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Pathogenesis and Immunity

HLA-DR+ CD38+ CD4+ T Lymphocytes Have Elevated CCR5 Expression and Produce the Majority of R5-Tropic HIV-1 RNA In Vivo

Amie L. Meditz, Michelle K. Haas, Joy M. Folkvord, Kelsey Melander, Russ Young, Martin McCarter, Samantha MaWhinney, Thomas B. Campbell, Yolanda Lie, Eoin Coakley, David N. Levy, Elizabeth Connick
Amie L. Meditz
1Division of Infectious Diseases, Department of Medicine, University of Colorado Denver, Aurora, Colorado
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Michelle K. Haas
1Division of Infectious Diseases, Department of Medicine, University of Colorado Denver, Aurora, Colorado
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Joy M. Folkvord
1Division of Infectious Diseases, Department of Medicine, University of Colorado Denver, Aurora, Colorado
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Kelsey Melander
1Division of Infectious Diseases, Department of Medicine, University of Colorado Denver, Aurora, Colorado
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Russ Young
1Division of Infectious Diseases, Department of Medicine, University of Colorado Denver, Aurora, Colorado
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Martin McCarter
2Department of Surgery, University of Colorado Denver, Aurora, Colorado
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Samantha MaWhinney
3Department of Biostatistics and Informatics, University of Colorado Denver, Aurora, Colorado
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Thomas B. Campbell
1Division of Infectious Diseases, Department of Medicine, University of Colorado Denver, Aurora, Colorado
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Yolanda Lie
4Monogram Biosciences, South San Francisco, California
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Eoin Coakley
4Monogram Biosciences, South San Francisco, California
‡Present address: Abbott Laboratories, Abbott Park, IL.
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David N. Levy
5New York University, College of Dentistry, New York, New York
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Elizabeth Connick
1Division of Infectious Diseases, Department of Medicine, University of Colorado Denver, Aurora, Colorado
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  • For correspondence: liz.connick@ucdenver.edu
DOI: 10.1128/JVI.02529-10
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  • Fig. 1.
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    Fig. 1.

    Representative flow cytometry plot of CD8-depleted PHA-stimulated PBMC 48 h after inoculation with R5-tropic HIV-1 GFP reporter virus. The cells were acquired from the lymphocyte gate of the forward-scatter versus side-scatter profile. The majority of GFP+ tonsil cells were CD4 negative. The cutoff between CD4+ and CD4− cells is indicated by the broken line. CD4+ dim cells were included in the CD4+ gate. Data were analyzed using FlowJo software (Tree Star). pos, positive.

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    Fig. 2.

    Percentages of DR/38 lymphocyte subsets in non-virus-producing (GFP−) and virus-producing (GFP+) PHA-stimulated PBMC inoculated with R5-tropic (A) and X4-tropic (B) HIV-1 GFP reporter viruses. Mean fluorescence intensity (MFI) of GFP within virus-producing DR/38 subsets of cells inoculated with R5-tropic (C) and X4-tropic (D) HIV-1 reporter viruses. Percentages of GFP+ cells within DR/38 subsets inoculated with R5-tropic (E) and X4-tropic (F) HIV-1 reporter viruses. PBMC from 10 individuals at low risk for HIV-1 infection were depleted of CD8+ cells, cultured for 2 days with PHA and IL-2, inoculated with HIV-1 GFP reporter viruses, and evaluated 48 h later by flow cytometry. For panels A through D, the percentages of DR/38 subsets of cells were determined after first gating on cells in the lymphocyte gate and then on GFP+ and GFP− cells. For panels E and F, the percentages of GFP+ cells were determined after first gating on cells in the lymphocyte gate and then on each DR/38 subset. Lines link the values from an individual subject.

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    Fig. 3.

    Percentages of CCR5+ (A) and CXCR4+ (C) and cell surface concentrations (B and D) of these receptors, respectively, on DR/38 CD4+ T-cell subsets in whole-blood (WB) samples, PBMC isolated by density centrifugation, and CD8-depleted PHA-stimulated PBMC cultured for 2 days. Peripheral blood samples were obtained from 6 individuals at low risk for HIV-1 infection and stained with antibodies to cell surface markers at each time point, and results were determined by flow cytometry. Chemokine receptor expression on DR/38 subsets was determined after first gating on cells in the lymphocyte gate, then on CD3+ CD4+ cells, and finally on each DR/38 subset. Asterisks indicate the values for PHA-stimulated PBMC that were different from the values for whole blood (P = 0.03 in all instances).

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    Fig. 4.

    Percentages of DR/38 CD4+ T-cell subsets in PBMC after 2 and 4 days of culture with PHA. PBMC from 6 individuals at low risk for HIV-1 infection were depleted of CD8+ cells and cultured with PHA. Using flow cytometry, the percentages of DR/38 subsets of cells were determined by first gating on cells in the lymphocyte gate and then on CD3+ CD4+ cells. Lines indicate paired values from one subject. Differences between day 2 and day 4 were significant within all subsets (P = 0.03).

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    Fig. 5.

    Representative flow cytometry plots of lymph node cells. The cells were acquired from the lymphocyte gate of the forward- versus side-scatter profile. A dot plot was used to define CD3+ CD4+ cells (A) and gates for CD38 (B) and HLA-DR (C) set with fluorescence minus one (FMO) controls. CD4+ CD3+ lymphocytes were evaluated in a CD38 versus HLA-DR plot (D), and CCR5 expression was evaluated in four DR 38 subsets using histograms (E). Data were analyzed using FlowJo software (Tree Star).

