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. 2007 Jun 20;2(6):e540.
doi: 10.1371/journal.pone.0000540.

Post-infection immunodeficiency virus control by neutralizing antibodies

Hiroyuki Yamamoto  1 , Miki Kawada, Akiko Takeda, Hiroko Igarashi, Tetsuro Matano
Affiliations

Post-infection immunodeficiency virus control by neutralizing antibodies

Hiroyuki Yamamoto et al. PLoS One. .

Abstract

Background: Unlike most acute viral infections controlled with the appearance of virus-specific neutralizing antibodies (NAbs), primary HIV infections are not met with such potent and early antibody responses. This brings into question if or how the presence of potent antibodies can contribute to primary HIV control, but protective efficacies of antiviral antibodies in primary HIV infections have remained elusive; and, it has been speculated that even NAb induction could have only a limited suppressive effect on primary HIV replication once infection is established. Here, in an attempt to answer this question, we examined the effect of passive NAb immunization post-infection on primary viral replication in a macaque AIDS model.

Methods and findings: The inoculums for passive immunization with simian immunodeficiency virus mac239 (SIVmac239)-specific neutralizing activity were prepared by purifying polyclonal immunoglobulin G from pooled plasma of six SIVmac239-infected rhesus macaques with NAb induction in the chronic phase. Passive immunization of rhesus macaques with the NAbs at day 7 after SIVmac239 challenge resulted in significant reduction of set-point plasma viral loads and preservation of central memory CD4 T lymphocyte counts, despite the limited detection period of the administered NAb responses. Peripheral lymph node dendritic cell (DC)-associated viral RNA loads showed a remarkable peak with the NAb administration, and DCs stimulated in vitro with NAb-preincubated SIV activated virus-specific CD4 T lymphocytes in an Fc-dependent manner, implying antibody-mediated virion uptake by DCs and enhanced T cell priming.

Conclusions: Our results present evidence indicating that potent antibody induction post-infection can result in primary immunodeficiency virus control and suggest direct and indirect contribution of its absence to initial control failure in HIV infections. Although difficulty in achieving requisite neutralizing titers for sterile HIV protection by prophylactic vaccination has been suggested, this study points out a possibility of non-sterile HIV control by prophylactic vaccine-induced, sub-sterile titers of NAbs post-infection, providing a rationale of vaccine-based NAb induction for primary HIV control.

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Conflict of interest statement

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

Figures

Figure 1
Figure 1. Effect of post-challenge passive NAb immunization on primary SIV infection.
(A) List of naive controls and NAb-immunized macaques. Experiments using macaques indicated by asterisk have previously been performed . (B) Plasma viral loads after SIVmac239 challenge (SIV RNA copies/ml). Left panel, naive controls; right panel, NAb-immunized macaques shown by red lines and naive controls by gray lines for comparison. (C) Statistical analysis of plasma viral loads around 3 months post-challenge between naive controls (n = 7) and NAb-immunized macaques (n = 4). The geometric mean (indicated by the longer bar) of viral loads in naive controls is 6.5×104 copies/ml, and its 95% confidence interval (indicated by the shorter bars) is 1.1×104−4.0×105 copies/ml. The geometric mean in NAb-immunized macaques is 9.1×102 copies/ml, and its 95% confidence interval is 1.6×102−5.1×103 copies/ml. The difference between the two groups was statistically significant by unpaired two-tailed t test (p = 0.0033) and by non-parametric Mann-Whitney U test (p = 0.0061). Viral loads of macaques NA1 and NA4 were calculated as the lower limit of detection shown as the dashed line (400 copies/ml). (D) Plasma NAb responses after challenge. (+), positive; (−), negative. All detected titers were no more than 1:2.
Figure 2
Figure 2. Central memory CD4+ T-cell counts in naive controls and NAb-immunized macaques.
(A) Peripheral CD4+ T-cell counts (cells/µl). (B) Peripheral CD95+CD28+ central memory CD4+ T-cell counts (cells/µl) . (C) Statistical comparison of CD28+CD95+ central memory CD4+ T-cell counts around 3 months post-challenge. The geometric mean (indicated by the longer bar) of central memory CD4+ T-cell counts in naive controls is 1.7×102 counts/µl, and its 95% confidence interval (indicated by the shorter bars) is 1.1×102−2.7×102 counts/µl. The geometric mean in NAb-immunized macaques is 4.3×102 counts/µl, and its 95% confidence interval is 2.9×102−6.3×102 counts/µl. The difference between the two groups was statistically significant by unpaired two-tailed t test (p = 0.0066) and by non-parametric Mann-Whitney U test (p = 0.0061).
Figure 3
Figure 3. SIV-specific CD8+ T-cell frequencies at week 8 post-challenge in naive controls and NAb-immunized macaques.
Figure 4
Figure 4. Effect of post-challenge passive NAb immunization in vaccinees.
(A) List of vaccinees with or without passive immunization. (B) Plasma viral loads after challenge (SIV RNA copies/ml). Left panel, MHC-I haplotype 90-088-Ij-positive macaques; right panel, 90-120-Ia-positive macaques. Red lines represent NAb-immunized vaccinees. (C) SIV-specific CD4+ T-cell and CD8+ T-cell frequencies at week 2 post-challenge.
Figure 5
Figure 5. Antibody-mediated SIV uptake by DCs and T cell priming.
(A) Peripheral lymph node-derived non-DC (CD1c−CD20− lymphocytes)-associated (left panel) and CD1c+CD20− DC-associated viral loads (right panel). (B) In vitro antigen presentation assay. Either in vitro-generated DCs (Exp. 1, Exp. 2, and Exp. 3) or positively-selected CD1c+ DCs (Exp. 4) prepared from PBMCs were pulsed with SIV alone (SIV), SIV preincubated with control antibodies (SIV+Control Ab), SIV preincubated with NAbs (SIV+Neutralizing Ab), or SIV preincubated with Fc-depleted NAbs (SIV+Neutralizing F[ab']2). Autologous PBMCs were cocultured with these pulsed DCs and then subjected to measurement of specific IFN-γ induction.
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