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B cell responses to HIV antigen are a potent correlate of viremia in HIV-1 infection and improve with PD-1 blockade - PubMed

  • ️Tue Jan 01 2013

B cell responses to HIV antigen are a potent correlate of viremia in HIV-1 infection and improve with PD-1 blockade

Katherine J Nicholas et al. PLoS One. 2013.

Abstract

Infection with Human Immunodeficiency Virus Type 1 (HIV-1) induces defects of both cellular and humoral immune responses. Impaired CD4+ T cell help and B cell dysfunction may partially explain the low frequency of broadly neutralizing antibodies in HIV-infected individuals. To understand the extent of B cell dysfunction during HIV infection, we assessed the level of B cell activation at baseline and after stimulation with a variety of antigens. Increased levels of viremia were associated with higher baseline expression of the activation marker CD86 on B cells and with decreased ability of B cells to increase expression of CD86 after in vitro stimulation with inactivated HIV-1. In a series of cell isolation experiments B cell responses to antigen were enhanced in the presence of autologous CD4+ T cells. HIV infected individuals had a higher frequency of PD-1 expression on B cells compared to HIV- subjects and PD-1 blockade improved B cell responsiveness to HIV antigen, suggesting that inhibitory molecule expression during HIV-1 infection may contribute to some of the observed B cell defects. Our findings demonstrate that during chronic HIV infection, B cells are activated and lose full capacity to respond to antigen, but suppression of inhibitory pressures as well as a robust CD4+ T cell response may help preserve B cell function.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. CD86+ B cells are more frequent in HIV+ than HIV- subjects and correlate with viremia.

PBMCs from HIV- (open circles) or HIV+ (closed circles) subjects were incubated overnight without stimulation and evaluated for surface level CD86 expression on B cells. HIV+ subjects had a higher frequency of CD86+ B cells compared to HIV- subjects (unpaired t-test not shown on graph, p=0.03). The frequency of CD19+CD86+ B cells in HIV+ individuals correlates with the level of viremia (r=.63; p=.003). Correlation statistics shown are derived from HIV+ subject data only and do not include data from HIV- subjects.

Figure 2
Figure 2. Change in CD25 expression on B and CD4+ T cells negatively correlates with viral load.

PBMCs were cultured overnight with or without anti-CD3 stimulation. Change in CD25 or CD86 expression was determined by subtracting the frequency of expression before stimulation from the frequency of expression after stimulation. (A) Representative plots of CD25 expression on CD4+ T cells and B cells with (bottom) and without (top) anti-CD3 stimulation. CD4+ T cell population shown is CD3+CD4+CD19- and B cell population shown is CD3-CD4-CD19+. (B-D) Change in expression of CD25 on CD4+ T cells (r= -.53; p= .056) (B), CD25 on B cells (r= -.63; p= .018) (C), and CD86 on B cells (r= -.44; p= .11) (D) correlates negatively with viral load.

Figure 3
Figure 3. Magnitude of B cell responses to inactivated HIV-1 inversely correlates with viral load.

(A) Expression of CD86 on B cells after stimulation of PBMC with HIV-1 MN control (left column) or HIV-1 MN (right column). Shown are representative plots from one individual (subject 10071).. (B) PBMCs from 21 HIV-infected individuals (closed circles) and 7 HIV-negative control subjects (open circles) were incubated with inactivated HIV-1 MN, and changes in CD86 expression on B cells were measured. Change was calculated by subtracting the frequency of CD86 expression from stimulation with the HIV-1 MN control (containing no HIV proteins) from stimulation with HIV-1 MN. CD86 expression on B cells in response to HIV-antigen in HIV infected individuals is negatively correlated with viral load (r= -.6; p= .006). Correlation statistics are only applied to HIV-infected individuals and do not include data from uninfected subjects.

Figure 4
Figure 4. Purified B cell responses to p24 are enhanced by addition of autologous CD4+ T cells.

Change in the frequency of CD86+ B cells in response to SEB (A) or HIV p24 antigen (B) was evaluated in total PBMC culture, purified B cell culture, or purified B cells co-cultured with autologous purified CD4+ T cells.

Figure 5
Figure 5. Frequency of PD-1 surface expression on lymphocytes is elevated during HIV infection.

Expression of PD-1 on B cells, CD4+ T cells, and CD8+ cells was measured directly ex vivo. (A) In HIV-infected individuals, PD-1 expression on CD4+ is not correlated with viral load (r=.33; p=.17). (B) In HIV-infected individuals PD-1 expression on CD8+ T cells correlated positively with viral load (r= .56; p=.01). (C) PD-1 expression is higher on B cells from HIV+ (closed circles) compared to HIV- (open circles) subjects (p=.04). (D) The frequency of PD-1 surface expression is significantly lower on B cells compared to CD4 (p< .0001) and CD8 T cells (p<.0001) in HIV infection.

Figure 6
Figure 6. PD-1 blockade improves B cell responses to stimulation with inactivated HIV-1.

PBMCs were cultured overnight with or without anti-PD-1 and stimulated with inactivated HIV-1 MN protein. Change in response to MN stimulation was calculated by subtracting stimulation with MN control protein from stimulation with HIV-1 MN protein (p= .003).

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References

    1. Lane HC, Masur H, Edgar LC, Whalen G, Rook AH et al. (1983) Abnormalities of B-cell activation and immunoregulation in patients with the acquired immunodeficiency syndrome. N Engl J Med 309: 453-458. doi:10.1056/NEJM198308253090803. PubMed: 6224088. - DOI - PubMed
    1. Förster R, Schweigard G, Johann S, Emrich T, Kremmer E et al. (1997) Abnormal expression of the B-cell homing chemokine receptor BLR1 during the progression of acquired immunodeficiency syndrome. Blood 90: 520–525. PubMed: 9226150. - PubMed
    1. Martínez-Maza O, Crabb E, Mitsuyasu RT, Fahey JL, Giorgi JV (1987) Infection with the human immunodeficiency virus (HIV) is associated with an in vivo increase in B lymphocyte activation and immaturity. Journal of Immunology 138: 3720–3724. PubMed: 2953790. - PubMed
    1. Pahwa R, Good R, Pahwa S (1987) Prematurity, hypogammaglobulinemia, and neuropathology with human immunodeficiency virus (HIV). Infection - Proceedings of the National Academy of Sciences of the United States of America 84: 3826. doi:10.1073/pnas.84.11.3826. - DOI - PMC - PubMed
    1. Morris L, Binley JM, Clas BA, Bonhoeffer S, Astill TP et al. (1998) HIV-1 antigen–specific and–nonspecific B cell responses are sensitive to combination antiretroviral therapy. J Exp Med 188: 233–245. doi:10.1084/jem.188.2.233. PubMed: 9670036. - DOI - PMC - PubMed

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