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Impairment of CD4(+) T cell responses during chronic virus infection prevents neutralizing antibody responses against virus escape mutants.

Ciurea A, Hunziker L, Klenerman P, Hengartner H, Zinkernagel RM - J. Exp. Med. (2001)

Bottom Line: Here we show that most of the antibody-escape viral mutants retain their immunogenicity.We present evidence that the failure of the infected host to mount effective humoral responses against emerging neutralization-escape mutants correlates with the rapid loss of CD4(+) T cell responsiveness during the establishment of viral persistence.Similar mechanisms may contribute to the persistence of some human pathogens such as hepatitis B and C viruses, and human immunodeficiency virus.

View Article: PubMed Central - PubMed

Affiliation: Institute for Experimental Immunology, University Hospital, CH-8091 Zürich, Switzerland. adrian.ciurea@dim.usz.ch

ABSTRACT
We have shown previously that neutralizing antibodies (nAbs) are important contributors to the long-term immune control of lymphocytic choriomeningitis virus infection, particularly if cytotoxic T cell responses are low or absent. Nevertheless, virus escape from the nAb response due to mutations within the surface glycoprotein gene may subsequently allow the virus to persist. Here we show that most of the antibody-escape viral mutants retain their immunogenicity. We present evidence that the failure of the infected host to mount effective humoral responses against emerging neutralization-escape mutants correlates with the rapid loss of CD4(+) T cell responsiveness during the establishment of viral persistence. Similar mechanisms may contribute to the persistence of some human pathogens such as hepatitis B and C viruses, and human immunodeficiency virus.

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Immunogenicity of LCMV-WE nAb-escape variants. (A–E) Sequential blood samples from CD8-depleted mice infected with 2 × 104 PFU of five nAb-escape variants WE-M7 (A), WE-M8 (B), WE-M9 (C), WE-M10 (D), and WE-M11 (E) were obtained for quantitation of nAb titers against the immunizing virus (•) and of nAb titers against LCMV-WE-wt (○). The dotted lines represent the autologous nAb response after infection of CD8-depleted mice with an equivalent dose of LCMV-WE-wt. The experiment was repeated in CD8−/− mice for variant WE-M7 (F). Data shown are the mean for three mice per group ± SEM. Neutr., neutralizing.
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Figure 7: Immunogenicity of LCMV-WE nAb-escape variants. (A–E) Sequential blood samples from CD8-depleted mice infected with 2 × 104 PFU of five nAb-escape variants WE-M7 (A), WE-M8 (B), WE-M9 (C), WE-M10 (D), and WE-M11 (E) were obtained for quantitation of nAb titers against the immunizing virus (•) and of nAb titers against LCMV-WE-wt (○). The dotted lines represent the autologous nAb response after infection of CD8-depleted mice with an equivalent dose of LCMV-WE-wt. The experiment was repeated in CD8−/− mice for variant WE-M7 (F). Data shown are the mean for three mice per group ± SEM. Neutr., neutralizing.

Mentions: In addition to insufficient CD4 T help, nAb responses against escape viruses might be low as a consequence of decreased immunogenicity of their envelope proteins. To study the immunogenicity of nAb-escape variants in vivo, we have chosen to use the model infection of mice depleted in vivo of CD8+ T cells by treatment with anti-CD8 monoclonal Abs. In contrast to CD8−/− mice, earlier virus control through the antiviral activity of reappearing CTLs takes place in this model 10. Therefore, due to the lower viremia, less Ab is masked by excess antigen. Escape mutants were tested in infections with 2 × 104 PFU, a dose available for all variants. Two isolates (WE-M10 and WE-M11) persisted for longer periods in CD8-depleted mice, whereas WE-M7, WE-M8, and WE-M9 were eliminated with similar kinetics as LCMV-WE-wt (Fig. 6 A). In contrast to our previous study 10, in which neutralization-resistant variants that showed enhanced persistence induced lower autologous nAb titers, all variants studied here raised autologous nAb responses similar to LCMV-WE-wt (Fig. 7A–E). Interestingly, heterologous nAb titers against LCMV-WE-wt in mice infected with variant viruses were at least as high as autologous titers, demonstrating a broad neutralizing response in these mice (Fig. 7A–E).


