PLoS One. 2009 Jun 19;4(6):e5966.

Tissue-specific B-cell dysfunction and generalized memory B-cell loss during acute SIV infection.

Peruchon S, Chaoul N, Burelout C, Delache B, Brochard P, Laurent P, Cognasse F, Prévot S, Garraud O, Le Grand R, Richard Y.

Source

Atomic Energy Commission, Institute of Emerging Diseases and Innovative Therapies, Division of Immuno-Virology, UMR-E1, Univ. Paris-Sud, Orsay, France.

Abstract

BACKGROUND:

Primary HIV-infected patients display severe and irreversible damage to different blood B-cell subsets which is not restored by highly efficient anti-retroviral therapy (HAART). Because longitudinal investigations of primary HIV-infection is limited by the availability of lymphoid organs, we studied the tissue-specific B-cell dysfunctions in acutely simian immunodeficiency virus (SIV) mac251-infected Cynomolgus macaques.

METHODS AND FINDINGS:

Experiments were performed on three groups of macaques infected for 14, 21 or 28 days and on three groups of animals treated with HAART for two-weeks either initiated at 4 h, 7 or 14 days post-infection (p.i.). We have simultaneously compared changes in B-cell phenotypes and functions and tissue organization of B-cell areas in various lymphoid organs. We showed that SIV induced a steady decline in SIgG-expressing memory (SIgD(-)CD27(+)) B-cells in spleen and lymph nodes during the first 4 weeks of infection, concomitant to selective homing/sequestration of B-cells to the small intestine and spleen. SIV non-specific Ig production was transiently increased before D14p.i., whereas SIV-specific Ig production was only detectable after D14p.i., coinciding with the presence of CD8(+) T-cells and IgG-expressing plasma cells within germinal centres. Transient B-cell apoptosis on D14p.i. and commitment to terminal differentiation contributed to memory B-cell loss. HAART abrogated B-cell apoptosis, homing to the small intestine and SIV-specific Ig production but had minimal effect on early Ig production, increased B-cell proportions in spleen and loss of memory B-cells. Therefore, virus-B-cell interactions and SIV-induced inflammatory cytokines may differently contribute to early B-cell dysfunction and impaired SIV/HIV-specific antibody response.

CONCLUSIONS:

These data establish tissue-specific impairments in B-cell trafficking and functions and a generalized and steady memory B-cell loss in secondary lymphoid organs. Characterization of underlying mechanisms would be helpful in designing new therapeutic strategies to dampen B-cell activation and increases HIV/SIV specific antibody response.

PMID:: 19543531; [PubMed - indexed for MEDLINE]
PMCID:: PMC2695011

Free PMC Article

Images from this publication.See all images (7) Free text

Figure 2

Functional impairment of B-cell response during early SIV infection.

(A) Splenocytes were cultured with medium, IL2+SAC, IL4+anti-Ig (H+L) Ab or IL2+IL10+anti-CD40 mAb for three days. Proliferative response was evaluated in at least four non-infected animals (Ctl, black diamond), two (P21, H21), three (P28, H28) and four (P14, H14) SIV-infected animals. Each point represents the stimulation index (SI) for one animal. Filled and open circles represent P and H animals, respectively. Bars represent the mean SI in each group. SEM is less than 27%. *, p values<0.05 are shown. (B) Apoptotic cell percentages were determined in splenocyte cultures from four non-infected animals (Ctl, black diamond) and two (P21, H21, P28) or three (P14, H14, H28) SIV-infected animals. Each point represents the percentage of hypodiploid B-cells for one animal. Filled and open circles represent P and H animals, respectively. Bars represent the mean% in each group. SEM is less than 12%. *, p values<0.05 are shown. (C) IgG and IgM concentration were quantified in plasma taken before infection (Ctl, n = 14 for IgG and n = 16 for IgM,diamond). IgG concentrations were quantified in plasma from 10 (D7p.i.), 8 (D14p.i.), 7 (D21p.i.) and 3 (D28p.i.) placebo-treated animals (Filled circle) and from 4 (D14p.i.), 5 (D21p.i.) and 5 (D28p.i.) HAART-treated animals (open circle). IgM concentrations were quantified in plasma from 16 (D7p.i.), 9 (D14p.i.), 7 (D21p.i.) and 3 (D28p.i.) placebo-treated animals (Filled circle) and from 4 (D14p.i.), 5 (D21p.i.) and 4 (D28p.i.) HAART-treated animals (open circle). Median concentration is indicated for each group. Significant difference (*: p<0.05; **: p<0.01; ***: p<0.001) between values is indicated. (D) SIV-specific Ig (G+A+M) concentrations were measured in plasma from seven (D14p.i.), five (D21p.i.) and three (D28p.i.) placebo-treated animals (Filled circle) and from two (D14p.i.), four (D21p.i.) and five (D28p.i.) HAART-treated animals (open circle). Median OD value is indicated for each group *, significant difference (p<0.05) between values is indicated. (E) IgG production was measured in supernatants from spleen B-cell cultures of two non-infected animals and four (P14), or two (P21) SIV-infected animals. Results are mean values±SEM. *, p values<0.05 are shown

