Research ArticleHIV

Integrin α4β7 expression on peripheral blood CD4+ T cells predicts HIV acquisition and disease progression outcomes

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Science Translational Medicine  24 Jan 2018:
Vol. 10, Issue 425, eaam6354
DOI: 10.1126/scitranslmed.aam6354
  • Fig. 1 Effect of preinfection β7Hi CD45RACD4+ T cell frequency on HIV acquisition risk in CAPRISA 004 study.

    (A) Parent gating strategy for the analysis of frozen PBMCs from the CAPRISA 004 study. The staining profile of PBMCs from a representative HIV-uninfected participant is shown. β7 gating is shown for one representative control and one case sample obtained at an HIV-uninfected time point. (B) Samples from 10 patients (x axis) were assayed from three to five HIV-uninfected visits (colored bars) depending on sample availability. Median coefficient of variation (CV) between HIV-uninfected time points for every individual was calculated. Individual CVs are indicated in boldface and in parentheses in the graph. (C) Sampling time points for the pre-HIV flow cytometry measurements. The number of days before HIV infection that the sample was obtained (x axis) is plotted against β7Hi frequency (y axis). The dashed line represents the median integrin β7Hi expression by CD4+ T cells. (D) Frequency of β7Hi CD45RACD4+ T cells in cases (n = 59) and controls (n = 106). Conditional logistic regression analysis was used to measure the effect of preinfection β7Hi frequency on HIV acquisition. (E) Spearman correlation between α4β7Hi CD4+ T cell frequency between the cervix and blood in the Nairobi/Uganda study (n = 54) (F) Infecting viral V2 motifs and pre-HIV frequencies of β7Hi CD4+ T cells. (G) Pre-HIV frequencies of β7Hi CD4+ T cells in cases infected by viruses with V2 loops containing the P/SDI/V and LDI/V motifs (n = 32). Differences between groups were analyzed using unpaired t test.

  • Fig. 2 Effect of preinfection β7Hi CD45RACD4+ T cell frequency on disease progression in patients that became infected in CAPRISA 004/002 study.

    (A) Correlation between preinfection β7Hi frequency and peak viral load (VL) (n = 49). (B) Correlation between preinfection β7Hi frequency and set-point VL (n = 49). (C) Frequency of preinfection β7Hi cells as a predictor of CD4+ T cell decline of <500 cells/μl (n = 48), analyzed using Cox regression models. (D) Preinfection β7Hi cells as a predictor of CD4+ T cell decline of <500 cells/μl in a multivariable Cox regression model correcting for age, study site, study arm, set-point VL, depomedroxyprogesterone acetate (DMPA) use, and HSV-2 status at baseline. (E) Correlation between preinfection β7Hi frequency and mean CD4/CD8 ratio <180 days after infection (n = 48). (F) Correlation between preinfection β7Hi frequency and mean CD4/CD8 ratio >180 days after infection (n = 48). (G) Median postinfection plasma expression of lipopolysaccharide binding protein (LBP) expression in cases with preinfection β7Hi CD4+ T cell expression above (n = 22) and below (n = 22) the median. (H) Longitudinal plasma LBP expression at 6-month intervals in CAPRISA 002 cases. Linear mixed models were used to compare LBP expression over time. Spearman correlation was used to analyze associations between the two variables.

  • Fig. 3 Depletion and post-ART recovery of β7Hi and CCR5+ CD4+ T cells in peripheral blood and cells isolated from the sigmoid colon during acute infection in RV254.

