HTC groups (P<0.05, ANOVA test). However, there was no significant difference in the expression levels of miR-28a-5p among these three groups (P>0.05, ANOVA test). Furthermore, multiple comparisons were carried out using the least significant difference (LSD) method. Figure 5 shows the different expression level of each miRNA in these three groups. Results from the comparison of the LTC and HTC groups indicated that six out of seven miRNAs (miR-29a, miR-151-3p, miR-223, miR-30a-3p, miR-19b, and miR-766) were significantly up-regulated (P<0.05, LSD test) in HTC group while miR-27a had no significant difference. The comparison between LTC and MTC groups showed that all the seven miRNAs were significantly up-regulated in MTC group (P<0.05, LSD test). While comparing MTC and HTC groups, only miR-27a showed a significant down-regulation in HTC group (P<0.001, LSD test). Altogether, our results showed that the expression levels of seven candidate miRNAs are significantly associated with CD4+ T cell count. Previous study showed that several host miRNAs play an important role in disease development (21-23)). For example, Patel et al. indicated that the miR-29a expression level was higher in PBMC and plasma from asymptomatic person (high CD4+ T cells) in whom virus replication is restricted, compared to symptomatic patients (low CD4+ T cells) in whom there is active viral replication (24)). Our results have shown that miR-29a, miR-223, miR-19b, miR-151-3p, miR-766 and miR-30a-3p have higher expression pattern in plasma from HIV-1 infected person with high CD4+ T cells compared to patients with low CD4+ T cells. Thus we hypothesize that the expression level of these six miRNAs may increase during HIV-1 latency and decrease during active viral replication although the mechanisms are still unknown. We noted that the baseline of CD4+ T cell count is very important. Compared with baseline CD4 <200 cell/µL, HIV-1 infected person with baseline CD4 >350 cell/µL or 200< CD4 ≤350 cell/µL showed similar expression pattern of above six miRNAs. A previous study has shown that patients with low level of CD4 + T cell count (CD4 <200 cell/µL) could impact immunological restoration (25). The CD4+ T cells are very important in forming immune response during HIV infection. So, our study showed that these six miRNAs could serve as useful biomarkers for monitoring the immune status of HIV/AIDS progression.

Figure 5 Different expression level of each miRNA in LTC (N=41), MTC (N=44) and HTC (N=43) groups using RT-qPCR. The least significant difference (LSD) method was used for pairwise comparison between all pairs of groups (*, P<0.05; **, P<0.01; ***, P<0.001; NS, not significant). Expression levels of the miRNAs were normalized to cel-miR-238 (Log2 relative level).

More and more researchers have attracted the attention of the role of miRNAs in pathogen-host interactions. Human miRNAs involved in many biological process, molecular function, and regulation pathways. During HIV-1 infections, miRNAs can either affect viral replication by targeting HIV-1 directly or modulate the expression of host genes and pathways essential for it by targeting host protein (26). For example, cellular miR-29a has been shown to inhibit HIV-1 replication by targeting the HIV-1 Nef transcripts (10,27). Also, cellular miR-28, miR-223, miR125b, miR-382 and miR-150 have been shown to be increased in resting primary CD4+ T cells compared to activated CD4+ T cells and can reduce HIV-1 replication by targeting HIV-1 mRNA transcripts (5). Our results also have shown a similar pattern of up-regulated miRNA expression such as miR-29a, miR-28 and miR-223 in plasma isolated from HIV-1 infected subjects. One study reported that miR-27a could decrease the phosphorylation of Akt and ERK, which could inhibit EV71 replication by targeting EGFR mRNA (28). The other study has demonstrated that miR-27a showed down-regulated in macrophages by targeting IL-10 through TLR2/4-driven inflammatory responses (29). Only 5% people known as HIV controllers can maintain high levels of T cells without antiretroviral therapy for more than 5 years (30). HIV/AIDS may cause serious complications including serious pneumonia, central nervous system complications, opportunistic infections and various viral-induced cancers (31,32). Previous studies have shown that over-expression of miR-19b and miR-151 was strongly associated with cancer invasion and metastasis (33-35). However, the mechanisms remain largely unknown. For the first time, our study has shown that higher level of miR-19b and miR-151-3p were expressed in HIV-1 patient plasma compared with healthy controls. Further studies are needed to reveal the function of them in HIV-1 infected subjects.


Conclusions

TLDA assays identified the differential expression of 231, 345, 315, and 257 miRNAs in plasma of healthy controls and HIV-1 LTC, MTC, and HTC groups, respectively. 5 miRNAs (miR-29a, miR-223, miR-27a, miR-151-3p and miR-19b) was combined as a useful biomarker for simple and efficient detection of HIV-1 infection. The biological mechanisms of these miRNAs need further investigation. Our results showed that the expression level of seven candidate miRNAs (miR-29a, miR-223, miR-766, miR-19b, miR-151-3p, miR-27a, and miR-30a-3p) were significantly associated with CD4+ T cell count and thus may serve as biomarkers for monitoring the HIV/AIDS immune progression. However, there are several limitations in our study. Firstly, not all of dysregulated miRNAs were confirmed in present study and other miRNAs might serve as more efficient biomarkers. Secondly, a larger numbers of subjects are required to confirm our study.


Acknowledgements

The authors thank Doulathunnisa Ali help to correct the manuscript and thank the patients who participated in our study.

Funding: This work was supported by the Natural Science Foundation of Jiangsu Province (bk20131451, bk20161583andbk20141030) and Jiangsu Province Science & Technology Demonstration Project for Emerging Infectious Diseases Control and Prevention (BE2015714).


Footnote

Conflicts of Interest: The authors have no conflicts of interest.

Ethical Statement: The study has been approved by the Ethics Committee of Jiangsu Provincial Center for Diseases Prevention and Control (approval number: JSCDCLL2013014). The written informed consent was obtained from all participants.


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doi: 10.21037/jphe.2017.05.11
Cite this article as: Qi Y, Hu H, Guo H, Xu P, Shi Z, Huan X, Zhu Z, Zhou M, Cui L. MicroRNA profiling in plasma of HIV-1 infected patients: potential markers of infection and immune status. J Public Health Emerg 2017;1:65.

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