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    Fig. 6.

    Percentages of CCR5+ (A) and CXCR4+ (B) and concentrations of these HIV-1 coreceptors (C and D), respectively, in DR/38 CD3+ CD4+ subsets of lymph node cells from HIV-1-seropositive individuals (n = 18) and HIV-1-seronegative individuals (n = 6). Each symbol represents the value for an individual. Short horizontal lines indicate median values for groups of individuals. P values indicate comparisons between DR+ 38+ cells and other subsets in seropositive subjects. Asterisks denote P values that were no longer statistically significant after Bonferroni's correction for multiple comparisons (cutoff, P = 0.017). Differences between DR+ 38+ cells and other subsets in seronegative subjects and differences between seropositive and seronegative subjects were not statistically significant after adjusting for multiple comparisons.

  • Fig. 7.
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    Fig. 7.

    HIV-1 RNA measurements within subsets of CD4/CD8 CD3+ lymph node cells (n = 6). (A) Numbers of HIV-1 RNA copies/105 cells; (B) percentages of CD4/CD8 subsets within CD8− CD3+ lymph node cells; (C) percentages of total RNA copies contributed by each CD4/CD8 subset after adjusting for percentages of subsets shown in panel B. For each box-and-whisker plot, the line indicates the median and the whiskers (error bars) indicate the range. Lymph node cells from untreated HIV-1-seropositive subjects were sorted into subsets on a cell sorter, and aliquots of 105 cells were frozen as pellets. HIV-1 RNA was then extracted and measured by PCR.

  • Fig. 8.
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    Fig. 8.

    HIV-1 RNA and DNA measurements within subsets of DR/38 CD8− CD3+ lymph node cells. (A) Numbers of HIV-1 RNA copies/105 cells; (B) percentages of DR/38 subsets within CD8− CD3+ lymph node cells; (C) percentages of total RNA copies contributed by each DR/38 subset after adjusting for percentages of subsets shown in panel B; (D) numbers of HIV-1 DNA copies/105 cells; (E) percentages of total DNA copies contributed by each DR/38 subset after adjusting for percentages of subsets shown in panel B. Lymph node cells from untreated HIV-1-seropositive subjects were sorted into subsets on a cell sorter, and aliquots of 105 cells were frozen as pellets. HIV-1 RNA and DNA were then extracted and measured by PCR.

  • Fig. 9.
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    Fig. 9.

    Percentage of CCR5+ (A) and number of CCR5 molecules (B) on CD4+ T cells within lymph node cell DR/38 subsets and predicted log10 HIV-1 RNA within the corresponding DR/38 CD8− CD3+ subset.

Tables

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  • Table 1.

    Demographic and clinical characteristics of HIV-1-seropositive and -seronegative subjects

    Group and subjectaAge (yr)SexbRaceNo. of CD4+ T cells/mm3No. of HIV-1 RNA copies (log10 copies/ml)
    HIV-1-seropositive subjects
        7740MCaucasian9135.26
        8726FCaucasian2564.36
        9034FBlack3324.86
        9136MBlack6914.49
        9529MHispanic9323.99
        10242FNative American6823.89
        10534MNative American5684.66
        10641MBlack7065.61
        11027MCaucasian6544.62
        11550MBlack7124.21
        11645FBlack2713.26
        11725FHispanic11174.35
        11829FBlack5883.62
        11929FCaucasian2573.85
        120*42FBlack3275.88
        121*36MBlack7204.26
        122*38FBlack4624.70
        12434FBlack8541.70
        12551FCaucasian3514.80
        12723FBlack5213.84
        12949FBlack5473.06
        13127MCaucasian5644.97
    HIV-1-seronegative subjects
        7642FCaucasian
        8972MCaucasian
        9635MCaucasian
        9773MCaucasian
        10844FCaucasian
        10958FHispanic
    • ↵a Asterisks denote the subjects who previously received antiretroviral therapy. At the time of enrollment in this study, they had been off therapy for 6 months or longer.

    • ↵b M, male; F, female.

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HLA-DR+ CD38+ CD4+ T Lymphocytes Have Elevated CCR5 Expression and Produce the Majority of R5-Tropic HIV-1 RNA In Vivo
Amie L. Meditz, Michelle K. Haas, Joy M. Folkvord, Kelsey Melander, Russ Young, Martin McCarter, Samantha MaWhinney, Thomas B. Campbell, Yolanda Lie, Eoin Coakley, David N. Levy, Elizabeth Connick
Journal of Virology Sep 2011, 85 (19) 10189-10200; DOI: 10.1128/JVI.02529-10

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HLA-DR+ CD38+ CD4+ T Lymphocytes Have Elevated CCR5 Expression and Produce the Majority of R5-Tropic HIV-1 RNA In Vivo
Amie L. Meditz, Michelle K. Haas, Joy M. Folkvord, Kelsey Melander, Russ Young, Martin McCarter, Samantha MaWhinney, Thomas B. Campbell, Yolanda Lie, Eoin Coakley, David N. Levy, Elizabeth Connick
Journal of Virology Sep 2011, 85 (19) 10189-10200; DOI: 10.1128/JVI.02529-10
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