Open Access

Compare mDCs and pDCs between two distinct patients groups in acute HIV-1 infection

Contributed equally
AIDS Research and Therapy201411:22

DOI: 10.1186/1742-6405-11-22

Received: 21 May 2014

Accepted: 22 July 2014

Published: 31 July 2014

Abstract

The role of DCs in primary HIV-1 infection remains uncertain. In this study, we enrolled two different groups of subjects with acute HIV-1 infection. One group progressed to CD4 counts below 200 cells/μl within 2 years of HIV-1 infection (CD4 Low Group), while the other group maintained CD4 counts above 500 cells/μl (CD4 High Group). We did not find statistical difference in the pDC number between the two groups during acute HIV-1 infection. However, the mDC number was significantly lower in the CD4 Low Group than in the CD4 High Group.

Keywords

Acute HIV-1 infection DCs Rapid disease progression

Introduction

Understanding how the innate immune response affects the outcome of HIV-1 infection in acute HIV-1 infection will open opportunities for vaccine development that can utilize the innate immunity to enhance viral control with minimal pathogenesis. Dendritic cells (DCs) are particularly important innate immune cells and HIV-1 exploits DCs to enhance infection. Thus, DCs are a critical link between virus, CD4+ T-cells, and CD8+ T-cells. DCs are divided into two broad subsets, myeloid (mDC) and plasmacytoid (pDC), based on phenotype, function, and tissue localization. Although details of these subsets are debated and vary based on species, pDCs are specialized early type 1 interferon-secreting cells that initiate antiviral adaptive immune responses. mDCs differentiate from immature bone marrow (BM)-derived precursors and function as peripheral sentinels by transmitting antigen derived signals to draining lymph nodes (LN). mDCs secrete high levels of interleukin-12 (IL-12) and are key players in amplifying adaptive immune responses[1]. Early immune events during HIV infection are associated with the rate of subsequent disease progression. A role for DCs in controlling HIV-1 replication during primary infection has been difficult to assess, given the difficulties in finding individuals with acute HIV infection. The aim of this study is to study the relationship between DCs number in acute infection and disease progression.

Materials and methods

Patients

35 patients recently infected with HIV-1 were recruited from an HIV-1-negative high-risk MSM (men who have sex with men) cohort. They were screened every 2 m for HIV-1 infection from October 2006 in the Beijing You’an Hospital [2]. Thirteen of the 35 patients showed rapid progression of HIV-1 disease, with CD4 counts < 200 cells/ul within 2 y post-infection (CD4 Low Group), while 22/35 cases enrolled in the study maintained a CD4 count higher than 500 cells/ul (CD4 High Group). The progression of early HIV-1 infection can be depicted as six discrete stages, as proposed by Fiebig et al. [3]. All the 35 enrolled patients were in Fiebig stage III. The project was reviewed and approved by the Beijing You’an Hospital Research Ethics Committee, and patients participated in the study following informed consent. Demographic and immunologic characteristics of the patients are reported in Table  1.
Table 1

Characteristics of patients in this study

Patient

Age

Initial CD4 count

Last CD4 count

Initial VL

VL set point

Days from the initial positive point to CD4 < 200 cells/ul

 

(year)

(cells/ul)

(cells/ul)

(copies/ml)

(copies/ml)

 

1

22

614

181

1,558

30,800

714

2

23

296

159

8,690

24,600

459

3

23

314

188

53,000

28,400

196

4

25

327

171

110,000

79,600

169

5

26

415

117

392,000

153,600

153

6

26

64

117

26,900,000

714,000

172

7

27

349

153

61,400

61,400

218

8

29

265

118

412,000

393,000

189

9

30

610

72

9,490

7,090

755

10

32

296

145

400,000

26,000

260

11

34

499

69

252,000

776,000

191

12

36

285

53

13,300

13,300

345

13

43

130

195

16,200

11,940

356

14

22

792

605

70,200

662

15

23

598

714

34,000

9,700

16

23

716

527

14,100

7,210

17

24

805

827

56,800

35,900

18

24

603

689

16,400

527

19

25

552

865

9,170

1,040

20

25

716

530

14,900

1,940

21

26

678

622

1,440

3,260

22

26

823

521

15,000

2,000

23

26

805

683

258,000

61,200

24

27

640

619

15,500

4,530

25

29

716

546

8,780

8,390

26

30

813

790

9,700

2,300

27

30

745

589

8,260

1,500

28

31

823

648

809

200

29

32

678

546

18,500

5,200

30

32

1148

1056

1,030

554

31

34

558

538

26,500

9,700

32

34

835

546

10,050

1,890

33

37

562

568

27,600

7,960

34

38

792

784

70,200

1,312

35

40

720

639

6,200

3,320

VL: viral load.

