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Loss of memory B cells impairs maintenance of long-term serologic memory during HIV-1 infection

Kehmia Titanji, Angelo De Milito, Alberto Cagigi, Rigmor Thorstensson, Sven Grützmeier, Ann Atlas, Bo Hejdeman, Frank P. Kroon, Lucia Lopalco, Anna Nilsson and Francesca Chiodi

Article Figures & Data

Figures

  • Figure 1.

    Memory (CD27+) B cells and progression of HIV infection. (A) Relationship between memory B-cell percentages and CD4+ T-cell counts. The relationship between memory B cells and CD4+ T cells in 80 subjects with CHI was tested by linear regression. (B) Comparison of memory B-cell percentages at different stages of HIV infection. PBMCs from HIV-negative controls and individuals with PHI or CHI, and LTNP patients were analyzed for percentage of cells staining double positive for CD19 and CD27 (CD19+CD27+) using fluorescence-activated cell sorter (FACS) analysis. The box plot for LTNP patients represents data pooled from 7 subjects, each sampled twice, with a 7-year interval between samples. (C) IgM+IgD+CD27+ and IgM-IgD-CD27+ B cells in controls, patients with PHI, and patients with CHI. Expression of IgM and IgD was analyzed in CD19+CD27+ (memory B cells) from HIV-negative controls and individuals with PHI or CHI.

  • Figure 2.

    Comparison of antimeasles and antipneumococcus antibody titers in uninfected and HIV-infected subjects. Antimeasles (A) and antipneumococcus (B) antibody titers were determined in plasma samples from 30 HIV-negative (controls), 26 PHI (16 in B), 40 CHI, and 7 LTNP subjects. The box plots for LTNP patients represents data from 7 subjects, each sampled 4 times, with an average of 2 years between samples. The ends of the boxes define the 25th and 75th percentiles, with a line at the median and error bars defining the 10th and 90th percentiles.

  • Figure 3.

    Production of specific Abs in culture. PBMCs from healthy controls, patients with CHI, and LTNP patients were stimulated with CpG ODN + IL-2 + IL10 + CD40 mAb. Cell culture supernatants were collected after 6 days of culture and used to measure anti-pneumococcus IgG and IgM, and anti-measles IgG and IgM Abs.

  • Figure 4.

    Total IgG-secreting and anti-measles IgG-secreting cells in HIV infection. PBMCs from 8 HIV-negative controls, 9 PHI subjects, and 20 CHI subjects were stimulated for 6 days with a combination of CpG, anti-CD40 mAb, IL-2, and IL-10. Stimulated PBMCs were then added to ELISPOT plate wells precoated with goat anti-human IgG or measles antigen. Results are expressed as number of total IgG-secreting (A) or anti-measles IgG-secreting (B) cells per 106 stimulated PBMCs. (C) Percentages of measles-specific ASCs were determined by dividing the number of measles IgG-secreting cells by the number of total IgG-secreting cells in controls, patients with PHI, and patients with CHI. The ends of the boxes define the 25th and 75th percentiles, with a line at the median and error bars defining the 10th and 90th percentiles.

  • Figure 5.

    Relationship between antimeasles ASCs, antimeasles antibody titers, and memory B-cell percentages in chronic HIV-1 infection. The strengths of association between (A) antimeasles antibody titers and anti-measles IgG ASCs per 106 stimulated PBMCs, (B) antimeasles antibody titers and percentages of measles-specific memory B cells, and (C) memory B cells and anti-measles IgG ASCs were tested using the Spearman rank order correlation test. Figures represent scatter plots of the results of the correlation test, with corresponding regression lines. Percentages of measles-specific memory B cells in panel B were determined by dividing the number of anti-measles IgG ASCs by the number of total IgG ASCs.

  • Figure 6.

    Effect of ART on CD4+ T-cell counts, HIV RNA, and specific antibody titers in primary and chronic HIV infection. Twenty-six individuals with PHI were sampled at baseline and after 6 months of ART, while 19 with CHI were sampled at baseline and 4 more times over a 24-month period of ART. (A) Changes in CD4+ T-cell counts and HIV RNA in subjects with PHI at baseline and after 6 months of therapy. (B) Changes in CD4+ T-cell counts and HIV RNA in subjects with CHI. (C) Antimeasles and anti-gp41 antibody titers in subjects with PHI at baseline and after 6 months of therapy. (D) Antimeasles and anti-gp41 antibody titers in subjects with CHI.

Tables

  • Table 1.

    Study population baseline characteristics

    Patients with PHIPatients with CHILTNP patients
    No. patients 41 40 7
    Median age, y (range) 32 (17-53) 43 (30-79) 42 (36-47)
    Median CD4+ T-cell counts (range) 645 (204-1412) 591 (68-850) 736 (520-908)
    Median HIV RNA, log10 copies/mL (range) 4.57 (2.69-5.46) 2.28 (1.7-4.5) 2.49 (1.7-3.34)
    Median time from ARS, d (range) 32 (10-84) NA NA
    Duration of HIV infection 3 mo ≥ 7 y ≥ 10 y
    ART Yes Yes No
    • Data in the table are expressed as median (range)

      PHI indicates primary HIV infection; CHI, chronic HIV infection; LTNP, long-term nonprogressors; ARS, antiretroviral syndrome; ART, antiretroviral therapy; and NA, not available