    (A and B) Frequencies of β7Hi (A) and CCR5+ (B) CD4+ T cells in the peripheral blood at different Fiebig (F) stages [HIV-uninfected (HIV; n = 9), FI (n = 8), FII (n = 11), FIII (n = 20), and chronic HIV–infected (CHI; n = 5)]. (C) Frequencies of β7Hi CD4+ T cells in the colon [HIV (n = 9), FI (n = 8), FII (n = 6), FIII (n = 13), and CHI (n = 5)]. (D) Frequencies of CCR5+ CD4+ T cells in the colon [HIV (n = 9), FI (n = 8), FII (n = 10), FIII (n = 18), and CHI (n = 8)]. (E and F) Frequencies of β7Hi (E) and CCR5+ (F) CD4+ T cells in the peripheral blood after antiretroviral therapy (ART) initiation in either FI [purple data points; at baseline (n = 8), 6 months (n = 8), and 24 months (n = 7)] or FIII [black data points; at baseline (n = 18), 6 months (n = 18), and 24 months (n = 14)]. (G) Frequencies of β7Hi CD4+ T cells in the colon after ART initiation in either FI [purple data points; baseline (n = 8), 6 months (n = 5), and 24 months (n = 3)] or FIII [black data points; baseline (n = 13), 6 months (n = 15), and 24 months (n = 9)] (H) CCR5+ CD4+ T cells in the colon after ART initiation in either FI [purple data points; at baseline (n = 8), 6 months (n = 6), and 24 months (n = 4)] or FIII [black data points; at baseline (n = 18), 6 months (n = 17), and 24 months (n = 9)]. The dashed lines represent the median of cells in healthy control participants (green; n = 9) and in CHI patients (red; n = 5). For (A) to (D), Kruskal-Wallis test was used, followed by a Dunn’s multiple comparisons test, to look for differences between HIV group and groups at different Fiebig stages. For (E) to (H), Friedman test was used to test for significant differences within each ART initiation group (FI and FIII). *P < 0.05, **P < 0.01, and ***P < 0.001.

  • Table 1 Characteristics of the CAPRISA 004 study population.

    IQR, interquartile range.

    VariableCases
    (n = 59)
    Median (IQR)
    Controls
    (n = 106)
    Median (IQR)
    P value
    Age*23 (20–25)22 (20–28)0.864
    Urban site19/59 (32.2)40/106 (37.7)0.503
    Tenofovir (TFV)
    arm*
    23/59 (39.0)43/106 (40.6)0.87
    DMPA use50/59 (84.7)85/106 (80.2)0.532
    Vaginal
    discharge
    25/59 (42.4)35/106 (33.0)0.242
    Ulcers1/59 (1.7)6/106 (5.7)0.423
    HSV-2 serostatus
    (at trial entry)
    32/59 (54.2)53/106 (50.0)0.629
    Sex acts, past 30
    days
    5 (2.5–6.6)5 (3–8)0.281
    Parity1 (1,2)1 (1,1)0.878

    *Part of the matching criteria.

    • Table 2 Multivariable analysis of HIV acquisition and integrin β7Hi CD4+ T cells using conditional logistic regression.
      VariablePaOR95% CI
      LowerUpper
      Integrin β7Hi CD45RACD4+ T cells0.0161.1631.0291.316
      Urban study site0.0910.3490.1031.181
      HSV-2 seropositive at trial entry0.2231.6060.7503.438
      Abnormal vaginal discharge0.2481.6460.7073.831
      Number of new casual partners in the last 30 days0.6690.9160.6141.367
      Median no. of sex acts per month0.1001.1100.9801.258
      Condom useNever0.4861*
      Always0.1340.3990.1201.327
      Occasionally0.3710.6230.2211.757
      Most times0.7400.8240.2622.587
      DMPA use0.2941.8800.5786.120

      *Reference category.

      • Table 3 Multivariable analysis of CD4+ T cell decline and integrin β7Hi CD4+ T cells using Cox regression.
        VariablePaHR95% CI
        LowerLower
        Integrin β7Hi CD45RA
        CD4+ T cells
        0.0392.1351.0394.389
        Age0.0411.1061.0041.219
        Urban study site0.5200.7470.3081.814
        Study arm0.1590.5980.2931.223
        Log10pVL (set point)<0.0012.5381.6493.905
        DMPA use0.8291.1260.3843.304
        HSV-2 seropositive at
        baseline
        0.9520.9750.4292.217

      Supplementary Materials

      • www.sciencetranslationalmedicine.org/cgi/content/full/10/425/eaam6354/DC1

        Materials and Methods

        Fig. S1. Effect of preinfection β7int CD45RA+CD4+ and β7Neg CD45RACD4+ T cell frequency on HIV acquisition.

        Fig. S2. Phenotype of β7Hi CD45RACD4+, β7int CD45RA+CD4+, and β7Neg CD45RACD4+ T cells.

        Fig. S3. Effect of preinfection α4β7+ CD4+ T cell frequency in the blood on SIV acquisition in NHPs exposed to weekly intravaginal challenges with SIVmac251.

        Fig. S4. Effect of preinfection β7int CD45RA+CD4+ and β7Neg CD45RACD4+ T cell frequency on disease progression in patients that became infected in CAPRISA 004/002 study.

        Fig. S5. Gating strategy used for the analysis of frozen PBMCs from the CAPRISA 004 study.