Impairment of CD4(+) T cell responses during chronic virus infection prevents neutralizing antibody responses against virus escape mutants.

Ciurea A, Hunziker L, Klenerman P, Hengartner H, Zinkernagel RM - J. Exp. Med. (2001)

Immunogenicity of LCMV-WE nAb-escape variants. (A–E) Sequential blood samples from CD8-depleted mice infected with 2 × 104 PFU of five nAb-escape variants WE-M7 (A), WE-M8 (B), WE-M9 (C), WE-M10 (D), and WE-M11 (E) were obtained for quantitation of nAb titers against the immunizing virus (•) and of nAb titers against LCMV-WE-wt (○). The dotted lines represent the autologous nAb response after infection of CD8-depleted mice with an equivalent dose of LCMV-WE-wt. The experiment was repeated in CD8−/− mice for variant WE-M7 (F). Data shown are the mean for three mice per group ± SEM. Neutr., neutralizing.
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Related In: Results  -  Collection

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Figure 7: Immunogenicity of LCMV-WE nAb-escape variants. (A–E) Sequential blood samples from CD8-depleted mice infected with 2 × 104 PFU of five nAb-escape variants WE-M7 (A), WE-M8 (B), WE-M9 (C), WE-M10 (D), and WE-M11 (E) were obtained for quantitation of nAb titers against the immunizing virus (•) and of nAb titers against LCMV-WE-wt (○). The dotted lines represent the autologous nAb response after infection of CD8-depleted mice with an equivalent dose of LCMV-WE-wt. The experiment was repeated in CD8−/− mice for variant WE-M7 (F). Data shown are the mean for three mice per group ± SEM. Neutr., neutralizing.
Mentions: In addition to insufficient CD4 T help, nAb responses against escape viruses might be low as a consequence of decreased immunogenicity of their envelope proteins. To study the immunogenicity of nAb-escape variants in vivo, we have chosen to use the model infection of mice depleted in vivo of CD8+ T cells by treatment with anti-CD8 monoclonal Abs. In contrast to CD8−/− mice, earlier virus control through the antiviral activity of reappearing CTLs takes place in this model 10. Therefore, due to the lower viremia, less Ab is masked by excess antigen. Escape mutants were tested in infections with 2 × 104 PFU, a dose available for all variants. Two isolates (WE-M10 and WE-M11) persisted for longer periods in CD8-depleted mice, whereas WE-M7, WE-M8, and WE-M9 were eliminated with similar kinetics as LCMV-WE-wt (Fig. 6 A). In contrast to our previous study 10, in which neutralization-resistant variants that showed enhanced persistence induced lower autologous nAb titers, all variants studied here raised autologous nAb responses similar to LCMV-WE-wt (Fig. 7A–E). Interestingly, heterologous nAb titers against LCMV-WE-wt in mice infected with variant viruses were at least as high as autologous titers, demonstrating a broad neutralizing response in these mice (Fig. 7A–E).

Bottom Line: Here we show that most of the antibody-escape viral mutants retain their immunogenicity.We present evidence that the failure of the infected host to mount effective humoral responses against emerging neutralization-escape mutants correlates with the rapid loss of CD4(+) T cell responsiveness during the establishment of viral persistence.Similar mechanisms may contribute to the persistence of some human pathogens such as hepatitis B and C viruses, and human immunodeficiency virus.

View Article: PubMed Central - PubMed

Affiliation: Institute for Experimental Immunology, University Hospital, CH-8091 Zürich, Switzerland. adrian.ciurea@dim.usz.ch

ABSTRACT
We have shown previously that neutralizing antibodies (nAbs) are important contributors to the long-term immune control of lymphocytic choriomeningitis virus infection, particularly if cytotoxic T cell responses are low or absent. Nevertheless, virus escape from the nAb response due to mutations within the surface glycoprotein gene may subsequently allow the virus to persist. Here we show that most of the antibody-escape viral mutants retain their immunogenicity. We present evidence that the failure of the infected host to mount effective humoral responses against emerging neutralization-escape mutants correlates with the rapid loss of CD4(+) T cell responsiveness during the establishment of viral persistence. Similar mechanisms may contribute to the persistence of some human pathogens such as hepatitis B and C viruses, and human immunodeficiency virus.

Show MeSH
Related in: MedlinePlus