Single mutations in the transmembrane envelope protein abrogate the immunosuppressive property of HIV-1

Retrovirology

Joachim Denner²  Marwan Semaan²  Alexey V Morozov¹  Vladimir A Morozov² 

[1] Present address: W.A. Engelhardt Institute of Molecular Biology, Vavilova 32, 119991, Moscow, Russia;Robert Koch Institute, Nordufer 20, D-13353, Berlin, Germany

关键词: Cytokine release;    Immunosuppression;    gp41;    Transmembrane envelope protein;    Pathogenesis;    HIV;   

Others  :  1209275
DOI  :  10.1186/1742-4690-9-67

 received in 2012-05-29, accepted in 2012-07-23,  发布年份 2012

【 摘 要 】

Background

The mechanism by which HIV-1 induces AIDS is still unknown. Previously, synthetic peptides corresponding to the conserved immunosuppressive (isu) domain in gp41 of HIV-1 had been shown to inhibit proliferation and to modulate cytokine expression of immune cells. The question is, whether the viral gp41 can do the same.

Results

We show for the first time that two trimeric forms of glycosylated gp41 released from transfected human cells modulated expression of cytokines and other genes in human PBMCs in the same manner, but at least seven hundred-fold stronger compared to that induced by the isu peptide. Single amino acid substitutions in the isu domain of gp41 introduced by site-directed mutagenesis abrogated this property. Furthermore, replication-competent HIV-1 with a mutation in the isu domain of gp41 did not modulate the cytokine expression, while wild-type virus did. Interestingly, most of the abrogating mutations were not reported in viral sequences derived from infected individuals, suggesting that mutated non-immunosuppressive viruses were eliminated by immune responses. Finally, immunisation of rats with gp41 mutated in the isu domain resulted in increased antibody responses compared with the non-mutated gp41. These results show that non-mutated gp41 is immunosuppressive in immunisation experiments, i.e. in vivo, and this has implications for the vaccine development.

Conclusions

These findings indicate that the isu domain of gp41 modulates cytokine expression in vitro and suppresses antibody response in vivo and therefore may contribute to the virus induced immunodeficiency.

【 授权许可】

   
2012 Morozov et al.; licensee BioMed Central Ltd.

【 图 表 】

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