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T cell independent secondary antibody responses to the envelope protein of simian immunodeficiency virus.

ABSTRACT: BACKGROUND: During human (HIV) and simian (SIV) immunodeficiency virus infection, loss of CD4+ T cells and progression to AIDS are associated with a decline in antibody titers to the viral Gag protein, while antibodies to the Env protein remain high, suggesting a T cell independent antibody response to Env. RESULTS: To explore differential regulation of Gag and Env antibody responses, immunocompetent BALB/c and T cell deficient nude mice were immunized with virus like particles (VLP) of simian immunodeficiency virus or adenoviral vectors expressing SIV Gag and Env. High levels of antibodies against Gag and Env could only be induced in immunocompetent mice, but not in the immunodeficient mice. Thus, neither cells expressing Env after adenoviral gene transfer nor VLPs induce a T cell independent primary anti-Env antibody response. However, secondary B cell responses to Env, but not to Gag, were observed in immunodeficient mice after transfer of primed B cells and boosting with VLPs or adenoviral vectors expressing Gag and Env. This T cell independent secondary antibody response to Env was reduced after stimulation with VLPs modified to contain monomeric membrane bound gp130 surface subunit of Env and undetectable after injection of soluble gp130. CONCLUSIONS: Membrane-bound trimeric Env seems to be responsible for the maintenance of high levels of anti-Env antibodies during progression to AIDS. This T cell independent secondary antibody response may prevent T cell-dependent affinity maturation and thus contribute to viral immune escape by favoring persistence of non-protective antibodies.

SUBMITTER: Nabi G

PROVIDER: S-EPMC3408358 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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T cell independent secondary antibody responses to the envelope protein of simian immunodeficiency virus.

Nabi Ghulam G Temchura Vladimir V Grossmann Claudius C Kuate Seraphin S Tenbusch Matthias M Überla Klaus K

Retrovirology 20120514

<h4>Background</h4>During human (HIV) and simian (SIV) immunodeficiency virus infection, loss of CD4+ T cells and progression to AIDS are associated with a decline in antibody titers to the viral Gag protein, while antibodies to the Env protein remain high, suggesting a T cell independent antibody response to Env.<h4>Results</h4>To explore differential regulation of Gag and Env antibody responses, immunocompetent BALB/c and T cell deficient nude mice were immunized with virus like particles (VLP ...[more]

PMID: 22583867

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Project description:The human immunodeficiency virus type 1 (HIV-1)/simian immunodeficiency virus (SIV) envelope spike (Env) mediates viral entry into host cells. The V3 loop of the gp120 component of the Env trimer contributes to the coreceptor binding site and is a target for neutralizing antibodies. We used cryo-electron tomography to visualize the binding of CD4 and the V3 loop monoclonal antibody (MAb) 36D5 to gp120 of the SIV Env trimer. Our results show that 36D5 binds gp120 at the base of the V3 loop and suggest that the antibody exerts its neutralization effect by blocking the coreceptor binding site. The antibody does this without altering the dynamics of the spike motion between closed and open states when CD4 is bound. The interaction between 36D5 and SIV gp120 is similar to the interaction between some broadly neutralizing anti-V3 loop antibodies and HIV-1 gp120. Two conformations of gp120 bound with CD4 are revealed, suggesting an intrinsic dynamic nature of the liganded Env trimer. CD4 binding substantially increases the binding of 36D5 to gp120 in the intact Env trimer, consistent with CD4-induced changes in the conformation of gp120 and the antibody binding site. Binding by MAb 36D5 does not substantially alter the proportions of the two CD4-bound conformations. The position of MAb 36D5 at the V3 base changes little between conformations, indicating that the V3 base serves as a pivot point during the transition between these two states.IMPORTANCE Glycoprotein spikes on the surfaces of SIV and HIV are the sole targets available to the immune system for antibody neutralization. Spikes evade the immune system by a combination of a thick layer of polysaccharide on the surface (the glycan shield) and movement between spike domains that masks the epitope conformation. Using SIV virions whose spikes were "decorated" with the primary cellular receptor (CD4) and an antibody (36D5) at part of the coreceptor binding site, we visualized multiple conformations trapped by the rapid freezing step, which were separated using statistical analysis. Our results show that the CD4-induced conformational dynamics of the spike enhances binding of the antibody.

Dataset Information

T cell independent secondary antibody responses to the envelope protein of simian immunodeficiency virus.

Publications

T cell independent secondary antibody responses to the envelope protein of simian immunodeficiency virus.

Similar Datasets

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