        Fig. S6. Effect of preinfection α4β7+ CD4+ T cell frequency in the gut and the blood on disease progression in RMs after intravenous injection with SIVmac239.

        Table S1. Characteristics of the Ugandan and Kenyan study populations.

        Table S2. Cohort characteristics (RV254 study).

        Table S3. Cohort characteristics (FSW cohort; Nairobi, Kenya).

        Table S4. Analysis of HIV acquisition and integrin β7Hi CD4+ T cells using conditional logistic regression in CAPRISA 004 (n = 165), in FSW cohort from Nairobi (n = 41), and in the combined cohort analysis (n = 206).

        Table S5. Correlation of other immunological markers on bulk CD4+ T cells and CD4+ T cell decline of <500 cells/μl in the CAPRISA 004 study.

        Table S6. Effect of preinfection integrin β7Hi CD4+ T cell frequency on postinfection plasma I-FABP and sCD14 expression using linear mixed model analysis adjusting for VL and CD4/CD8 ratio.

        Table S7. Primary data (provided as an Excel file).

        References (4448)

      • Supplementary Material for:

        Integrin α4β7 expression on peripheral blood CD4+ T cells predicts HIV acquisition and disease progression outcomes

        Aida Sivro, Alexandra Schuetz, Daniel Sheward, Vineet Joag, Sergey Yegorov, Lenine J. Liebenberg, Nonhlanhla Yende-Zuma, Andrew Stalker, Ruth S. Mwatelah, Philippe Selhorst, Nigel Garrett, Natasha Samsunder, Anisha Balgobin, Fatima Nawaz, Claudia Cicala, James Arthos, Anthony S. Fauci, Aggrey Omu Anzala, Joshua Kimani, Bernard S. Bagaya, Noah Kiwanuka, Carolyn Williamson, Rupert Kaul, Jo-Ann S. Passmore, Nittaya Phanuphak, Jintanat Ananworanich, Aftab Ansari, Quarraisha Abdool Karim, Salim S. Abdool Karim, Lyle R. McKinnon,* on behalf of the CAPRISA004 and RV254 study groups

        *Corresponding author. Email: lyle.mckinnon{at}umanitoba.ca

        Published 24 January 2018, Sci. Transl. Med. 10, eaam6354 (2018)
        DOI: 10.1126/scitranslmed.aam6354

        This PDF file includes:

        • Materials and Methods
        • Fig. S1. Effect of preinfection β7 int CD45RA+CD4+ and β7 Neg CD45RACD4+ T cell frequency on HIV acquisition.
        • Fig. S2. Phenotype of β7 Hi CD45RACD4+, β7int CD45RA+CD4+, and β7Neg CD45RACD4+ T cells.
        • Fig. S3. Effect of preinfection α4β7 + CD4+ T cell frequency in the blood on SIV acquisition in NHPs exposed to weekly intravaginal challenges with SIVmac251.
        • Fig. S4. Effect of preinfection β7 int CD45RA+CD4+ and β7 Neg CD45RACD4+ T cell frequency on disease progression in patients that became infected in CAPRISA 004/002 study.
        • Fig. S5. Gating strategy used for the analysis of frozen PBMCs from the CAPRISA 004 study.
        • Fig. S6. Effect of preinfection α4β7 + CD4+ T cell frequency in the gut and the blood on disease progression in RMs after intravenous injection with SIVmac239.
        • Table S1. Characteristics of the Ugandan and Kenyan study populations.
        • Table S2. Cohort characteristics (RV254 study).
        • Table S3. Cohort characteristics (FSW cohort; Nairobi, Kenya).
        • Table S4. Analysis of HIV acquisition and integrin β7Hi CD4+ T cells using conditional logistic regression in CAPRISA 004 (n = 165), in FSW cohort from Nairobi (n = 41), and in the combined cohort analysis (n = 206).
        • Table S5. Correlation of other immunological markers on bulk CD4+ T cells and CD4+ T cell decline of <500 cells/μl in the CAPRISA 004 study.
        • Table S6. Effect of preinfection integrin β7Hi CD4+ T cell frequency on postinfection plasma I-FABP and sCD14 expression using linear mixed model analysis adjusting for VL and CD4/CD8 ratio.
        • References (4448)

        [Download PDF]

        Other Supplementary Material for this manuscript includes the following:

        • Table S7. Primary data (provided as an Excel file).

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