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

Abstract

BackgroundPrimary 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 FindingsExperiments 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.ConclusionsThese 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.

New therapy to revert dysfunctional antibody responses during HIV-1 infection

“…Thus, the authors speculate that B cells, including mB Act cells, home away from the circulation to lymphoid tissues early after infection (at 2 weeks) and return to the circulation at 12 weeks after infection. This possibility is consistent with a previously published study in which a decline in the number of circulating total B cells was reported in SIV mac251 -infected cynomolgus macaques 2 weeks after infection as a result of B cell trafficking to lymphoid organs, with preferential accumulation in spleen and intestine (9). Furthermore, altered expression of the chemokine receptor/ligand pair CXCR5/CXCL13, important for homing of B cells, has been reported during HIV-1 infection, especially in patients with low CD4 + T cell counts (10).…”

“…The model outlined here is based on data generated by Titanji et al (3) and Peruchon et al (9). During the early stages of SIV infection (2 weeks), mBAct cells leave the blood to home to lymphoid tissues.…”

Acute depletion of activated memory B cells involves the PD-1 pathway in rapidly progressing SIV-infected macaques

“…Depletion of mB Act cells from the blood likely occurs via a combination of mechanisms, including migration to other sites/tissues, decreased survival, and/or increased apoptosis. A recent study suggested that the decrease in circulating memory B cells following SIV infection mainly resulted from trafficking to lymphoid organs, with a rebound occurring once the cells returned back to the circulation from the tissues (14). This may be the case in the typical progressors, in which we observed a rebound in memory B cells by week 12, but not in rapid progressors, in which memory B cell loss was sustained.…”

“…An association between loss of total memory B cells and loss of CD4 + T cells was previously shown in HIV-infected individuals (12), which suggested that total memory B cell loss may be a useful marker of disease progression. While comparable B cell dysfunctions have been identified in SIV-infected RMs (8,9,14,28), the kinetics, specific B cell subsets affected, mechanisms involved, and role of B cell defects in rapid disease progression are not well defined. Here, we demonstrated that mB Act cells are rapidly depleted following pathogenic SIV infection and that this depletion strongly influences disease progression.…”

“…Loss of total memory B cells was previously shown to be an important pathogenic mechanism in viremic HIV-infected individuals, leading to impaired HIV-specific and non-HIV-specific humoral immune responses (10)(11)(12)(13). A recent study of acute SIV infection in RMs also described a generalized loss of total memory B cells as an important factor in B cell dysfunction (14). Although these previous studies suggest an important role for general B cell dysfunction in disease pathogenesis, the B cell compartment of rapidly progressing animals has not been thoroughly characterized.…”