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

  • Yanmei Jiao1,

    Affiliated with

    • Xin Sun1,

      Affiliated with

      • Xiaojie Huang1,

        Affiliated with

        • Wei Li1,

          Affiliated with

          • Tong Zhang1Email author and

            Affiliated with

            • Hao Wu1Email author

              Affiliated with

              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].
              http://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.

              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

              References

              1. Lehman TL, O’Halloran KP, Hoover EA, Avery PR: Utilizing the FIV model to understand dendritic cell dysfunction and the potential role of dendritic cell immunization in HIV infection. Vet Immunol Immunopathol. 2010, 134: 75-81. 10.1016/j.vetimm.2009.10.012PubMed CentralView ArticlePubMed
              2. Jiao Y, Zhang T, Wang R, Zhang H, Huang X, Yin J, Zhang L, Xu X, Wu H: Plasma IP-10 is associated with rapid disease progression in early HIV-1 infection. Viral Immunol. 2012, 25: 333-337. 10.1089/vim.2012.0011View ArticlePubMed
              3. Fiebig EW, Wright DJ, Rawal BD, Garrett PE, Schumacher RT, Peddada L, Heldebrant C, Smith R, Conrad A, Kleinman SH, Busch MP: Dynamics of HIV viremia and antibody seroconversion in plasma donors: implications for diagnosis and staging of primary HIV infection. AIDS. 2003, 17: 1871-1879. 10.1097/00002030-200309050-00005View ArticlePubMed
              4. Pacanowski J, Kahi S, Baillet M, Lebon P, Deveau C, Goujard C, Meyer L, Oksenhendler E, Sinet M, Hosmalin A: Reduced blood CD123+ (lymphoid) and CD11c + (myeloid) dendritic cell numbers in primary HIV-1 infection. Blood. 2001, 98: 3016-3021. 10.1182/blood.V98.10.3016View ArticlePubMed
              5. Zhang M, Zhang H, Zhang T, Ji Y, Jiao Y, Wu H: Longitudinal changes of peripheral blood DC subsets and regulatory T cells in Chinese chronic HIV-1-infected patients during antiretroviral therapy. PLoS One. 2012, 7: e37966- 10.1371/journal.pone.0037966PubMed CentralView ArticlePubMed
              6. McMichael AJ, Borrow P, Tomaras GD, Goonetilleke N, Haynes BF: The immune response during acute HIV-1 infection: clues for vaccine development. Nat Rev Immunol. 2010, 10: 11-23.PubMed CentralView ArticlePubMed
              7. Killian MS, Fujimura SH, Hecht FM, Levy JA: Similar changes in plasmacytoid dendritic cell and CD4 T-cell counts during primary HIV-1 infection and treatment. AIDS. 2006, 20: 1247-1252. 10.1097/01.aids.0000232231.34253.bdView ArticlePubMed
              8. Schmidt B, Fujimura SH, Martin JN, Levy JA: Variations in plasmacytoid dendritic cell (PDC) and myeloid dendritic cell (MDC) levels in HIV-infected subjects on and off antiretroviral therapy. J Clin Immunol. 2006, 26: 55-64. 10.1007/s10875-006-8401-3View ArticlePubMed
              9. Donaghy H, Pozniak A, Gazzard B, Qazi N, Gilmour J, Gotch F, Patterson S: Loss of blood CD11c (+) myeloid and CD11c (-) plasmacytoid dendritic cells in patients with HIV-1 infection correlates with HIV-1 RNA virus load. Blood. 2001, 98: 2574-2576. 10.1182/blood.V98.8.2574View ArticlePubMed
              10. Meyers JH, Justement JS, Hallahan CW, Blair ET, Sun YA, O’Shea MA, Roby G, Kottilil S, Moir S, Kovacs CM, Chun TW, Fauci AS: Impact of HIV on cell survival and antiviral activity of plasmacytoid dendritic cells. PLoS One. 2007, 2: e458- 10.1371/journal.pone.0000458PubMed CentralView ArticlePubMed
              11. Borrow P, Bhardwaj N: Innate immune responses in primary HIV-1 infection. Curr Opin HIV AIDS. 2008, 3: 36-44. 10.1097/COH.0b013e3282f2bce7PubMed CentralView ArticlePubMed
              12. Takaori-Kondo A: APOBEC family proteins: novel antiviral innate immunity. Int J Hematol. 2006, 83: 213-216. 10.1532/IJH97.05187View ArticlePubMed

              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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