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. 2009 Oct;83(20):10347-57.
doi: 10.1128/JVI.00880-09. Epub 2009 Aug 5.

Effect of B-cell depletion on viral replication and clinical outcome of simian immunodeficiency virus infection in a natural host

Thaidra Gaufin  1 , Melissa Pattison, Rajeev Gautam, Crystal Stoulig, Jason Dufour, Jeanne MacFarland, Daniel Mandell, Coty Tatum, Matthew H Marx, Ruy M Ribeiro, David Montefiori, Cristian Apetrei, Ivona Pandrea
Affiliations

Effect of B-cell depletion on viral replication and clinical outcome of simian immunodeficiency virus infection in a natural host

Thaidra Gaufin et al. J Virol. 2009 Oct.

Abstract

Simian immunodeficiency virus (SIV)-infected African nonhuman primates do not progress to AIDS in spite of high and persistent viral loads (VLs). Some authors consider the high viral replication observed in chronic natural SIV infections to be due to lower anti-SIV antibody titers than those in rhesus macaques, suggesting a role of antibodies in controlling viral replication. We therefore investigated the impact of antibody responses on the outcome of acute and chronic SIVagm replication in African green monkeys (AGMs). Nine AGMs were infected with SIVagm.sab. Four AGMs were infused with 50 mg/kg of body weight anti-CD20 (rituximab; a gift from Genentech) every 21 days, starting from day -7 postinfection up to 184 days. The remaining AGMs were used as controls and received SIVagm only. Rituximab-treated AGMs were successfully depleted of CD20 cells in peripheral blood, lymph nodes (LNs), and intestine, as shown by the dynamics of CD20+ and CD79a+ cells. There was no significant difference in VLs between CD20-depleted AGMs and control monkeys: peak VLs ranged from 10(7) to 10(8) copies/ml; set-point values were 10(4) to 10(5) SIV RNA copies/ml. Levels of acute mucosal CD4+ T-cell depletion were similar for treated and nontreated animals. SIVagm seroconversion was delayed for the CD20-depleted AGMs compared to results for the controls. There was a significant difference in both the timing and magnitude of neutralizing antibody responses for CD20-depleted AGMs compared to results for controls. CD20 depletion significantly altered the histological structure of the germinal centers in the LNs and Peyer's patches. Our results, although obtained with a limited number of animals, suggest that humoral immune responses play only a minor role in the control of SIV viral replication during acute and chronic SIV infection in natural hosts.

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Figures

FIG. 1.
FIG. 1.
Effect of rituximab infusion on CD20+ B cells of AGMs. CD20+ B-cell concentrations are shown in blood (a), lymph nodes (c), or intestine (d). Rituximab infusion induced a depletion of B cells and did not mask the CD20 molecule, as shown by the CD79a staining (b). Black symbols and lines denote the control monkeys (AGMC). Red symbols and lines denote AGMs that received rituximab infusions (AGMD). Day 0 is the day of SIV inoculation. Rituximab was infused every 21 days beginning 1 week prior to SIV inoculation. Immunohistochemistry for CD20 in the intestine (e) or lymph nodes (f) confirmed flow cytometry data. Low residual levels of CD20 were detected by IHC in two AGMs (f). The residual CD20 staining is dim, fragmented, and located only on the side of the cell or in between the cells (f, lower right panel), unlike the strong, continuous CD20 immunostaining that delineates the entire membrane in the LNs of nondepleted animals (f, lower left panel).
FIG. 2.
FIG. 2.
Impact of B-cell depletion following rituximab administration on anti-SIVagm.sab humoral immune responses. SIVagm.sab-specific peptide enzyme-linked immunosorbent assay testing showed ablation of both anti-SIVagm gp41 (a) and anti-SIVagm V3 (b) antibody production in CD20-depleted AGMs (red symbols and lines) compared to results for controls (black symbols and lines). (c) Neutralizing antibody testing showed ablation of neutralizing antibody production in CD20-depleted AGMs (red symbols and lines) compared to results for controls (black symbols and lines). Day 0 corresponds to SIV inoculation. Rituximab was infused every 21 days beginning 1 week prior to SIV inoculation.
FIG. 3.
FIG. 3.
Impact of B-cell depletion following rituximab administration on SIVagm.sab replication. Ablation of humoral immune responses had no significant impact on SIVagm.sab replication in AGMs, as illustrated by the dynamics of SIVagm.sab VLs in plasma (a), PBMCs (b), lymph nodes (c), or intestine (d). Black symbols and lines denote the control AGMs. Red symbols and lines denote rituximab-infused AGMs. Day 0 is the day of SIV inoculation. Rituximab was infused every 21 days beginning 1 week prior to SIV inoculation.
FIG. 4.
FIG. 4.
CD4+ T-cell dynamics in SIVagm.sab-infected CD20-depleted and control AGMs. Changes in peripheral blood CD4+ T-cell counts (a) or percentages (b) or changes of CD4+ T cells in the intestine (c) in rituximab-infused AGMs (red symbols and lines) and in control AGMs (black symbols and lines) are shown.
FIG. 5.
FIG. 5.
Kinetic expression of immune activation and T-cell proliferation in SIVagm.sab-infected CD20-depleted and control AGMs. Dynamics of CD4+ and CD8+ T-cell immune activation (as defined by changes in the expression of -DR markers) in blood (a and b). Dynamics of CD4+ and CD8+ T-cell proliferation (as defined by changes in the expression of Ki-67) in blood (c and d). Flow cytometry data were confirmed by the measurement of plasma cytokines: 1L-1rα (e), IL-2R (f), IL-12 (g), or IFN-α (h). Rituximab-infused AGMs are shown as red symbols and lines; control AGMs are shown as black symbols and lines. The dynamics of plasma cytokines (quantified in pg/ml) are shown as n-fold increases over baseline levels.
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