Tissue-Specific B-Cell Dysfunction and Generalized Memory B-Cell Loss during Acute SIV Infection

PLoS ONE. PLoS ONE;4(6):e5966.

Figure 3

HAART has minimal effects on SIV-induced changes in B-cells.

(A) The curve represents changes in plasma viral load (pVL, Log10copies/ml) in placebo-treated animals (median values) Arrows indicate the time of initiation of the two-week HAART treatment (4H, 7 or 14 days p.i.). Placebo and HAART-treated animals were therefore sacrificed at D14 p.i. (P14, H14), D21p.i. (P21, H21) and D28p.i. (P28, H28). (B) Plasma viral load (pVL, Log10copies/ml) at sacrifice in placebo- (open symbol) and HAART-treated (hatched symbol) animals are shown. Median value±IQ is indicated for each group. Significant differences (*: p<0.05; **: p<0.01) between groups are indicated. (C, D) CD4 T-cell (C) or B-cell (D) counts in placebo- (black bars) and HAART-treated (hatched bars) animals as compared to baseline values of the same animals before infection (open bars) are shown. Median value±IQ is indicated for each group. Significant differences (*: p<0.05; **: p<0.01) between groups are indicated. (E, F): Left panels. Percentages of blood B-cells before infection (E, pre, black square, n = 13), in non-infected animals (black square in F, n = 2 and G, n = 3), in placebo- (black circle, n = 3) and HAART-treated (open circles, n = 3) SIV-infected animals. Mean percentage±SEM is indicated for each group. Non significant p values between placebo and HAART-treated groups are indicated. Right panels. The relative percentages of naive (SIgD+ CD27−, open area), memory (SIgD− CD27+, hatched area) and MGZ (SIgD+ CD27+, black area) B-cells were determined in controls (Ctl, 13 blood samples before exposure to SIV) for blood (E) or three non-infected animals for spleen (F).Three placebo- (P14, P21 and P28) or HAART-treated (H14, H21 and H28) SIV-infected animals were similarly investigated. Mean percentage±SEM is indicated for each group. ND: Not Done

Tissue-Specific B-Cell Dysfunction and Generalized Memory B-Cell Loss during Acute SIV Infection

PLoS ONE. PLoS ONE;4(6):e5966.

PubMed

Result Filters

Display Settings:

Send to:

Tissue-specific B-cell dysfunction and generalized memory B-cell loss during acute SIV infection.

Source

Abstract

BACKGROUND:

METHODS AND FINDINGS:

CONCLUSIONS:

Publication Types, MeSH Terms, Substances

Publication Types

MeSH Terms

Substances

LinkOut - more resources

Full Text Sources

Supplemental Content

Save items

Related citations in PubMed

Cited by 9 PubMed Central articles

Related information

Recent activity

Simple NCBI Directory

Getting Started

Resources

Popular

Featured

NCBI Information