Flow cytometric analysis

To identify DCs, the following antibodies from BD Pharmingen (San Diego, CA, USA) were used: Lin-FITC, CD123-PE and CD11c-APC. At least 200,000 events were acquired for each sample. mDCs were identified as Lin-CD123-CD11c+, while pDCs were Lin-CD123 + CD11c-(Figure 1a). DC counts were calculated as follows, using hemocytometer data for lymphocytes and monocytes and flow cytometry data for DC windows, as described previously[4, 5].
https://static-content.springer.com/image/art%3A10.1186%2F1742-6405-11-22/MediaObjects/12981_2014_Article_312_Fig1_HTML.jpg
Figure 1

Comparison of DCs between the three groups. (a) Analysis of pDC and mDC by flow cytometry, Comparison pDC (b) and mDC (c) number between normal control and CD4 High Group and CD4 Low Group. Bars indicate median with interquartile range. ***p < 0.001, **p < 0.01, *p < 0.05.

Absolute blood CD4+ T-cell counts were measured using a FACSCalibur flow cytometer (BD, Franklin Lakes, NJ, USA). Viral load was measured by the Amplicor (Roche Diagnostic Systems, Indianapolis, IN, USA) HIV-1 monitor ultrasensitive method with a detection limit of 40 copies/mL of plasma.

Assays for plasma HIV-1 RNA

Plasma HIV RNA was quantified by real-time PCR (Roche, Germany), a super-sensitive method. The sensitivity of detection of this assay was 40 copies/ml.

Statistical analysis

Comparisons were performed using the nonparametric independent sample tests, and all reported p values were two-sided and considered significant at p < 0.05. All data were analyzed using SPSS statistical software (version 16.0; SPSS, Chicago, IL, USA).

Results

To study the relationship between DCs and disease progression, we compared the pDC and mDC number in Fiebig stage III between the CD4 High, CD4 Low, and normal control groups. We found a higher pDC number in normal controls compared with the CD4 High and CD4 Low groups (Figure 1b). The pDC number between the CD4 High and the CD4 Low groups did not differ significantly (Figure 1b). However, mDCs were significantly lower in the CD4 Low relative to CD4 High and normal controls (Figure 1c). There was no statistically significant difference in the mDC number between the CD4 High and normal controls (Figure 1c). DC numbers were negatively correlated with HIV viral load (Table 2).
Table 2

Results of spearman correlation analysis

 

Viral load

Viral load set point

pDC

-0.323*

-0.350*

mDC

-0.233

-0.282

Correlation coefficients (Spearman correlation analysis) are shown.

*P < 0.05.

Discussion

Our results are consistent with reports that DCs are markedly reduced in number during acute HIV-1 infection[69], particularly pDCs. The mechanism behind the decline in pDC numbers in acute HIV infection is not clear. It could be because of apoptosis as a direct result of infection[10, 11] or mediated by TRAIL and Fas ligand–Fas interactions; it could be a consequence of compromised production of pDC precursors because of bone marrow infection; or it may reflect pDC migration to lymphoid tissues after HIV-induced activation.

mDCs express apolipoprotein B mRNA editing enzyme catalytic polypeptides (APOBECs), proteins that deaminate cytidine to uridine in nascent minus-strand viral DNA, blocking HIV replication[11, 12]. Mature mDCs increase APOBECG expression, explaining their relative resistance to HIV-1 infection. mDCs capture and process HIV-1, and present associated antigens to T-cells. Thus, the loss of mDCs may on the one hand decrease APOBECG expression. On the other hand, the loss of mDCs decrease their ability of capture and process HIV-1 and present associated antigen to T cells. Therefore, this may explain why the loss of mDC in acute HIV infection could lead to rapid disease progression.

In conclusion, we found that the loss of mDC rather than pDC from the blood during acute HIV infection is associated with rapid disease progression. However, key questions remain to be answered regarding tissue distribution, development, and functional regulation.

Notes

Declarations

Acknowledgments

This study was supported in part by the National Natural Science Foundation of China (81101250, 81371803), the National 12th Five-Year Major Projects of China (2012ZX10001-003, 2012ZX10001-006), Beijing Science and Technology Program funded (D141100000314005) and the Beijing Key Laboratory (BZ0089).

Authors’ Affiliations

(1)
Center for Infectious Diseases, Beijing You-an Hospital, Capital Medical University

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Copyright

© Jiao et al.; licensee BioMed Central Ltd. 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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